TREM2 agonists

Abstract

The invention provides compounds having the general formula (I) wherein A, A1, A2, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8a, R8b, and R9 are as described herein, compositions including the compounds, processes of manufacturing the5 compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with TREM2.

Description

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

[0002] Case: P39695

[0003] TREM2 AGONISTS

[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 Triggering Receptor Expressed on Myeloid cells 2 (TREM2) agonists for the treatment or prevention of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

[0006] Background of the Invention

[0007] Microglia are immune cells resident in the central nervous system (CNS) which play a crucial role in the CNS development and maintenance of brain homeostasis through synaptic pruning and removal of apoptotic neurons (Paolicelli R. C. et al., Science 2011, 9;333(6048): 1456-8 doi: 10.1126 / science.1202529). Microglia are also key players in response to neurodegenerative conditions and neuropathological lesions, whereby they shift into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to the lesion sites and phagocytosis of dead cells and debris. (Lue L. F. et al., Mol. Neurobiol. 2010, 41(2-3): 115-28, doi:

[0008] 10.1007 / S12035-010-8106-8).

[0009] Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions.

[0010] TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is one of these cell surface receptors, which in brain is selectively expressed on microglia and plays a key role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https: / / doi.org / 10.1038 / nri1106). TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a

[0011] CNE / 06.10.2025 single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs. Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25): 15866-77). Given its short extracellular domain, DAP12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Aβ oligomers. Stimulation of the TREM2 / DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP12, which results in recruitment of Syk kinase to activate downstream signaling molecules.

[0012] Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C. et al., Nat Commun 6, 6176, 2015, doi: org / 10.1038 / ncomms7176; Poliani et al., J Clin Invest, 2015 May;125(5):2161-70, doi: 10.1172 / JCI77983; Zhao et al., Neuron, 2018 Mar 7;97(5):1023-1031. e7, doi: 10.1016 / j.neuron.2018.01.031; Keren-Shaul H. et al., Cell, 2017 Jun 15;169(7):1276-1290.el7. doi: 10.1016 / j.cell.2017.05.018).

[0013] Genetic variants of TREM2 have been implicated in a multitude of neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi: org / 10.1186 / sl3024-022-00588-y). TREM2 variants resulting in lack of TREM2 expression were identified as the cause of the Nasu-Hakola Disease (NHD), or Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy (PLOSL), a fatal condition manifesting with progressive pre-senile dementia and characterized by loss of myelin and bone abnormalities, consistent with TREM2 expression in myeloid cells microglia and osteoclasts (Paloneva, J. et al., Am J Hum Genet. 2002,71(3):656-62, doi: 10.1086 / 342259). Similarly, missense mutations of TREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several of these TREM2 variants have been implicated with impaired microglia function and their reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86). Moreover, genomic-wide association studies (GWAS) showed a strong link between a number of rare loss of function (LoF) variants of TREM2 and an increased risk of late onset Alzheimer’s disease (LOAD) (Guerreiro R. et al., N Engl J Med. 2013, 368(2): 117-27; Jonsson T. et al., N Engl J Med. 2013, 368(2): 107-16). Amongst those, the R47H variant, a LoF mutation associated with structural alterations within the extracellular domain of TREM2 resulting in impaired ability to bind endogenous ligands, was linked to a ca. 3 fold increased risk of LOAD (Sudom, A. et al., J Biol Chem. 2018 10;293(32): 12634-12646; doi: 10.1074 / jbc.RA118.002352). Studies are ongoing to elucidate the mechanism by which TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks.

[0014] In light of all this evidence, pharmacological activation of TREM2 appears to be a viable therapeutic intervention. The small molecules disclosed herein are potent and selective agonists of TREM2.

[0015] Summary of the Invention

[0016] In a first aspect, the present invention provides compounds of formula (I)

[0017]

[0018] wherein A, A1, A2, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8a, R8b, and R9are as defined herein. In further aspects, the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).

[0019] Detailed Description of the Invention

[0020] Definitions

[0021] 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.

[0022] The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, yet non-limiting example of alkyl is methyl.

[0023] The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C1-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non-limiting example of alkoxy is methoxy. The term “alkoxyalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, preferably methoxy. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, most preferably methoxy. A particularly preferred, yet non-limiting example of alkoxyalkyl is 2-m ethoxy ethyl.

[0024] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0025] Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).

[0026] The term “cyano” refers to a group -CN, i.e. a nitrile group.

[0027] The term “amino” refers to a group –NH2.

[0028] The term “hydroxy” refers to a group -OH.

[0029] The term “oxo” refers to a =0 moiety.

[0030] The term “cycloalkyl” refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-10-cycloalkyl”). In some 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. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl and bicyclofl.1. l]pentanyl.

[0031] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C6-C10-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g. 9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl. The term "heteroaryl" refers to a monocyclic aromatic ring system having a total of 5 to 6 ring members and containing one or more heteroatoms. Preferably, the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, the heteroaryl comprises 1 to 3 heteroatoms independently selected from O, S and N. Most preferably, the heteroaryl comprises 1 to 2 heteroatoms independently selected from O, S and N. Some preferred, yet non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; l,2,4-oxadiazol-5-yl; pyridyl (e.g. 2-pyridyl); pyrazolyl (e.g. pyrazol-l-yl); triazolyl; tetrazolyl; pyrazinyl; and imidazolyl (e.g. imidazole-1-yl). A preferred, yet non-limiting example of heteroaryl includes pyrazolyl.

[0032] The term “heterocyclyl” refers to a saturated or partly unsaturated monocyclic ring system of 3 to 6 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. Some non-limiting examples of heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridinyl, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, and thietanyl. Preferred, yet non-limiting examples of heterocyclyl groups include 1,2-dihydropyridinyl and oxetanyl.

[0033] 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. Ppreferred, yet nonlimiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1 -difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. A particularly, yet non-limiting example of haloalkyl is trifluoromethyl (CF3).

[0034] The term “haloalkoxy” refers to an alkoxy group as defined herein, 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.

[0035] Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 1,1 -difluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0036] The term “halocycloalkyl” refers to a cycloalkyl group as defined herein, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “halocycloalkyl” refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of halocycloalkyl are 2,2-difluorocyclopropyl, 2-fluorocyclopropyl, 1 -fluorocyclopropyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl, 4,4-difluorocyclohexyl, and 1 -fluorocyclohexyl.

[0037] The term “haloheterocyclyl” refers to a heterocyclyl group as defined herein, wherein at least one of the hydrogen atoms of the heterocyclyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloheterocyclyl” refers to a heterocyclyl group wherein 1, 2 or 3 hydrogen atoms of the heterocyclyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloheterocyclyl are 3-chlorotetrahydrofuran, 3 -fluorotetrahydrofuran, 3 -chlorothiomorpholine, and 3-fluorothiomorpholine.

[0038] The term “cycloalkylalkyl” 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 cycloalkyl group, preferably cyclopropyl. Preferably, “cycloalkylalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred, yet non-limiting example of cycloalkylalkyl is cyclopropylmethyl.

[0039] The term “cycloalkylalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, preferably cyclopropyl. Preferably, “cycloalkylalkoxy” refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred, yet non-limiting example of cycloalkylalkoxy is cyclopropylmethoxy.

[0040] The term “heterocyclylalkyl” 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 heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred, yet non-limiting example of heterocyclylalkyl is oxetanylmethyl. The term “heterocyclylalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkoxy” refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred, yet non-limiting example of heterocyclylalkoxy is oxetanylmethoxy.

[0041] The term “heterocyclyloxy” refers to a heterocyclyl group as defined herein, wherein the heterocyclyl group is bound to the parent molecule trough an oxygen atom. A particularly preferred, yet non-limiting example of heterocyclyloxy is oxetanyloxy.

[0042] 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.

[0043] 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.

[0044] The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2. The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0045] 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.

[0046] The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0047] Compounds of the Invention

[0048] In a first aspect, the present invention provides a compound of formula (I)

[0049]

[0050] or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0051] X1and X2are each independently selected from the group consisting of N and CH; A is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl and C3-C10-cycloalkyl;

[0052] A1is selected from the group consisting of N and CR10;

[0053] A2is selected from the group consisting of O and CR11R12;

[0054] R1, R2and R3are each independently selected from the group consisting of halogen, C1-C6-alkyl and halo-C1-C6-alkyl; R4is selected from the group consisting of hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-cycloalkyl-C1-C6-alkyl;

[0055] R5is selected from the group consisting of hydrogen and C1-C6-alkyl;

[0056] R6and R7are each independently selected from the group consisting of hydrogen, Ci- Ce-alkyl, and halo- C1-C6-alkyl; or

[0057] R6and R7, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl;

[0058] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C3-C10-cycloalkyl-Ci-Ce- alkoxy, C3-C10-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6- membered heterocyclyl, 3- to 6-membered heterocyclyl-C1-C6-alkyl, 3- to 6- membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-Ci-Ce- alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-Cs-Cio- cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3- Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy;

[0059] R8bis selected from the group consisting of hydrogen and C1-C6-alkyl;

[0060] R9is selected from the group consisting of hydrogen and C1-C6-alkyl;

[0061] R10is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce- alkyl; and

[0062] R11and R12are each independently selected from the group consisting of hydrogen and halogen.

[0063] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1and X2are each independently selected from the group consisting of N and CH; A is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl and C3-C10-cycloalkyl;

[0064] A1is selected from the group consisting of N and CR10;

[0065] A2is selected from the group consisting of O and CR11R12;

[0066] R1, R2and R3are each independently selected from the group consisting of halogen, C1-C6-alkyl and halo-C1-C6-alkyl;

[0067] R4is selected from the group consisting of hydrogen, C1-C6-alkyl, and C3-C10- cycloalkyl;

[0068] R5is selected from the group consisting of hydrogen and C1-C6-alkyl;

[0069] R6and R7are each independently selected from the group consisting of hydrogen, Ci- Ce-alkyl, and halo- C1-C6-alkyl; or

[0070] R6and R7, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl;

[0071] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C3-C10-cycloalkyl-Ci-Ce- alkoxy, C3-C10-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6- membered heterocyclyl, 3- to 6-membered heterocyclyl-C1-C6-alkyl, 3- to 6- membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-Ci-Ce- alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-Cs-Cio- cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3- Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy;

[0072] R8bis selected from the group consisting of hydrogen and C1-C6-alkyl;

[0073] R9is selected from the group consisting of hydrogen and C1-C6-alkyl; R10is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce- alkyl; and

[0074] R11and R12are each independently selected from the group consisting of hydrogen and halogen.

[0075] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0076] (i) X1is CH and X2is N; or

[0077] (ii) X1and X2are both N.

[0078] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1is CH and X2is N.

[0079] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1and X2are both N.

[0080] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (If) or (Ig):

[0081]

[0082] wherein A, A2, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, and R9are as defined herein.

[0083] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (Ih) or (li):

[0084]

[0085] wherein A, A2, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, and R9are as defined herein.

[0086] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (Ij) or (Ik):

[0087]

[0088] wherein A, A2, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, and R9are as defined herein.

[0089] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (II) or (Im):

[0090]

[0091] wherein A, A2, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, and R9are as defined herein.

[0092] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0093] A1is selected from the group consisting of N and CR10;

[0094] A2is O; and

[0095] R10is hydrogen.

[0096] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0097] A1is CR10;

[0098] A2is O; and

[0099] R10is hydrogen.

[0100] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0101] A1is N; and

[0102] A2is O.

[0103] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0104] A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl; R1is selected from the group consisting of halogen and halo-C1-C6-alkyl;

[0105] R2is selected from the group consisting of hydrogen and halogen; and

[0106] R3is selected from the group consisting of hydrogen and halogen.

[0107] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0108] A is selected from the group consisting of phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo[1.1.1]pentane;

[0109] R1is selected from the group consisting of fluoro, chloro, CHF2, and CF3;

[0110] R2is selected from the group consisting of hydrogen and fluoro; and

[0111] R3is selected from the group consisting of hydrogen and fluoro. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0112] A is selected from the group consisting of phenyl and bicyclo[1.1.1]pentane; R1is selected from the group consisting of fluoro, chloro and CF3;

[0113] R2is selected from the group consisting of hydrogen and fluoro; and

[0114] R3is selected from the group consisting of hydrogen and fluoro.

[0115] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the group

[0116]

[0117]

[0118] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the group

[0119]

[0120] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: A is C6-C10-aryl;

[0121] R1is halogen;

[0122] R2is selected from the group consisting of hydrogen and halogen; and

[0123] R3is hydrogen.

[0124] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0125] A is phenyl;

[0126] R1is selected from the group consisting of fluoro and chloro;

[0127] R2is selected from the group consisting of hydrogen and fluoro; and

[0128] R3is hydrogen.

[0129] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl.

[0130] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of methyl and cyclopropyl.

[0131] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is C1-C6-alkyl.

[0132] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is methyl.

[0133] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R5is selected from the group consisting of hydrogen and methyl.

[0134] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R5is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0135] R6is selected from the group consisting of hydrogen and halo- C1-C6-alkyl; and R7is hydrogen; or

[0136] R6and R7, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl.

[0137] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0138] R6is selected from the group consisting of hydrogen and CF3; and

[0139] R7is hydrogen; or

[0140] R6and R7, taken together with the carbon atom to which they are attached, form a cyclopropyl.

[0141] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R6and R7are both hydrogen.

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

[0143] R4is selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; R5is selected from the group consisting of hydrogen and C1-C6-alkyl;

[0144] R6is selected from the group consisting of hydrogen and halo- C1-C6-alkyl; and R7is hydrogen; or

[0145] R6and R7, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl.

[0146] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0147] R4is selected from the group consisting of methyl and cyclopropyl;

[0148] R5is selected from the group consisting of hydrogen and methyl;

[0149] R6is selected from the group consisting of hydrogen and CF3; and

[0150] R7is hydrogen; or

[0151] R6and R7, taken together with the carbon atom to which they are attached, form a cyclopropyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0152] R4is Ci-Ce-alkyl;

[0153] R5is hydrogen;

[0154] R6is hydrogen; and

[0155] R7is hydrogen.

[0156] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0157] R4is methyl;

[0158] R5is hydrogen;

[0159] R6is hydrogen; and

[0160] R7is hydrogen.

[0161] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0162] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl, Ci-Ce- alkoxy, and C3-C10-cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl; and

[0163] R8bis hydrogen.

[0164] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0165] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl; and

[0166] R8bis hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0167] R8ais selected from the group consisting of 1H-pyrazolyl, pyrazinyl, 1H-pyridazin-6- one, 1H-pyrazin-2-one, and 1H-pyridin-2-one, wherein said 1H-pyrazolyl, pyrazinyl, 1H-pyridazin-6-one, 1H-pyrazin-2-one, and 1H-pyridin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and

[0168] R8bis hydrogen.

[0169] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0170] R8ais selected from the group consisting of 1H-pyrazolyl and 1H-pyridin-2-one, wherein said 1H-pyrazolyl and 1H-pyridin-2-one are substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl; and R8bis hydrogen.

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

[0172] R8ais selected from the group consisting of:

[0173]

[0174]

[0175] R8bis hydrogen.

[0176] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0177]

[0178]

[0179] R8bis hydrogen.

[0180] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0181] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl;

[0182] R8bis hydrogen; and

[0183] R9is hydrogen.

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

[0185] R8ais selected from the group consisting of 1H-pyrazolyl and 1H-pyridin-2-one, wherein said 1H-pyrazolyl and 1H-pyridin-2-one are substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;

[0186] R8bis hydrogen; and

[0187] R9is hydrogen.

[0188] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0189] R8ais selected from the group consisting:

[0190]

[0191] R8bis hydrogen; and

[0192] R9is hydrogen.

[0193] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0194] A1is selected from the group consisting of N and CR10;

[0195] A2is O;

[0196] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl;

[0197] R8bis hydrogen;

[0198] R9is hydrogen; and

[0199] R10is hydrogen.

[0200] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0201] A1is selected from the group consisting of N and CR10; A2is O;

[0202] R8ais selected from the group consisting of 1H-pyrazolyl and 1H-pyridin-2-one, wherein said 1H-pyrazolyl and 1H-pyridin-2-one are substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;

[0203] R8bis hydrogen;

[0204] R9is hydrogen; and

[0205] R10is hydrogen.

[0206] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0207] A1is selected from the group consisting of N and CR10;

[0208] A2is O;

[0209]

[0210] R8bis hydrogen;

[0211] R9is hydrogen; and

[0212] R10is hydrogen.

[0213] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R9is selected from the group consisting hydrogen and methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R9is hydrogen.

[0214] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0215] (i) X1is CH and X2is N; or

[0216] (ii) X1and X2are both N;

[0217] A1is selected from the group consisting of N and CR10;

[0218] A2is O;

[0219] A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl; R1is selected from the group consisting of halogen and halo-C1-C6-alkyl;

[0220] R2is selected from the group consisting of hydrogen and halogen;

[0221] R3is selected from the group consisting of hydrogen and halogen;

[0222] R4is selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; R5is selected from the group consisting of hydrogen and C1-C6-alkyl;

[0223] R6is selected from the group consisting of hydrogen and halo- C1-C6-alkyl; and R7is hydrogen; or

[0224] R6and R7, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl;

[0225] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl, Ci-Ce- alkoxy, and C3-C10-cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl;

[0226] R8bis hydrogen;

[0227] R9is hydrogen; and

[0228] R10is hydrogen.

[0229] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0230] (i) X1is CH and X2is N; or

[0231] (ii) X1and X2are both N; A1is selected from the group consisting of N and CR10;

[0232] A2is O;

[0233] A is selected from the group consisting of phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo[1.1.1]pentane;

[0234] R1is selected from the group consisting of fluoro, chloro, CHF2, and CF3;

[0235] R2is selected from the group consisting of hydrogen and fluoro;

[0236] R3is selected from the group consisting of hydrogen and fluoro;

[0237] R4is selected from the group consisting of methyl and cyclopropyl;

[0238] R5is selected from the group consisting of hydrogen and methyl;

[0239] R6is selected from the group consisting of hydrogen and CF3; and

[0240] R7is hydrogen; or

[0241] R6and R7, taken together with the carbon atom to which they are attached, form a cyclopropyl;

[0242] R8ais selected from the group consisting of 1H-pyrazolyl, pyrazinyl, 1H-pyridazin-6- one, 1H-pyrazin-2-one, and 1H-pyridin-2-one, wherein said 1H-pyrazolyl, pyrazinyl, 1H-pyridazin-6-one, 1H-pyrazin-2-one, and 1H-pyridin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl;

[0243] R8bis hydrogen;

[0244] R9is hydrogen; and

[0245] R10is hydrogen.

[0246] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0247] (i) X1is CH and X2is N; or

[0248] (ii) X1and X2are both N;

[0249] A1is selected from the group consisting of N and CR10;

[0250] A2is O;

[0251] A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl;

[0252] R1is selected from the group consisting of halogen and halo-C1-C6-alkyl;

[0253] R2is selected from the group consisting of hydrogen and halogen;

[0254] R3is selected from the group consisting of hydrogen and halogen;

[0255] R4is selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; R5is selected from the group consisting of hydrogen and C1-C6-alkyl;

[0256] R6is selected from the group consisting of hydrogen and halo- C1-C6-alkyl; and R7is hydrogen; or

[0257] R6and R7, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl;

[0258] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl;

[0259] R8bis hydrogen;

[0260] R9is hydrogen; and

[0261] R10is hydrogen.

[0262] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0263] (i) X1is CH and X2is N; or

[0264] (ii) X1and X2are both N;

[0265] A1is selected from the group consisting of N and CR10;

[0266] A2is O;

[0267] A is selected from the group consisting of phenyl and bicyclo[1.1.1]pentane;

[0268] R1is selected from the group consisting of fluoro, chloro and CF3;

[0269] R2is selected from the group consisting of hydrogen and fluoro;

[0270] R3is selected from the group consisting of hydrogen and fluoro;

[0271] R4is selected from the group consisting of methyl and cyclopropyl;

[0272] R5is selected from the group consisting of hydrogen and methyl;

[0273] R6is selected from the group consisting of hydrogen and CF3; and

[0274] R7is hydrogen; or

[0275] R6and R7, taken together with the carbon atom to which they are attached, form a cyclopropyl; R8ais selected from the group consisting of IH-pyrazolyl and lH-pyridin-2-one, wherein said IH-pyrazolyl and lH-pyridin-2-one are substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;

[0276] R8bis hydrogen;

[0277] R9is hydrogen; and

[0278] R10is hydrogen.

[0279] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0280] (i) X1is CH and X2is N; or

[0281] (ii) X1and X2are both N;

[0282] A1is selected from the group consisting of N and CR10;

[0283] A2is O;

[0284] A is C6-C10-aryl;

[0285] R1is halogen;

[0286] R2is selected from the group consisting of hydrogen and halogen;

[0287] R3is hydrogen;

[0288] R4is Ci-Ce-alkyl;

[0289] R5is hydrogen;

[0290] R6is hydrogen;

[0291] R7is hydrogen;

[0292] R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl;

[0293] R8bis hydrogen;

[0294] R9is hydrogen; and

[0295] R10is hydrogen.

[0296] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or

[0297] (ii) X1and X2are both N;

[0298] A1is selected from the group consisting of N and CR10;

[0299] A2is O;

[0300] A is phenyl;

[0301] R1is selected from the group consisting of fluoro and chloro;

[0302] R2is selected from the group consisting of hydrogen and fluoro;

[0303] R3is hydrogen;

[0304] R4is methyl;

[0305] R5is hydrogen;

[0306] R6is hydrogen;

[0307] R7is hydrogen;

[0308] R8ais selected from the group consisting of 1H-pyrazolyl and 1H-pyridin-2-one, wherein said 1H-pyrazolyl and 1H-pyridin-2-one are substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;

[0309] R8bis hydrogen;

[0310] R9is hydrogen; and

[0311] R10is hydrogen.

[0312] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from:

[0313] (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0314] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0315] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0316] (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2R)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0317] rel-(laS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0318] rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0319] rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0320] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0321] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0322] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0323] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0324] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0325] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0326] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0327] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0328] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0329] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0330] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0331] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0332] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0333] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0334] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0335] rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin- 4-y 1 ] - 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one;

[0336] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin- 4-y 1 ] - 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one;

[0337] rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin- 4-y 1 ] - 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one;

[0338] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin- 4-y 1 ] - 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one;

[0339] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one;

[0340] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one;

[0341] (lRS,laSR,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2SR)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-l-(trifluoromethyl)-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0342] (laSR,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2SR)-2-(l-methylpyrazol-4- yl)morpholin-4-yl] spiro[1a,7b-dihydrocyclopropa[c][2,6]naphthyridine-1,1'-cyclopropane]-3-one; rel-(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;

[0343] rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;

[0344] rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;

[0345] rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;

[0346] rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one;

[0347] rel-(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one;

[0348] rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(2R*,4R*)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-ll-[3- (trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1 (7), 8, 10-trien-6-one; rel-(2S*,4S*)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-ll-[3- (trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1 (7), 8, 10-trien-6-one;

[0349] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel- (laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-2- oxo-4-pyridyl)tetrahydropyran-4-yl]- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one;

[0350] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-2- oxo-4-pyridyl)tetrahydropyran-4-yl]- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one;

[0351] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-2-oxo- 4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-2-oxo- 4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0352] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0353] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0354] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l -cyclopropyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0355] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l -cyclopropyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0356] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0357] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0358] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0359] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0360] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0361] rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2- fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2- fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l -cyclopropyl- 2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropyl- 2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0362] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropyl- 2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0363] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropyl- 2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0364] rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (4,4-difluorocyclohexyl)-2-methyl- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one;

[0365] rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (4,4-difluorocyclohexyl)-2-methyl- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one;

[0366] rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (4,4-difluorocyclohexyl)-2-methyl- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one;

[0367] rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (4,4-difluorocyclohexyl)-2-methyl- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one;

[0368] rel-(2R*,4R*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(2,4- difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2S*,4S*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(2,4- difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2R*,4R*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(2,4- difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2S*,4S*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(2,4- difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2R*,4R*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(4,4- difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one; rel-(2S*,4S*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(4,4- difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one;

[0369] rel-(2R*,4R*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(4,4- difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one;

[0370] rel-(2S*,4S*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-ll-(4,4- difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one;

[0371] rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-1(11),7,9-trien-6-one; rel-(2R*,4R*)-11-(4-chloro-2-fluoro-phenyl)-9-[rel-(2S*,4R*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-1(11),7,9-trien-6-one; rel-(2S*,4S*)-11-(4-chloro-2-fluoro-phenyl)-9-[rel-(2R*,4S*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-1(11),7,9-trien-6-one; rel-(2S*,4S*)-11-(4-chloro-2-fluoro-phenyl)-9-[rel-(2S*,4R*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca-1(11),7,9-trien-6-one;

[0372] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-7- (2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-7- (2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]- 7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]- 7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0373] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0374] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0375] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0376] rel-(laR*,7bR*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; 7-(4-chloro-2-fluoro-phenyl)-5-[2-(5-methoxypyrazin-2-yl)tetrahydropyran-4-yl]-2-methyl- la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0377] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-5-[rel-(2S*,4R*)-2-(5-keto-4-methyl-pyrazin- 2-yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0378] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-5-[rel-(2R*,4S*)-2-(5-keto-4-methyl-pyrazin- 2-yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0379] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo- pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0380] rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0381] rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0382] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxopyridazin-4-yl)oxan-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxopyridazin-4-yl)oxan-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0383] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6-oxo- pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0384] rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4- fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4- fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4- fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4- fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one; rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0385] rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0386] rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0387] rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one; rel-(1aR*,7bR*)-5-[rel-(2S*,4R*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one; rel-(1aS*,7bS*)-5-[rel-(2R*,4S*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one; rel-(1aS*,7bS*)-5-[rel-(2S*,4R*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;

[0388] rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0389] rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0390] rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0391] rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7- (2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-5-[rel-(2R*,4S*)-2-(5-methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0392] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-5-[rel-(2S*,4R*)-2-(5-methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0393] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-5-[rel-(2R*,4S*)-2-(5-methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0394] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-5-[rel-(2S*,4R*)-2-(5-methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0395] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(4-methyl-5-oxo- pyrazin-2-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0396] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(4-methyl-5-oxo- pyrazin-2-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0397] rel-(laS*,7bS*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0398] rel-(laS*,7bS*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0399] rel-(laR*,7bR*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0400] rel-(laR*,7bR*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0401] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0402] rel-(laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0403] rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0404] (laR*,7bR*)-7-[2-fluoro-4-(trifluoromethyl)phenyl]-5-[rel-(2R*,4S*)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0405] (laR*,7bR*)-7-[2-fluoro-4-(trifluoromethyl)phenyl]-5-[rel-(2S*,4R*)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0406] (laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-keto-pyridazin-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0407] (laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-keto-pyridazin-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0408] (laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0409] (laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2R*,4S*)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0410] (laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2R*,4S*)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0411] ( 1 aR*, 7bR*)-7-(4-chlorophenyl)-5 - [rel - (2 S *,4R*)-2-(6-keto- 1 -methyl-3 - pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*,4S*,6S)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0412] rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*,4R*,6R)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0413] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*,4S*,6S)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0414] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*,4R*,6R)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0415] rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*,4S*,6R)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0416] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*,4R*,6S)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0417] rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*,4R*,6S)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0418] rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*,4S*,6R)-2-(l-cyclopropylpyrazol-4- yl)-6-methyl-tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0419] (laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-keto-pyridazin-4-yl)tetrahydropyran-4- yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0420] (laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-keto-pyridazin-4-yl)tetrahydropyran-4- yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0421] (laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-keto-pyridazin-3-yl)tetrahydropyran-4- yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one; (laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-keto-pyridazin-3-yl)tetrahydropyran-4- yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0422] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l,5-dimethyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0423] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l,5-dimethyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0424] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l,5-dimethyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0425] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l,5-dimethyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;

[0426] ( 1 aR*, 7bR*)-7-(2,4-difluorophenyl)-5 - [rel-(2R*,4 S *)-2-(2-keto- 1 -methyl-4- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0427] (laR*,7bR*)-7-(2,4-difluorophenyl)-5-[rel-(2S*,4R*)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0428] rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0429] rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0430] rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0431] rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one; rel-(1aR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;

[0432] rel-(1aR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;

[0433] rel-(1aS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;

[0434] rel-(1aS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;

[0435] rel-(laR*,7bR*)-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-5-[rel-(2R*,4S*)- 2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0436] rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(4-methyl-5-oxo- pyrazin-2-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3- one;

[0437] rel-(laS*,7bS*)-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-5-[rel-(2R*,4S*)- 2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0438] rel-(laS*,7bS*)-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-5-[rel-(2S*,4R*)- 2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0439] rel-(laR*,7bR*)-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-5-[rac-rel- (2R*,4S*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0440] rel-(laR*,7bR*)-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-5-[rac-rel- (2S*,4R*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0441] (laR*,7bR*)-5-[rel-(2R*,4S*)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-2- methyl-7-[4-(trifluoromethyl)phenyl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one; (laR*,7bR*)-5-[rel-(2S*,4R*)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-2- methyl-7-[4-(trifluoromethyl)phenyl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one; and

[0442] (laR*,7bR*)-7-[4-(difluoromethyl)-2-fluoro-phenyl]-5-[rel-(2S*,4R*)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cy clopropafc] [2, 6]naphthyri din-3 -one and ( 1 aR*, 7bR*)-7- [4-(difluoromethyl)-2-fluoro- phenyl]-5-[rel-(2R*,4S*)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl- la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one.

[0443] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from:

[0444] rel-(laS*,7bS*)-7-(4-chloro-2-fhroro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;

[0445] rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one;

[0446] rel-(2S*,4S*)-l l-(4-chloro-2-fhroro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;

[0447] rel-(2S*,4S*)-l l-(4-chloro-2-fhroro-phenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one; rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(laS*,7bS*)-7-(4-chloro-2-fhroro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; and

[0448] rel-(laS*,7bS*)-7-(4-chloro-2-fhroro-phenyl)-2-cyclopropyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one.

[0449] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(laS*,7bS*)-7-(4-chloro-2-fluoro- phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one.

[0450] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one.

[0451] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one.

[0452] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one.

[0453] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one.

[0454] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one.

[0455] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one.

[0456] 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 or acids.

[0457] 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.

[0458] 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. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention.

[0459] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Processes of Manufacturing

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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).

[0464] A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0465] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0466] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0467] 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.

[0468] The following abbreviations are used in the present text:

[0469] 4-DPAIPN l,3-Dicyano-2,4,5,6-tetrakis(N, N-diphenylamino)-benzene (CAS: 1846598-27-3)

[0470] °C degrees Celsius

[0471] aq. aqueous

[0472] CAS Chemical Abstracts Service registry number DCE 1,2-di chloroethane

[0473] DCM dichloromethane

[0474] dba dib enzy li deneacetone

[0475] DEA diethylamine

[0476] DIPEA N, N-diisopropylethylamine

[0477] DMF dimethylformamide

[0478] DMSO-d6 hexadeuterodimethylsulfoxide

[0479] ECso half maximal effective concentration

[0480] eq equivalent

[0481] ESI electron spray ionization

[0482] Et ethyl

[0483] Ex. Example

[0484] HATU hexafluorophosphate Azabenzotri azole Tetramethyl Uronium HBTU hexafluorophosphate benzotriazole tetramethyl uronium HPLC high performance liquid chromatography

[0485] coupling constant

[0486] m / z mass-to-charge ratio

[0487] mg milligram

[0488] min minute

[0489] ml milliliter

[0490] mm millimeter

[0491] mmol millimole

[0492] MS mass spectrometry

[0493] NBS N-bromosuccinimide

[0494] neg. negative

[0495] NMR nuclear magnetic resonance spectroscopy

[0496] PE petroleum ether

[0497] pH potential of hydrogen

[0498] pos. positive

[0499] POY3 phosphorus oxitrihalide

[0500] psi pounds per square inch

[0501] R Rectus according to the Cahn-Ingold-Prelog priority rules rt room temperature

[0502] RP reverse phase

[0503] RPM revolutions per minute

[0504] R, R-TADDOL phosphoramidite (3aS,8aS)-4,4,8,8-tetrakis(3,5-dimethylphenyl)tetrahydro- N, N,2,2-tetramethyl-l,3-dioxolo[4,5-e][l,3,2]dioxaphosphepin-6-amine (CAS:

[0505] 840454-58-2)

[0506] S, S-TADDOL phosphoramidite (3aS,8aS)-4,4,8,8-tetrakis(3,5-dimethylphenyl)tetrahydro- N, N,2,2-tetramethyl-l,3-dioxolo[4,5-e][l,3,2]dioxaphosphepin-6-amine (CAS:

[0507] 840504-21-4)

[0508] s second

[0509] S Sinister according to the Cahn-Ingold-Prelog priority rules sat. saturated

[0510] SFC supercritical fluid chromatography

[0511] T3P propanephosphonic acid anhydride

[0512] TBME tert-butyl methyl ether

[0513] TBTU 2-(lH-benzotri azole- 1 -yl)- 1, 1,3,3-tetramethylaminium tetrafluoroborate

[0514] THF tetrahydrofuran

[0515] TLC thin layer chromatography

[0516] pl microliter

[0517] pm micrometer

[0518] pmol micromoles

[0519] XantPhos-Pd-G3 [(4,5 -Bi s(diphenylphosphino)-9, 9-dimethylxanthene)-2-(2 '-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate

[0520] XPhos-Pd-G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'- amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate

[0521] aD specific rotation at 589 nm

[0522] 5 chemical shift in parts per million

[0523] Scheme 1

[0524]

[0525] The present compounds of formula la can be prepared as described in Scheme 1 by reacting intermediate 1 with amine 2 in presence of a base like N, N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form 3 (nucleophilic substitution). In addition, compound 3 can be reacted with amine 2 using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), a suitable ligand such as XantPhos and a base such as cesium carbonate or sodium tert.-butoxide) to form compound 3 (metal-catalysed coupling). Reacting intermediate 3 with a boronic acid (or a boronic acid derivative) 4 under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) leads to the formation of compound 5. Halogenation of this compound with N-bromosuccinimide or N-iodosuccinimide (NY³S, 6) in a suitable solvent leads to formation of 7 which can be converted to the free acid 8 under hydrolysis conditions with a base such as LiOH, NaOH or KOH in water and optionally a suitable organic co-solvent such as THF or dioxane. Intermediate 10 can be obtained by coupling with amine 9 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU or the like. A cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid allows to transform intermediate 10 into compounds of formula la.

[0526] Scheme 2

[0527]

[0528] The present compounds of formula lb can be prepared as described in Scheme 2 by reacting intermediate 11 first with a boronic acid (or a boronic acid derivative) 4 under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound 12. This intermediate can be reacted with a nitrite source such as NaNO₂, tBuONO, or isoamyl nitrite followed by a copper(II) halide 13 to obtain compounds of formula 14. Ester hydrolysis under the action of a base such as LiOH, NaOH or KOH in water and optionally a suitable organic co-solvent such as THF or dioxane followed by coupling with amine 9 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU or the like leads to formation of 16. Cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid leads to the formation of compounds of formula 17. The organozinc compounds 18 can be obtained from the corresponding halogen derivatives by reaction with zinc under anhydrous conditions. This organometallic reagent can then be reacted with intermediate 17 using palladium-catalysed conditions to produce compounds of formula lb. Alternatively, compound 17 can be reacted first with boronic acid derivative 19 using a palladium catalyst and a base to form intermediate 20, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound lb. Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine.

[0529] Scheme 3

[0530]

[0531] The present compounds of formula la can be prepared as described in Scheme 3 by reacting intermediate 21 first with a boronic acid (or a boronic acid derivative) 4 under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compounds of formula 22. Halogenation of this compound with N-bromosuccinimide or N-iodosuccinimide 6 in a suitable solvent leads to formation of 23 which can be converted to the free acid 24 under hydrolysis conditions with a base such as LiOH, NaOH or KOH in water and optionally a suitable organic co-solvent such as THF or dioxane. Intermediate 25 can be obtained by coupling with amine 9 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU or the like followed by cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid. Finally, by reacting intermediate 26 with amine 2 in presence of a base like N, N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone (nucleophilic substitution) or, alternatively, reacting compound 26 with amine 2 using palladium-catalysed coupling conditions with a palladium source such as tris(dibenzylideneacetone) dipalladium(O), a suitable ligand such as XantPhos and a base such as cesium carbonate or sodium tert.-butoxide (metal-catalysed coupling) produces compounds of formula la.

[0532] Scheme 4

[0533]

[0534] The present compounds of formula Ic can be prepared as described in Scheme 4 by reacting intermediate 27 with a dialkyloxalate such as dimethyloxalate 28 in the presence of a base such as NaH, LiHMDS or LDA in an appropriate solvent such as DMF, THF or dioxane.

[0535] Hydrolysis of intermediate 29 using a base such as LiOH, NaOH or KOH in water and optionally a suitable organic co-solvent such as methanol, THF or dioxane followed by cyclization with urea (31) in an appropriate solvent without or without an additional acid produces intermediate 32. Intermediate 33 can be obtained by coupling with amine 4 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU or the like and halogenation can be achieved by using N-halosuccinimide 6 in a suitable solvent producing intermediate 34. Reaction of this compound with an inorganic halogenation reagent such as phosphorous oxychloride or phosphorous oxybromide 35 with or without an additional base gives intermediate 36. Intermediate 37 can be obtained by reacting compound 36 with amine 2 in presence of a base like N, N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form 37 (nucleophilic substitution). In addition, compound 36 can be reacted with amine 2 using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), a suitable ligand such as XantPhos and a base such as cesium carbonate or sodium tert.-butoxide) to form compound 37 (metal-catalysed coupling). Finally, a cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid allows to transform intermediate 37 into compounds of formula Ic.

[0536] Scheme 5

[0537]

[0538] The present compounds of formula la can be prepared as described in Scheme 5 by coupling intermediate 38 with amine 4 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU or the like producing intermediate 39. A cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid allows to transform intermediate 39 into compounds of formula 40. Compounds of formula 41 can be obtained by oxidation of intermediate 40 using an appropriate oxidation agent such as organic peracids (3-chloroperoxybenzoic acid), hydrogen peroxide, organic peroxides, hypohalites or metallic oxidants (sodium tungstate) in an appropriate solvent. Reacting intermediate 41 with a carboxylic acid 42 in the presence of an oxidant such as a persulfate in an appropriate solvent leads to compounds of formula 43. Finally, by reacting intermediate 43 with amine 2 in presence of a base like N, N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form compounds of formula la (nucleophilic substitution).

[0539] Scheme 6

[0540]

[0541] The present compounds of formula Ic can be prepared as described in Scheme 6 starting from a cyclic ketone of formula 27 and reacting with a dialkyloxalate such as diethyloxalate 44 in the presence of a base such as NaH, LiHMDS or LDA in an appropriate solvent such as DMF, THF or dioxane. Cyclization of intermediate 45 with urea (31) in an appropriate solvent without or without an additional acid produces intermediate 46. Halogenation is achieved by using N-halosuccinimide 6 in a suitable solvent producing intermediate 47 which is then transformed into the di-halogenated derivative 48 which is achieved with a phosphoryl halide 35 (POYE, wherein Y1is halogen), such as phosphoryl chloride or phosphoryl bromide. The ester group of 48 is then saponified, for instance under basic conditions. When using a alcoholate base (such as sodium methanolate) alkoxy pyrimidine carboxylic acid 49 is obtained. Intermediate 50 can be obtained by coupling with amine 9 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU or the like. A cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid allows to transform intermediate 50 into tricyclic 51. Cleavage of the alkyl group with a Bronsted or Lewis acid provides the free hydroxy group in intermediate 52 which can be converted into a leaving group (a halide or a pseudohalide such as a chloride, a triflate or a nonaflate) using a phosphoryl halide or an activated sulfonyl reagent such as an triflic anhydride or halide. Intermediate 53 can be reacted with boronic acid derivative 19 in a Suzuki cross-coupling using a palladium catalyst and a base to form intermediate 54, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound Id. Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine.

[0542] Scheme 7

[0543]

[0544] Compounds of general formula le can be prepared as described in Scheme 7 starting from intermediate 55. Intermediate 56 is obtained by amide formation through hydrolysis under basic conditions and coupling with amine 9 using amide coupling reagents such as HATU, HBTU, EDC, T3P, TBTU, or alternatively through direct amide formation under thermal conditions. Cyclization using palladium-catalyzed conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate, a suitable ligand such as (tBu)2PMeHBF4 or PCy3, a suitable base such as Cs₂CO₃, K3PO4, and an additive such as cesium pivaloate or 1 -adamantanecarboxylic acid. This process can also be performed in an enantioselective manner by using a chiral catalyst which is formed from a a palladium source such as tris(dibenzylideneacetone) dipalladium(O), bis(dibenzylideneacetone) palladium(O) or palladium(II) acetate and a chiral ligand such as (S, S)-TADDOL or (R, R)-TADDOL-based phosphoramidites afford intermediate 57. Reaction of this compound with an inorganic halogenation reagent such as phosphorous oxychloride or phosphorous oxybromide with or without an additional base gives intermediate 58. Compound 59 can be obtained through the reaction of 58 with a boronic acid (or a boronic acid derivative) 4 under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate). Finally, 59 can be reacted with boronic acid derivative 19 in a Suzuki crosscoupling using a palladium catalyst and a base to form intermediate 60, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound of general formula le. Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine. Alternatively, intermediate 57 can be reacted with boronic acid derivative 19 in a Suzuki cross-coupling using a palladium catalyst and a base to form intermediate 61, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound 62. Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine. Intermediate 62 can then be reacted with a carboxylic acid or an activated derivative under photocatalytic conditions in the presence of a photosensitizer such as 1,3-dicyano-2,4,5,6-tetrakis(diphenylamino)benzene to form compound le.

[0545] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the process is as described in any one of schemes 1 to 5.

[0546] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, when manufactured according to any one of the processes described herein. TREM2 Agonistic Activity

[0547] Compounds of the present invention are TREM2 agonists. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for restoring the function of human TREM2 in a subject in need thereof.

[0548] In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof.

[0549] 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 restoring the function of human TREM2 in a subject in need thereof.

[0550] In a further aspect, the present invention provides a method for restoring the function of human TREM2 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.

[0551] TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit.

[0552] To perform the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 μL of DMEM media without Phenolred and supplemented with 5% FBS.

[0553] Compounds in dose response (1:3) were diluted in DMSO (highest concentration 10mM) and added to the cells from a Low Dead Volume plate using the ECHO (0-20 uM), diluting 500x (20 nL in 10 pl cell suspension; highest concentration 20uM, DMSO concentration 0.2% in all wells). Neutral (DMSO) and stimulator (1μM tool compound) controls were also added.

[0554] Cells were incubated for 30 minutes at 37°C, 5% CO2and 95% humidity. After compound addition and incubation, 2.5μL of lysis buffer was added by using the Certus. After a quick spin, plates were shaken for 30 minutes at 450 RPM, at room temperature and in the dark. After complete lysis, AlphaLisa reagents were added by Certus to the lysate, and fluorescence intensity was measured using a Pherastar plate reader (Excitation:

[0555] 680nm / Emission: 615nm). EC50values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound.

[0556] TREM2 agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in Table 1.

[0557] Table 1

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566] Using the Compounds of the Invention

[0567] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as described herein for use as a therapeutically active substance.

[0568] In a further aspect, the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 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 stereoisomer thereof, or a pharmaceutical composition described herein.

[0569] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0570] 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 a loss of function of human TREM2 in a subject in need thereof.

[0571] In one embodiment, said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

[0572] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease.

[0573] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.

[0574] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.

[0575] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.

[0576] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease.

[0577] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia.

[0578] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis.

[0579] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.

[0580] Pharmaceutical Compositions and Administration

[0581] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0582] In one embodiment, there is provided a pharmaceutical composition according to Example 192 or 193.

[0583] 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).

[0584] 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.

[0585] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0586] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0587] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0588] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0589] 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.

[0590] 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.

[0591] Examples

[0592] 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.

[0593] 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.

[0594] 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 present patent application, an asterisk * next to "R" or "S" means that the absolute stereochemistry was assigned arbitrarily.

[0595] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0596] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0597] The following intermediates were prepared according to the procedures provided herein, are commercially available or can be prepared according to literature procedures.

[0598]

[0599]

[0600] Chiral Separation of Intermediate Al:

[0601] 2-(l-Methylpyrazol-4-yl)morpholine (Intermediate Al) was separated by chiral SFC (column AD-H, 5 um, 100 x 4.6 mm, 20-40% MeOH + 0,2% diethylamine) to yield (+)- 2-(l-methylpyrazol-4-yl)morpholine (+)-Al as the first eluting enantiomer and (-)- 2-(l-methylpyrazol-4-yl)morpholine (-)- as the second eluting enantiomer. (+)- 2-(l-methylpyrazol-4-yl)morpholine: yellow oil, aD(589nm) 20 °C = +13.36° (c = 0.1 g / 1, MeOH).

[0602] Intermediate A2: 4-(4-bromotetrahydropyran-2-yl)- 1 -methyl-pyrazole

[0603]

[0604] To a solution of l-methylpyrazole-4-carbaldehyde (2 g, 18.2 mmol) in DCM (25 ml) was added 3-buten-l-ol (1.38 g, 1.64 ml, 19.1 mmol) under argon. HBr (33% solution in acetic acid, 13.4 g, 9.9 mL, 54.5 mmol) was added at rt in one portion and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was carefully quenched with saturated NaHCO3solution and washed with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 0 - 50% EtOAc / EtOH (3:1) in heptane) to afford 4-(4-bromotetrahydropyran-2-yl)-l -methyl-pyrazole (2.87 g, 62% yield) as light yellow oil. LC-MS: m / z = 245.1 [M+H]+, ESI pos.

[0605] Intermediate A3: bromo-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc

[0606]

[0607] A dry flask was charged with Li (146 mg, 21.1 mmol, 6.3 eq) and naphthalene (257 mg, 2.01 mmol, 0.6 eq). The flask was evacuated and back-filled with N2 (3 times). ZnCl₂ (1.9 M solution in 2-MeTHF, 5.3 mL, 10.04 mmol, 3.0 eq) was added and reaction mixture was sonicated for 20 min. After stirring overnight, Li was fully consumed and the precipitation of black Rieke Zn was observed. A dry flask was charged with 4-(4-bromotetrahydropyran-2-yl)-1-methyl-pyrazole (Intermediate A2, 0.82 g, 3.35 mmol, 1.0 eq), evacuated and back-filled with N2 (3 times). THF (2.5 mL) was added and the solution was degassed by bubbling argon through for 5-10 min. This solution was then added to the earlier prepared Rieke Zn suspension and the reaction mixture was stirred first at rt for 3 h and then at 50 °C for 1.5 h. The reaction mixture was cooled to rt, and the supernatant was used as such in the next step (bromo-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc as a ca. 0.36 M solution in THF).

[0608]

[0609] Intermediate A5: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridine

[0610]

[0611] Step 1: r6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0612]

[0613] To a solution of 2-methoxyisonicotinaldehyde (1.0 g, 7.29 mmol) in di chloromethane (10 ml) was added at 3-butyn-l-ol (767 mg, 0.833 ml, 10.94 mmol) under argon. Then the mixture was cooled to -10 °C and trifluoromethanesulfonic acid (3.28 g, 1.92 ml, 21.9 mmol) was added. After stirring for 30 min at -10 °C the mixture was warmed to room temperature and stirring was continued overnight. The reaction mixture was diluted with saturated NaHCO₃-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (870 mg, 32% yield) as colorless oil, LC-MS: m / z = 340.1 [M+H]+, ESI pos.

[0614] Step 2: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-

[0615]

[0616] To a solution of [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (870 mg, 2.31 mmol) in 1,4-dioxane (15 ml) were added bis(pinacolato)diboron (1.17 g, 4.62 mmol), potassium acetate (906 mg, 9.23 mmol) and PdCl₂(dppf)·CH₂Cl₂ (189 mg, 0.231 mmol, 0.10 eq). The mixture was purged and backfilled with argon three times, then stirred at 90 °C for 2 h. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-80%) to afford 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (656 mg, 81% yield) as colorless oil, LC-MS: m / z = 318.3 [M+H]+, ESI pos.

[0617] Intermediate A6: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine

[0618]

[0619] The title compound was prepared in analogy to Intermediate A5 from 6-methoxynicotinaldehyde instead of 2-methoxyisonicotinaldehyde. Light yellow oil, LC-MS: m / z = 318.3 [M+H]+, ESI pos. Intermediate A7: 2-methyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0620]

[0621] Intermediate A7 was prepared in analogy to Intermediate A5 using l-methyl-6-oxo-pyridazine-3-carbaldehyde (CAS: 1467710-08-2) instead of 2-methoxyisoni cotinaldehyde as an off-white solid, LC-MS: m / z: 319.2 [M+H]+, ESI pos.

[0622] Intermediate A8: 2-cyclopropyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0623]

[0624] Intermediate A8 was prepared in analogy to Intermediate All using 6-chloro-2-cyclopropyl-4-methyl-pyridazin-3-one (CAS: 2810820-48-3) instead of 5-chloro-2-cyclopropyl-pyridazin-3-one to afford 2-cyclopropyl-4-methyl-6-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one as a yellow oil, MS m / z: 415.2 [M+H]+, ESI pos.

[0625] Intermediate A9: 2,4-dimethyl-6-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0626]

[0627] Intermediate A9 was prepared in analogy to Intermediate All using 6-chloro-2,4-dimethyl-pyridazin-3-one CAS: 1114563-58-4 instead of 5-chloro-2-cyclopropyl-pyridazin-3-one to afford 2,4-dimethyl-6-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one as a yellow oil. LC-MS: m / z = 389.3 [M+H]+, ESI pos.

[0628] Intermediate A10: 2-methyl-5-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0629]

[0630] 1: 16-(l-methvl-6-oxo-

[0631]

[0632] ;in-4-vl)-3, 6-dihvdro-2H-pvran-4-

[0633]

[0634] trifluoromethanesulfonate

[0635]

[0636] To a solution of l-methyl-6-oxo-pyridazine-4-carbaldehyde (6.0 g, 43.4 mmol) in DCM (80 ml) was added 3-butyn-l-ol (3.65 g, 52.1 mmol), then the mixture was degassed with nitrogen three times and cooled to 0 °C. Trifluoromethanesulfonic acid (11.5 ml, 130 mmol) was added dropwise under nitrogen and the mixture was stirred at -10 °C for 1 h. The reaction mixture was poured into sat. aq. NaHCO₃ solution (50 ml), then extracted with DCM (30 ml x 3), and the combined organic layers were washed with brine (20 ml x 3), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by RP chromatography (C180 - 100% CH3CN in H2O). The eluent was partly concentrated to remove CH3CN, then extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (50 ml), dried over Na₂SO₄, and concentrated in vacuo to give to [6-(l-methyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (3.5 g, 24% yield) as light-yellow oil. MS m / z: 341.1 [M+H]+, ESI pos.

[0637] Step 2: 2-methyl-5-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0638]

[0639] To a solution of [6-(l-methyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (2.0 g, 5.88 mmol) in 1,4-dioxane (50 ml) were added 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.58 g, 7.05 mmol), potassium acetate (1.73 g, 17.63 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-PdCl₂(dppf)·CH₂Cl₂ (240 mg, 0.29 mmol, 0.05 eq). Then the mixture was degassed with nitrogen three times, and the reaction was stirred at 90 °C for 1 h under nitrogen. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, PE / EtOAc 0-30%) and concentrated in vacuo to afford 2-methyl-5-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one (1.2 g, 55% yield) as yellow solid, MS m / z: 375.3 [M+H]+, ESI pos. Intermediate All: 2-cyclopropyl-5-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0640] -5-vinyl-pyridazin-3-one

[0641]

[0642] To a colorless solution of 5-chloro-2-cyclopropyl-pyridazin-3-one (CAS: 14628-34-3, 56.0 g, 262.6 mmol, 1.0 eq.) in 1,4-dioxane (1000 mL) and H2O (100 mL) were added potassium trimethyl(vinyl)boranuide (52.41 g, 393.9 mmol, 1.5 eq.) and Cs₂CO₃ (171.12 g, 525.2 mmol, 2.0 eq.). The reaction mixture was purged three times with N2. Pd(dppf)C12-DCM (6.43 g, 7.88 mmol, 0.03 eq.) was added to the reaction mixture under N2 and the reaction mixture was stirred at 90 °C for 4 h. H2O (500 mL) was added to the reaction and extracted with EtOAc (2 x 500 ml). The combined extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 75% EtOAc in PE) to give 2-cyclopropyl-5-vinyl-pyridazin-3-one (33.0 g, 203.47 mmol, 65.9% yield) as a yellow solid. LC-MS: m / z = 163.2 [M+H]+, ESI pos.

[0643] Step 2: l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde

[0644]

[0645] Ozone was bubbled through a solution of 2-cyclopropyl-5-vinyl-pyridazin-3-one (33.0 g, 203.47 mmol, 1.0 eq.) in DCM (200 mL) and MeOH (200 mL) at -70 °C for 30 min. Then, N2 was bubbled into the mixture at -70 °C to strip the ozone. The reaction turned into blue suspension which was allowed to warm to 0 °C and to this solution was added dropwise a solution of PPh₃ (106.65 g, 406.93 mmol, 2.0 eq.) in DCM (200 mL). The mixture was stirred Ih at 25 °C under N2 which yielded a yellow solution. The reaction mixture was concentrated and 150 mL MeOH were added upon which a white solid precipitated. The solid was filtered off and the filtrate was concentrated in vacuo. Purification by preparative HPLC (Phenomenex Luna C l 8, 150 / 25 mm, 10 pm 30 - 40% CH3CN in H2O) yielded l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde (22.8 g, 68.3% yield) as pink solid, confirmed). LC-MS: m / z = 183.2 [M+H₃O]⁺, ESI pos.

[0646] Step 3: 16-(l-cyclopropyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl1

[0647] tri fluoromethanesulfonate

[0648]

[0649] To a solution of l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde (12.8 g, 77.97 mmol, 1.0 eq.) in DCM (320 mL) was added 3-butyn-l-ol (6.56 g, 93.57 mmol, 1.2 eq.). The mixture was purged with N2, then cooled to -10 °C. Trifluoromethanesulfonic acid (20.64 mL, 233.92 mmol, 3.0 eq.) was added under inert atmosphere. The resulting black solution was stirred at -10 °C for 2 h. The reaction mixture was then poured on sat. aq. NaHCO₃ (200 mL) and stirred at rt for 1 h. The aqueous layer was extracted with DCM (2 x 200 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex luna C18, 150 x 25 mm, 10 pm, 20 - 30% CH3CN in H2O) and the organic solvents were removed under reduced pressure. The remaining aqueous solution was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to yield [6-(l-cyclopropyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (11.0 g, 37.0% yield) as yellow oil. LCMS: m / z = 367.0 [M+H]+, ESI pos.

[0650] Step 4: 2-cyclopropyl-5-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one

[0651]

[0652] To a yellow solution of [6-(l-cyclopropyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (9.6 g, 26.21 mmol, 1.0 eq.) in 1,4-dioxane (200 mL) were added 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (11.52 g, 31.45 mmol, 1.2 eq.), Pd(dppf)C12-DCM (1.07 g, 1.31 mmol, 0.05 eq.) and KO Ac (7.72 g, 78.62 mmol, 3.0 eq.). The flask was purged three times with N2 and the reaction mixture was stirred at 90 °C for 1 h. The reaction was then concentrated and the residue was purified by flash column chromatography (silica gel, 75% EtOAc in PE) to give 2-cyclopropyl-5-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one (6 g, 64.3% yield) as yellow gum. LCMS: m / z = 401.1 [M+H]+, ESI pos. ¹H NMR (400 MHz, CDCl₃) 8 = 7.79 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 0.9 Hz, 1H), 6.45 (br s, 1H), 5.06 (br d, J = 1.2 Hz, 1H), 4.24 - 4.08 (m, 1H), 4.03 - 3.91 (m, 1H), 3.84 - 3.72 (m, 1H), 2.44 -2.33 (m, 1H), 2.30 -2.21 (m, 1H), 1.76 - 1.66 (m, 8H), 1.17 - 1.10 (m, 2H), 1.08 - 1.00 (m, 2H), 0.94 (br t, J = 6.6 Hz, 12H). Intermediate A12: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazine

[0653]

[0654] Intermediate A12 was prepared in analogy to Intermediate A5 using 5-methoxypyrazine-2-carbaldehyde instead of 2-methoxyisonicotinaldehyde, light yellow solid, MS m / z: 319.2 [M+H]+, ESI pos.

[0655] Intermediate A13: 1-cyclopropyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[0656]

[0657] The title compound was prepared in analogy to Intermediate A5 from l-cyclopropylpyrazole-4-carbaldehyde (CAS 1082066-00-9) and 4-pentyn-2-ol instead of 3-butyn-l-ol. Brown oil MS m / z: 331.2 [M+H]+, ESI pos.

[0658] Intermediate A14: 1-methyl-5-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one

[0659]

[0660] Intermediate A14 was obtained in analogy to Intermediate A10 using l-methyl-6-oxo-pyridine-3-carbaldehyde (CAS: 98279-50-6) instead of l-methyl-6-oxo-pyridazine-4-carbaldehyde in step 1 to afford l-methyl-5-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one (5.5 g, 91.0% yield) as a brown oil. LC-MS: m / z = 374.2 [M+H]+, ESI pos.

[0661] Intermediate A15: 3-methoxy-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazine

[0662]

[0663] Intermediate A15 was obtained in alaogy to Intermediate All using 3-chloro-6-methoxypyridazine (CAS: 1722-10-7) instead of 5-chloro-2-cyclopropyl-pyridazin-3-one to afford 3-methoxy-6-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazine (3.0 g, 65.2% yield) as a brown oil. LC-MS: m / z = 319.1 [M+H]+, ESI pos.

[0664] Intermediate Bl: re / -(laRS,7bRS)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0665] Step 1: methyl 3-amino-6-chloro-2-(4-chloro-2-fluoro-phenyl)pyridine-4-carboxylate

[0666]

[0667] To a solution of methyl 3-amino-2,6-dichloro-pyridine-4-carboxylate (1 g, 4.52 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was added at rt 4-chloro-2-fluorobenzeneboronic acid (788.8 mg, 4.52 mmol, 1.0 eq) followed by Cs₂CO₃ (4.42 g, 13.6 mmol, 3.0 eq) in water (10 mL). The mixture was purged with argon before adding PdCl₂(dppf)·CH₂Cl₂ (369.5 mg, 0.45 mmol, 0.10 eq). The mixture was further purged with argon then stirred at rt overnight. The residue was treated with aq. sat. NaHCO₃ (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 25% EtOAc in heptane) to yield methyl 3-amino-6-chloro-2-(4-chloro-2-fluoro-phenyl)pyridine-4-carboxylate (990 mg, 69.4% yield) as yellow solid. LC-MS: m / z = 315.2 [M+H]+.

[0668] Step 2: methyl 3-bromo-6-chloro-2-(4-chloro-2-fluoro-phenyl)pyridine-4-carboxylate

[0669]

[0670] To a solution of methyl 3-amino-6-chloro-2-(4-chloro-2-fluoro-phenyl)pyridine-4-carboxylate (0.960 g, 3.1 mmol, 1.0 eq) in CH3CN (30 mL) was added at room temperature CuBr2 (1.02 g, 4.6 mmol, 1.5 eq) followed dropwise by tert-butyl nitrite (523.57 mg, 603.2 pL, 4.57 mmol, 1.5 eq). After 3.5 h the mixture was treated with aq. sat. NaHCO3(150 mL) and H2O (150 mL) and extracted with EtOAc (2 x 250 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 15% EtOAc in heptane) to yield methyl 3-bromo-6-chloro-2-(4-chloro-2-fluoro-phenyl)pyridine-4-carboxylate (703 mg, 60.9% yield) as white solid. LC-MS: m / z = 378.1 [M+H]+.

[0671] Step 3: 3-bromo-6-chloro-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-pyridine-4-carboxamide

[0672]

[0673] To a solution of methyl 3-bromo-6-chloro-2-(4-chloro-2-fluoro-phenyl)pyridine-4-carboxylate (663 mg, 1.75 mmol, 1.0 eq) in THF (15 mL) was added at rt a solution of LiOH·H₂O (110.1 mg, 2.62 mmol, 1.5 eq) in water (1.5 mL). The mixture was warmed to 50 °C and stirred at 50 °C for 2 h. The mixture was concentrated in vacuo and the crude lithium salt was dissolved in DMF (10 mL) and treated with DIPEA (678.2 mg, 916.5 pL, 5.25 mmol, 3.0 eq), HATU (864.7 mg, 2.27 mmol, 1.300 eq) and N-methylcyclopropanamine hydrochloride (282.3 mg, 2.62 mmol, 1.5 eq). The mixture was stirred at rt for 3 h. The reaction mixture was then treated with aq. sat. NaHCO₃ (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo (and co-distilled once with toluene). The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in heptane) to yield 3-bromo-6-chloro-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-pyridine-4-carboxamide (630 mg, 86.1% yield) as white foam. LC-MS: m / z = 417.1 [M+H]+.

[0674] Step 4: (1aRS,7bRS)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one

[0675]

[0676] A vial was charged with 3-bromo-6-chloro-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-pyridine-4-carboxamide (493.3 mg, 1.18 mmol, 1.0 eq), Cs₂CO₃ (576.7 mg, 1.77 mmol, 1.5 eq), PCy₃ (33.1 mg, 0.12 mmol, 0.10 eq) and 1 -adamantanecarboxylic acid (63.8 mg, 0.35 mmol, 0.30 eq). Toluene (15 mL) was added and the mixture was purged with argon. After addition of Pd(dba)₂ (33.9 mg, 59.0 µmol, 0.05 eq) degassing was repeated for 5 min. The tube was sealed and heated to 120 °C for 7 h. The mixture was then treated with aq. sat. NaHCO₃ (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 -30% EtOAc in heptane) to yield (laRS,7bRS)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (229 mg, 57.6% yield) as yellow solid. LC-MS: m / z = 337.1 [M+H]+.

[0677] Chiral Separation of Intermediate Bl:

[0678] Intermedaite B1 was separated by chiral SFC (chiral C4, 5 µm, 250 x 20 mm, 27% MeOH in CO₂) to afford two stereoisomers.

[0679] Intermediate B2: re / -(laS*,7bS*)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (103 mg) as white foam as first eluting isomer. LC-MS: m / z = 337.2 [M+H]+.

[0680] Intemediate B3: re / -(laR*,7bR*)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (97 mg) as white foam as second eluting isomer. LC-MS: m / z = 337.2 [M+H]+.

[0681] Intermediate B4: (laR*,7bR*) 5 chloro-2-methyl la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0682]

[0683] 5-bromo-2-chloro-N-cyclopropyl-N-methyl-isonicotinamide (CAS: 1857113-43-9, 5.41 g, 18.7 mmol, 1.0 eq.), Cs₂CO₃ (9.13 g, 28.0 mmol, 1.5 eq.), S, S-TADDOL phosphoramidite (CAS: 840504-21-4, 609 mg, 0.934 mmol, 0.050 eq.) and adamantane- 1 -carboxylic acid (674 mg, 3.74 mmol, 0.20 eq.) were suspended in toluene (80 mL) and the suspension was degassed with Argon. Pd(dba)₂ (537 mg, 0.934 mmol, 0.050 eq.) was added, and the mixture was purged with argon and then stirred at 120 °C for 16 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc / EtOH (3:1) in heptane) to afford (laR*,7bR*)-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.81 g, 46% yield) as a light yellow solid. LC-MS: m / z = 209.1 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily. Intermediate B5: (laR*,7bR*)-7-bromo-5 chloro-2-methyl-la,7b-dihydro- 1H-cyclopropa[c][2,6]naphthyridin-3-one

[0684]

[0685] To a solution of (laR*,7bR*)-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (Intermediate B4,2.75 g, 13.2 mmol, 1.0 eq.) in DCM (68.8 ml) was added 3 -chloroperoxybenzoic acid (7.38 g, 33.0 mmol, 2.5 eq.). The mixture was stirred at rt for 24 h. The mixture was poured into 5% aq. Na₂S₂O₅ and DCM and stirred for 10 min. The aqueous layer was separated and extracted two times with DCM. The combined organic layers were washed with half-sat. aq. NaHCO₃, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0 - 100% EtOAc / EtOH (3: 1) in heptane) to afford (laR*,7bR*)-5-chloro-2-methyl-6-oxido-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-6-ium-3-one (2.16 g, 73% yield) as an off-white solid. LC-MS: m / z = 225.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0686] aR*,7bR*)-7-bromo-5-chloro-2-methyl-la,7b-dihydro-lH-

[0687]

[0688] To a solution of (laR*,7bR*)-5-chloro-2-methyl-6-oxido-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-6-ium-3-one (1.70 g, 7.57 mmol, 1.0 eq.) in DCM (68.0 ml) was added POBr₃ (4.34 g, 15.1 mmol, 2.0 eq.). The mixture was purged with nitrogen, then stirred at rt for 16 h. The reaction mixture was added to sat. aq. NaHCO₃ at 45 °C and extracted twice with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 10 - 100% EtOAc / EtOH (3: 1) in heptane) to afford (laR*,7bR*)-7-bromo-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (937 mg, 43% yield) as a light yellow solid. LC-MS: m / z = 287.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0689] Intermediate B6: (laR*,7bR*) ■7-bromo-5 chloro-2-methyl-la,7b-dihydrO' 1H-cyclopropa[c][2,6]naphthyridin-3-one

[0690]

[0691] Intermediate B5 was synthesized in analogy to Intermediate B4 using R,R-TADDOL phosphoramidite (CAS: 840454-58-2) instead of S, S-TADDOL phosphoramidite as ligand to yield (laS*,7bS*)-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.01 g, 45.5%) as light yellow solid. LC-MS: m / z = 209.1 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0692] Intermediate B7: (laR*,7bR*)-7-bromo-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0693]

[0694] Intermediate B7 was synthesized in analogy to Intermediate B4 using Intermediate B6 in the first step to yield (laR*,7bR*)-7-bromo-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (525.1 mg, 51.2%) as off-white solid. LC-MS: m / z = 288.9 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0695] In the subsequent synthetic descriptions, we describe the access to the stereoisomers obtained from Intermediates B4 or B5. Likewise, the corresponding epimers are obtained using Intermediates B6 or B7, and all relative or absolute configuration was assigned arbitrarily.

[0696] Intermediate B8: 5 chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro- 1H-cyclopropa[c][2,6]naphthyridin-3-one

[0697]

[0698] Step 1: methyl 3-amino-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylate

[0699]

[0700] To a solution of methyl 3-amino-2,6-dichloro-pyridine-4-carboxylate (5.00 g, 22.6 mmol, 1.0 eq) in 1,4-dioxane (80 ml) and H2O (8 ml) were added (2,4-difluorophenyl)boronic acid (3.57 g, 22.6 mmol, 1.0 eq), Cs₂CO₃ (18.4 g, 56.6 mmol, 2.5 eq) and PdCl₂(dppf)·DCM (924 mg, 1.13 mmol, 0.050 eq). The mixture was purged and backfilled with nitrogen three times, then stirred at rt for 2 h. The reaction mixture was diluted with H2O and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) and the crude product was triturated with MeOH to afford methyl 3-amino-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylate (4.60 g, 68% yield) as a yellow solid. LC-MS: m / z = 299.1 [M+H]+, ESI pos.

[0701] Step 2: methyl 3-bromo-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylate

[0702]

[0703] To a solution of methyl 3-amino-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylate (4.00 g, 13.4 mmol, 1.0 eq) in CH3CN (50 ml) was added CuBr2 (4.49 g, 20.1 mmol, 1.5 eq) in batches. Tert-butyl nitrite (2.07 g, 20.1 mmol, 1.5 eq) was then added dropwise at 0 °C, and the mixture was stirred at rt for 1 h. The reaction mixture was filtered through celite, and the filtrate was diluted with H2O and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) to afford methyl 3-bromo-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylate (4.10 g, 84% yield) as a yellow solid. LC-MS: m / z = 361.9 [M+H]+, 363.9 [M+H]+, ESI pos.

[0704] Step 3: 3-bromo-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylic acid

[0705]

[0706] To a solution of methyl 3-bromo-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylate (4.00 g, 11.0 mmol, 1.0 eq) in MeOH (6 ml), THF (30 ml) and H2O (6 ml) was added LiOH- H2O (926 mg, 22.1 mmol, 2.0 eq). The mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O, acidified to pH 5 with 1 M HC1 and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated to afford 3-bromo-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylic acid (3.80 g, 99% yield) as a yellow solid. LC-MS: m / z = 347.8 [M+H]+, 349.8 [M+2+H]+, ESI pos.

[0707] Step 4: 3-bromo-6-chloro-N-cyclopropyl-2-(2,4-difluorophenyl)-N-methyl-pyridine-4-carboxamide

[0708]

[0709] To a solution of 3-bromo-6-chloro-2-(2,4-difluorophenyl)pyridine-4-carboxylic acid (3.80 g, 10.9 mmol, 1.0 eq) in DMF (60 ml) were added DIPEA (9.50 ml, 54.5 mmol, 5.0 eq) and HATU (4.97 g, 13.1 mmol, 1.2 eq). The mixture was stirred at rt for 10 min. N-methylcyclopropanamine hydrochloride (1.76 g, 16.4 mmol, 1.5 eq) was added and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with H2O and extracted three times with EtOAc. The combined organic layers were washed two times with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0 - 35% EtOAc in PE) to afford 3- bromo-6-chloro-N-cyclopropyl-2-(2,4-difluorophenyl)-N-methyl-pyridine-4-carboxamide (3.00 g, 69% yield) as a yellow solid. LC-MS: m / z = 401.0 [M+H]+, ESI pos.

[0710] chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-

[0711]

[0712] To a solution of 3-bromo-6-chloro-N-cyclopropyl-2-(2,4-difluorophenyl)-N-methyl-pyridine-4-carboxamide (2.50 g, 6.22 mmol, 1.0 eq) in toluene (70 ml) were added adamantane- 1 -carboxylic acid (337 mg, 1.87 mmol, 0.30 eq), Cs₂CO₃ (3.05 g, 9.36 mmol, 1.5 eq), tricyclohexylphosphane (175 mg, 0.62 mmol, 0.10 eq) and Pd(dba)2 (179 mg, 0.31 mmol, 0.050 eq). The mixture was purged and backfilled with nitrogen three times, then stirred at 120 °C for 12 h. The reaction mixture was filtered through celite and concentrated. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to afford 5-chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.70 g, 85% yield) as a yellow solid. LC-MS: m / z = 321.2 [M+H]+, ESI pos.

[0713] Intermediate B9: 5-chloro-7-(4-chlorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0714]

[0715] Intermediate B9 was synthesized in analogy to Intermediate B8 using 4-chlorophenylboronic acid (CAS: 1679-18-1) in step 1 to afford 5-chloro-7-(4-chlorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.5 g, 62.7% yield) as yellow solid. LC-MS: 319.3 [M+H]+, ESI pos.

[0716] Intermediate BIO: 5-chloro-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0717]

[0718] 1: Methyl 3-amino-2-bromo-6-chloro-pyridine-4-carboxylate

[0719]

[0720] To a suspension of methyl 5-amino-2-chloropyridine-4-carboxylate (15.0 g, 80.4 mmol, 1.0 eq) in DCM (180 ml) was added NBS (15.0 g, 84.4 mmol, 1.1 eq) in portions. The mixture was stirred at rt for 16 h. The reaction mixture was poured into half sat. aq. NaHCO₃ (300 ml) and extracted with DCM (3 x 200 ml). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-15% EtOAc in PE) to afford methyl 3-amino-2-bromo-6-chloro-pyridine-4-carboxylate (25.4 g, quant, yield) as a yellow solid. LC-MS: m / z = 265.1 [M+H]+, ESI pos.

[0721] 2: methyl 3-amino-6-chloro-2-(4-chloro-2,6-difluoro-i

[0722]

[0723] :-4-carboxylate

[0724]

[0725] To a solution of methyl 3-amino-2-bromo-6-chloro-pyridine-4-carboxylate (10.0 g, 37.7 mmol, 1.0 eq) in toluene (200 ml) were added 4-chloro-2,6-difluorophenylboronic acid (9.42 g, 49.0 mmol, 1.3 eq), DIPEA (14.6 g, 113 mmol, 3.0 eq) and [P(tBu)3]Pd(crotyl)Cl (752 mg, 1.88 mmol, 0.050 eq). The mixture was degassed with N2 three times and then stirred at 80 °C for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in PE) followed by preparative HPLC to afford methyl 3-amino-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylate (4.50 g, 35.9% yield) as a light yellow solid. LC-MS: m / z = 333.1 [M+H]+, ESI pos. Step 3: methyl 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylate

[0726]

[0727] To a solution of methyl 3-amino-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylate (4.50 g, 13.5 mmol, 1.0 eq) and CuBr2 (4.22 g, 18.9 mmol, 1.4 eq) in CH3CN (80 ml) was added dropwise tert-butyl nitrite (2.79 g, 27.0 mmol, 2.0 eq) at 0 °C. The mixture was stirred at rt for 2 h. The mixture was poured into H2O (200 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20% EtOAc in PE) to afford methyl 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylate (4.90 g, 88.6% yield) as colorless oil. LC-MS: m / z = 396.0 [M+H]+, ESI pos.

[0728] Step 4: 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylic acid

[0729]

[0730] To a solution of methyl 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylate (4.90 g, 12.3 mmol, 1.0 eq) in THF (40 ml) and H2O (20 ml) was added LiOH- H2O (1.55 g, 37.0 mmol, 3.0 eq). The mixture was stirred at rt for 2 h. The mixture was adjusted to pH 3 with IM aq. HC1 and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na₂SO₄, and concentrated in vacuo to afford 3-bromo-6-chloro-2-(4-chl oro-2, 6-difluoro-phenyl)pyridine-4-carboxylic acid (4.70 g, 96.5% yield) as a light yellow solid, which was used without further purification. LC-MS: m / z = 381.9 [M+H]+, ESI pos.

[0731] Step 5: 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)-N-cyclopropyl-N-methyl-pyridine-4-carb oxami de

[0732]

[0733] To a solution of 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)pyridine-4-carboxylic acid (4.50 g, 11.8 mmol, 1.0 eq) in DMF (60 ml) were added HATU (6.70 g, 17.6 mmol, 1.5 eq), DIPEA (7.59 g, 58.8 mmol, 5.0 eq) and N-methylcyclopropanamine hydrochloride (1.52 g, 14.1 mmol, 1.2 eq). The mixture was stirred at rt for 4 h. The mixture was diluted with H2O (300 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine (2 x 200 ml), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to afford 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)-N-cyclopropyl-N-methyl-pyridine-4-carboxamide (5.30 g, 93.1% yield) as light yellow oil. LC-MS: m / z = 434.9 [M+H]+, ESI pos.

[0734] Step 6; 5-chloro-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-la,7b-dihydro-l H- idin-3-one

[0735]

[0736] To a solution of 3-bromo-6-chloro-2-(4-chloro-2,6-difluoro-phenyl)-N-cyclopropyl-N-methyl-pyridine-4-carboxamide (4.70 g, 10.8 mmol, 1.0 eq) in 1,3,5-trimethyl-benzene (80.0 ml) were added Cs₂CO₃ (7.02 g, 21.6 mmol, 2.0 eq), Pd(dba)2 (310 mg, 0.54 mmol, 0.050 eq), adamantane-1-carboxylic acid (583 mg, 3.23 mmol, 0.30 eq) and tricyclohexylphosphine (302 mg, 1.08 mmol, 0.10 eq). The mixture was degassed with N2 and then stirred at 160 °C for 8 h. The reaction mixture was poured into H2O (100 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-100% EtOAc in PE) to afford 5-chloro-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.60 g, 41.8% yield) as a light yellow solid. LC-MS: m / z = 356.0 [M+H]+, ESI pos. Intermediate Bll: 5-chloro-7-(4,4-difluorocyclohexen-l-yl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0737]

[0738] Intermediate Bll was synthesized in analogy to Intermediate B8 using 2-(4,4-difluorocyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.52 g, 22.62 mmol, 1.0 eq) in the first step to yield 5-chloro-7-(4,4-difluorocyclohexen-l-yl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.3 g, 43.3% yield) as yellow solid. LC-MS: 325.1 [M+H]+, ESI pos.

[0739] Intermediate Bll: (laR*,7bR*) 5 chloro-7-(2,4-difluorophenyl)-2-methyl la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0740]

[0741] To a solution of re / -(laR*,7bR*)-7-bromo-5-chloro-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (277 mg, 0.533 mmol, 1.0 eq) in 1,4-dioxane (5 ml) and H2O (1 ml) was added (2,4-difluorophenyl)boronic acid (42.1 mg, 0.266 mmol, 0.50 eq), cesium carbonate (763 mg, 2.34 mmol, 4.4 eq) and PdCl₂(dppf)·CH₂Cl₂ (44.0 mg, 0.0533 mmol, 0.10 eq). The mixture was purged and backfilled with argon three times, then stirred at 50 °C for 25 h. The reaction mixture was poured into H2O and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica gel, EtOAc in heptane 0 - 100%) to afford re / -(laR*,7bR*)-5-chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (85.0 mg, 50% yield) as a yellow solid. LC-MS: m / z = 321.3 [M+H]+, ESI pos.

[0742] The following Intermediates B13 to B21 were prepared in analogy to B12 by starting from the indicated intermediates. *The stereochemistry was assigned arbitrarily.

[0743]

[0744]

[0745]

[0746] Example 1: (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0747] o-6-r(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1pyridine-4-carboxylate

[0748]

[0749] To a solution of methyl 3-amino-2,6-dichloro-pyridine-4-carboxylate (1 g, 4.85 mmol, 1.0 eq) in DMF (10 mL) was added N-ethyldiisopropylamine (1.88 g, 2.54 mL, 14.56 mmol, 3.0 eq) followed by (2S)-2-(l-methylpyrazol-4-yl)morpholine (Intermediate (+)-Al, 892.7 mg, 5.34 mmol, 1.1 eq). The mixture was stirred at 120 °C for 1 h. The reaction mixture was then diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine and dried over Na₂SO₄ and the volatiles evaporated under reduced pressure. The crude was triturated with 10 mL Et2O (10 mL) and dried under reduced pressure to afford methyl 2-chloro-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (1.06 g, 61.8% yield) as off-white solid. Step 2: methyl 2-(4-chloro-2-fluoro-phenyl)-6-l(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yllpyridine-4-carboxylate

[0750]

[0751] To a thin suspension of methyl 2-chloro-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (1.06 g, 3.16 mmol, 1.0 eq) in 1,4-dioxane (12.5 mL) was added 4-chloro-2-fluorobenzeneboronic acid (578.4 mg, 3.32 mmol, 1.05 eq) followed by Cs₂CO₃ (3.1 g, 9.48 mmol, 3.0 eq). The mixture was degassed by bubbling argon for 10 min. PdCl2(dppf)·CH2Cl2 (77.4 mg, 94.78 umol, 0.030 eq) was added followed by further degassing with argon. The mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure, dissolved in EtOAc and filtered through a pad of silica. The filtrate was diluted with water and the organic layer was separated, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was further triturated with PrOH and dried under reduced pressure to afford methyl 2-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (982 mg, 67.1% yield) as off-white solid. LC-MS: m / z = 431.2 [M+H]+, ESI pos.

[0752] Step 3: methyl 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-l(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1pyridine-4-carboxylate

[0753]

[0754] To a solution of methyl 2-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (977 mg, 2.27 mmol, 1.0 eq) in DCM (20 mL) was added NBS (444 mg, 2.49 mmol, 1.1 eq) in 2 portions over 10 min. The mixture was stirred overnight at rt. Once the reaction reached completion, the volatiles were evaporated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford methyl 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (806 mg, 64.8% yield) as yellow solid along its regioisomer methyl 3-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (234 mg, 20.2% yield) as light yellow solid. LC-MS: m / z = 511.2 [M+H]+, ESI pos.

[0755] Step 4: 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-l(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yllpyridine-4-carboxylic acid

[0756]

[0757] To a solution of methyl 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (797 mg, 1.56 mmol, 1.0 eq) in THF (3 mL) was added aqueous LiOH (IM, 6.25 mL, 6.25 mmol, 4.0 eq). The resulting mixture was stirred at 50 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue redissolved in a mixture of EtOAc and aqueous sat. NH4CI. The two layers were separated and the aqueous layer washed twice with DCM. All organic layers were combined, dried over Na2SO4and concentrated under reduced pressure to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylic acid (723 mg, 82.1% yield) as an off-white solid. The product was used as is without further purification. LC-MS: m / z = 497.2 [M+H]+, ESI pos.

[0758] Step 5: 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-6-l(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1pyridine-4-carboxamide

[0759]

[0760] 3-Bromo-2-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylic acid (500 mg, 1.01 mmol, 1.0 eq) was dissolved DMF (8.6 mL). DIPEA (391.1 mg, 524 pL, 3.03 mmol, 3.0 eq) and cyclopropyl(methyl)amine (86.1 mg, 1.21 mmol, 1.2 eq) were added. The reaction mixture was stirred for a few minutes and HATU (2.45 g, 6.44 mmol, 1.2 eq) was added. After the reaction reached completion, the reaction mixture was then diluted with EtOAc and water and the two layers separated. The aqueous layer was further extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (410 mg, 66.7% yield) as light yellow solid. LC-MS: m / z = 550.2 [M+H]+, ESI pos.

[0761] S,7bRS)-7-(4-chloro-2-fluoro-

[0762]

[0763] i-2-methyl-5-r(2S)-2-(l-:

[0764]

[0765] -4-

[0766]

[0767] -4- |-la,7b-dihvdro-lH-i

[0768]

[0769] in-3 -one

[0770] A sealed vial was charged with 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl- 6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (474 mg, 0.86 mmol, 1.0 eq), PCy3(48.4 mg, 0.17 mmol, 0.20 eq), adamantane carboxylic acid (31.1 mg, 0.17 mmol, 0.20 eq), Cs₂CO₃ (422.1 mg, 1.3 mmol, 1.5 eq) and toluene (17.5 mL). The resulting mixture was purged with Ar for a few minutes before adding Pd2(dba)3 (79.1 mg, 86.4 pmol, 0.10 eq). Then the reaction mixture was stirred at 120 °C overnight. The resulting mixture was diluted with EtOAc and water. The two layers were separated and the aqueous phase further washed with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was then purified by flash column chromatography (silica gel, 0 -100 % EtOAc in heptane). The compound was then purified by reversed phase HPLC (YMC-Triart C18, 12 nm, 5 pm, 100 x 30 mm, CH3CN / H2O + 0.1% HCOOH) to afford (laRS,7bRS)- 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (108 mg, 25.4% yield) as white solid as a mixture of two diastereoisomers. LC-MS: m / z = 468.3 [M+H]+, ESI pos.

[0771] Examples 2 and 3: re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0772]

[0773] Example 2 Example 3 Separation of the diastereoisomers of Example 1 by chiral SFC (OZ-H, 5 pm, 250 x 20 mm, 43% MeOH in CO2) yielded two isomers:

[0774] Isomer 1 (Example 2): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (27.2 mg, 25% yield) as first eluting isomer as an off-white powders. LC-MS: m / z = 468.3 [M+H]+, ESI pos. 'H NMR (300 MHz, DMSO-de) 8 = 7.72 (s, 1H), 7.60 - 7.53 (m, 2H), 7.43 (s, 1H), 7.43 - 7.39 (m, 1H), 7.37 (s, 1H), 4.51 (dd, J = 2.4, 10.5 Hz, 1H), 4.18 (br d, J= 12.5 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.80 (s, 3H), 3.68 (dt, J = 2.7, 11.5 Hz, 1H), 3.25 - 3.17 (m, 1H), 3.14 (s, 3H), 3.01 - 2.91 (m, 1H), 2.87 (dd, J = 10.7, 12.7 Hz, 1H), 1.87 (dt, J = 6.1, 8.7 Hz, 1H), 1.26 (ddd, J = 4.9, 6.2, 9.6 Hz, 1H), 0.29 - 0.23 (m, 1H). *The stereochemistry was assigned arbitrarily.

[0775] Isomer 2 (Example 3): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (27.2 mg, 25% yield) as second eluting isomer as an off-white powder. LC-MS: m / z = 468.3 [M+H]+, ESI pos. 'H NMR (300 MHz, DMSO-d6) 6 = 7.72 (s, 1H), 7.60 - 7.53 (m, 2H), 7.45 - 7.39 (m, 2H), 7.37 (s, 1H), 4.51 (dd, J = 2.6, 10.3 Hz, 1H), 4.23 - 4.15 (m, 1H), 4.05 - 3.94 (m, 2H), 3.80 (s, 3H), 3.67 (dt, J = 2.7, 11.5 Hz, 1H), 3.21 (ddd, J = 4.0, 6.3, 8.2 Hz, 1H), 3.14 (s, 3H), 3.01 -2.83 (m, 2H), 1.87 (dt, J = 6.0, 8.8 Hz, 1H), 1.26 (ddd, J = 4.8, 6.3, 9.6 Hz, 1H), 0.31 - 0.22 (m, 1H). *The stereochemistry was assigned arbitrarily.

[0776] Example 4: (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2R)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0777]

[0778] Step 1: 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-6-l(2R)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide

[0779]

[0780] The title compound was prepared in analogy to Example 1, Steps 1-5 using using (2R)-2-(l-methylpyrazol-4-yl)morpholine (Intermediate (-)-Al, 892.7 mg, 5.34 mmol, 1.1 eq) as reagent in Step 1 yielding 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-6-[(2R)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (404 mg) as light yellow solid. LC-MS: m / z = 564.1 [M+H]+, ESI pos.

[0781] Step 2: ( 1 aRS, 7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - 1 (2R)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl1-la,7b-dihydro-lH-cyclopropalcir2,61naphthyridin-3-one

[0782] A vial was charged with 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-6-[(2R)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (200 mg, 0.36 mmol, 1.0 eq), (zBu)2PMeHBF4 (18.1 mg, 72.9 pmol, 0.20 eq), K3PO4 (116.0 mg, 0.55 mmol, 1.5 eq), cesium pivaloate (25.6 mg, 0.11 mmol, 0.30 eq), and toluene (7.5 mL). The resulting mixture was purged with argon for a few minutes before adding Pd(OAc)2 (8.2 mg, 36.4 pmol, 0.10 eq). The vial was sealed and the reaction mixture was stirred at 120 °C overnight. The reaction mixture was filtered through a pad of silica and the filtrate was diluted with EtOAc and water. The two layers were separated and the aqueous layer further washed with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was then purified by flash chromatography (silica gel, gradient 0 - 100% EtOAc in heptane) to afford ( 1 aRS, 7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [(2R)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (59.1 mg, 32.9% yield) as light yellow solid as a mixture of stereoisomers. LC-MS: m / z = 468.3 [M+H]+, ESI pos.

[0783] Examples 5 - 8: re / -(laR*,7bR*)-7-(4-chloro-2,6-difhioro-phenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(l aS*, 7bS*)-7-(4-chl oro-2, 6-difhioro-phenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel- (laR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel- (1 aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0784]

[0785] Example 5 Example 6 Example? Examples

[0786] Step 1: methyl 2-chloro-6-r2-(l-methylpyrazol-4-yl)morpholin-4-yl1pyridine-4-carboxylate

[0787]

[0788] The title compound was prepared in analogy to Example 1, Step 1 using racemic 2-(l-methylpyrazol-4-yl)morpholine (Intermediate Al, 3.65 g, 21.84 mmol, 1.0 eq) as reagent, yielding methyl 2-chloro-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (3.52 g, 43.1% yield) as off-white solid. LC-MS: m / z = 337.1 [M+H]+, ESI pos.

[0789] Step 2: methyl 2-(4-chloro-2,6-difluoro-phenyl)-6-r2-(l-methylpyrazol-4-yl)morpholin-4-

[0790]

[0791] A reaction tube was filled with 2-(4-chloro-2,6-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (448.3 mg, 1.63 mmol, 1.1 eq), methyl 2-chloro-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (500 mg, 1.48 mmol, 1.0 eq) and toluene (15 mL). Then was added a solution of K3PO4 (0.95 g, 4.45 mmol, 3.0 eq) in water (3 mL). The resulting mixture was purged with argon for a few minutes before adding APhos-Pd-G3 (94.3 mg, 148.5 pmol, 0.10 eq). After further 5 min of degassing, the tube was sealed and the reaction mixture heated to 110 °C overnight. The mixture was treated with aq. sat. NaHCO₃ (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over Na2SO4and the volatiles evaporated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 80% EtOAc / EtOH (3:1) in heptane). A second purification by reversed phase column chromatography (RP18, 30 – 100% CH3CN in water) yielded methyl 2-(4-chloro-2,6-difluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (180 mg, 27.0% yield) as yellow solid. LC-MS: m / z = 449.3 [M+H]+, ESI pos.

[0792] ifluoro-

[0793]

[0794] -4-

[0795]

[0796] To a solution of methyl 2-(4-chl oro-2, 6-difluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (160 mg, 0.36 mmol, 1.0 eq) in DCM (3 mL) was added NBS (63.4 mg, 0.36 mmol, 1.0 eq) in 2 portions over the course of 15 min. After complete addition, the mixture was stirred at rt for 30 min. Then a second portion of NBS (5.1 mg, 28.5 pmol, 0.08 eq) was added and stirred for additional 30 min. The mixture was quenched with aq. sat. NaHCO3 (10 mL) and extracted with DCM (2 x 10 mL). The organic layers were dried over Na2SO4and the volatiles evaporated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 20 - 100% EtOAc in heptane) to yield both regioisomers methyl 3-bromo-6-(4-chl oro-2, 6-difluoro-phenyl)-2-[2-(l -methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (23 mg, 10.5% yield) as colorless oil and methyl 3-bromo-2-(4-chloro-2,6-difluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (165 mg, 87.7% yield) as yellow foam. LC-MS: m / z = 527.3, [M+H]+, ESI pos. Step 4: 3-bromo-2-(4-chloro-2,6-difluoro-phenyl)-N-cyclopropyl-N-methyl-6-12-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide

[0797]

[0798] To a solution of methyl 3-bromo-2-(4-chloro-2,6-difluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (150 mg, 0.28 mmol, 1.0 eq) in THF (2.5 mL) was added a solution of LiOH·H2O (17.9 mg, 0.43 mmol, 1.5 eq) in water (250 µL). The mixture was stirred at 50 °C for 3 h after which it was concentrated in vacuo. The crude lithium salt was then dissolved in DMF (2.5 mL) and treated with DIPEA (110.2 mg, 149 pL, 0.85 mmol, 3.0 eq), HATU (140.5 mg, 0.37 mmol, 1.0 eq) and N-methylcyclopropanamine hydrochloride (45.9 mg, 0.43 mmol, 1.5 eq). The reaction mixture was stirred at rt for 3 days. The mixture was treated with aq. sat. NaHCO₃ (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were dried over Na2SO4and the volatiles evaporated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 20 - 70% EtOAc / EtOH (3:1) in heptane) to yield 3-bromo-2-(4-chloro-2,6-difluoro-phenyl)-N-cyclopropyl-N-methyl-6-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (135 mg, 83.8% yield) as light yellow amorphous solid. LC-MS: m / z = 566.4 [M+H]+, ESI pos.

[0799] Step 5: 7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-12-(l-methylpyrazol-4-yl)morpholin-4-yl1-1 a,7b-dihydro- IH-cyclopropal cl 12, 61naphthyri din-3 -one

[0800]

[0801] A reaction tube was filled with 3-bromo-2-(4-chloro-2,6-difluoro-phenyl)-N-cyclopropyl-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (124 mg, 0.22 mmol, 1.0 eq), Cs₂CO₃ (106.9 mg, 0.33 mmol, 1.5 eq), PCy3(6.1 mg, 21.9 pmol, 0.10 eq) and 1-adamantanecarboxylic acid (11.8 mg, 65.6 pmol, 0.30 eq). Toluene (3.5 mL) was added, and the mixture was degassed for 10 min by bubbling Ar through the mixture. After addition of Pd(dba)2 (6.3 mg, 10.9 pmol, 0.05 eq) degassing was repeated for 5 min. After further 5 min of degassing, the tube was sealed and the reaction mixture heated to 120 °C for 4 h. The mixture was treated with aq. sat. NaHCO₃ (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were dried over Na2SO4and the volatiles evaporated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 70% EtOAc / EtOH (3:1) in heptane) to yield 7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one (52 mg, 48.9% yield) as light yellow foam as a mixture of 4 stereoisomers. LC-MS: m / z = 486.4 [M+H]+, ESI pos.

[0802] -

[0803]

[0804] idin-3-one and rel-( 1 aS *,7b S *)-7-(4-chl oro-2, 6-difluoro-i

[0805]

[0806] i-2-methyl-5-

[0807]

[0808] -4- -4- |-la,7b-dihvdro-lH-i

[0809]

[0810] i din-3 -one and rel- )-7-(4-chl oro-2, 6-difluoro-

[0811]

[0812] i-2-methyl-5-|

[0813]

[0814] -4- -4- |-la,7b-dihvdro-lH-i

[0815]

[0816] i din-3 -one and rel- -7-(4-chloro-2,6-difluoro-

[0817]

[0818] i-2-methyl-5-|

[0819]

[0820] -4-

[0821]

[0822] -4- |-la,7b-dihvdro-lH-i

[0823]

[0824] -3 -one

[0825] The mixture of stereoisomers from Step 5 was submitted to chiral separation by SFC (chiral 4-Cellulose, 5 pm, 250 x 20 mm, 10% EtOH in CO2) to yield a first fraction A containing two enantiomers (Isomer 1 and Isomer 2 eluting together as the first and second eluting isomers) as well as additional 2 single stereoisomers (Isomer 3 eluting as third eluting isomer and Isomer 4 as fourth eluting isomer). Fraction A was further separated by chiral SFC (Chiralpak AD-H, 5 pm, 250 x 20 mm, 15% MeOH in CO2). Eventually were obtained four stereoisomers:

[0826] Isomer 1 (Example 5): re / -(laS*,7bS*)-7-(4-chloro-2,6-difhioro-phenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (9 mg, 17.3% yield) as light yellow foam. LC-MS: m / z = 486.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0827] Isomer 2 (Example 6): re / -(laR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (9 mg, 17.3% yield) as light yellow foam. LC-MS: m / z = 486.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0828] Isomer 3 (Example 7): re / -(laS*,7bS*)-7-(4-chloro-2,6-difhioro-phenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (10 mg, 18% yield, 94% purity) as yellow foam. LC-MS: m / z = 486.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily. Isomer 4 (Example 8): re / -(laR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (10 mg, 19% yield) as yellow foam. LC-MS: m / z = 486.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0829] Examples 9- 12: re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel-( 1 aS *, 7b S *)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [rel-(2 S *,4R*)-2-( 1 -methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fhioro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0830]

[0831] To a solution of re / -(laS*,7bS*)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (Intermediate B2, 94 mg, 0.28 mmol, 1.0 eq) in THF (750 pL) was added XantPhos-Pd-G3 (28.8 mg, 27.9 pmol, 0.1 eq). The tube was sealed with a septum and the mixture was purged with nitrogen. Then was added by syringe a freshly prepared bromo-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc solution (Intermediate A3, ca. 0.12 M in THF, 3.48 mL, 0.42 mmol, 1.5 eq). The reaction mixture was warmed to 50 °C and stirred for 4 h. The mixture was quenched with 1 M HC1 (0.6 mL), basified with sat. aq. NaHCO₃ (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20 - 70% EtOAc / EtOH (3:1) in heptane) to yield re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (105 mg, 85% yield) as yellow oil as a mixture of four stereoisomers. LC-MS: m / z = 467.4 [M+H]+, ESI pos. Chiral separation (Chiralpak IA, 12 nm, 5 pm, 250 x 20 mm, 29% EtOH in CO2) afforded four stereoisomers. Isomer 1 (Example 9): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (7.3 mg, 5.6% yield) as colorless oil as first eluting isomer. LC-MS: m / z = 467.3 [M+H]+. *The stereochemistry was assigned arbitrarily.

[0832] Isomer 2 (Example 10): re / -(laS*,7bS*)-7-(4-chloro-2-fhioro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (32 mg, 24.6%) as white foam as second eluting stereoisomer. LC-MS: m / z = 467.3 [M+H]+. *The stereochemistry was assigned arbitrarily.

[0833] Isomer 3 (Example 11): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -f2R*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (8.4 mg, 5.9% yield) as colorless oil as third eluting isomer. LC-MS: m / z = 467.3 [M+H]+. *The stereochemistry was assigned arbitrarily.

[0834] Isomer 4 (Example 12): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (26.7 mg, 20.5%) as white foam as fourth eluting isomer. LC-MS: m / z = 467.3 [M+H]+. *The stereochemistry was assigned arbitrarily.

[0835] Examples 13 - 16: re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fhioro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fhioro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0836]

[0837] The four title compounds were preapred in analogy ic Examples 9-12, Step 5 using rel( 1 aR*, 7bR*)-5 -chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one (Intermediate B3). Purification of the crude material by flash column chromatography (SiO2, 20-70% EtOAc / EtOH (3:1) in heptane) yielded reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (96 mg, 78% yield) as yellow oil as mixture of four stereoisomers. LC-MS: m / z = 467.4 [M+H]+, ESI pos. Chiral separation (chiral IA, 12 nm, 5 pm, 250x20 mm, 29% EtOH in CO2) afforded three fractions, the first fraction containing pure Isomer 1, the second fraction containing a mixture of Isomer 2 and Isomer 3 and a third fraction containing pure Isomer 4. Isomers 2 and 3 were separated by chiral SFC (chiral separation (chiral OD-H, 5 pm, 250x20 mm, 22% MeOH in CO2). Finally were obtained the following isomers:

[0838] Isomer 1 (Example 13): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4R*)-2-(l -methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (6.7 mg, 5% yield) as white foam as first eluting isomer from the first chiral separation.

[0839] Isomer 2 (Example 14): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (4.2 mg, 3% yield) as yellow oil as colorless oil as first eluting isomer from the second separation.

[0840] Isomer 3 (Example 15): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (22.9 mg, 19% yield) as white foam as second eluting isomer from the second separation.

[0841] Isomer 4 (Example 16): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (30.5 mg, 25% yield) as white foam as second eluting isomer from the first chiral separation.

[0842] Examples 17 - 20: reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel- (laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0843]

[0844] Example 17 Example 18 Example 19 Example 20

[0845] 1: 3-bromo-2-(4-chloro-2-fluoro-

[0846]

[0847] in-4-yl]pyridine-4-carboxylic acid

[0848]

[0849] The title compound was prepared in analogy to Example 1, Steps 1-5 using using racemic 2-(l-methylpyrazol-4-yl)morpholine (Intermediate Al, 3.93 g, 5.34 mmol, 1.1 eq) as reagent in Step 1 yielding 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylic acid (514 mg) as off-white solid. LC-MS: m / z = 495.0 [M+H]+, ESI pos. Step 2: 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N, N-dicyclopropyl-6-r2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide

[0850]

[0851] 3-Bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylic acid (116 mg, 0.23 mmol, 1.0 eq) was dissolved in DMF (2.5 mL). DIPEA (181.4 mg, 242.91 uL, 1.4 mmol, 6.0 eq) was added. The mixture was cooled to 0 °C with an ice bath before adding HATU (106.8 mg, 0.28 mmol, 1.2 eq). The reaction mixture was stirred at this temperature for 30 min before adding dicyclopropylamine (34.1 mg, 0.35 mmol, 1.5 eq). The reaction mixture was then stirred at rt for another hour. The reaction mixture was then diluted in EtOAc and water and the two layers separated. The aqueous layer was further extracted with EtOAc. All organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N, N-dicyclopropyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (117 mg, 86.7% yield) as light yellow solid. LC-MS: m / z = 576.5 [M+H]+, ESI pos.

[0852]

[0853] vl)morpholin-4-vl]-la,7b-dihvdro-lH-cvclopr

[0854]

[0855] ri din-3 -one and rel- -4-

[0856]

[0857] A vial was charged with 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N, N-dicyclopropyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (117 mg, 0.20 mmol, 1.0 eq) and toluene (4.0 mL). The mixture was purged with Ar for a few minutes before adding 1-adamantanecarboxylic acid (7.34 mg, 40.7 pmol, 0.20 eq), Cs₂CO₃ (99.5 mg, 0.31 mmol, 1.50 eq) and PCy3(11.4 mg, 40.7 pmol, 0.20 eq). The resulting mixture was purged again with Ar before adding Pd2(dba)3 (18.6mg, 20.4 pmol, 0.10 eq). The vial was sealed and the resulting mixture was heated to 120 °C overnight. The resulting mixture was diluted with EtOAc and water. The two layers were separated and the aqueous phase further washed with EtOAc. All organic phases were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was then purified by flash chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford 7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[2-(l-methylpyrazol-4-yl)morpholino]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (64 mg, 63.7% yield) as orange solid as a mixture of stereoisomers. LC-MS: m / z = 494.17 [M+H]+, ESI pos. The mixture of stereoisomers was submitted to chiral separation by SFC (chiral Cellulose SZ, 5 pm, 250 x 20 mm, 40% MeOH in CO2) to yield two single enantiomers (Isomer 1 as first eluting isomer and Isomer 2 as second eluting isomer) as well as additional two stereoisomers (Isomer 3 and Isomer 4) eluting together. The latter were further separated by chiral SFC (Chiralpak IK, 5 pm, 250 x 20 mm, 55% MeOH in CO2) yielding Isomer 3 as first eluting isomer and Isomer 4 as second eluting isomer. Eventually were obtained four stereoisomers:

[0858] Isomer 1 (Example 17): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 - one (3 mg, 16.7% yield) as off-white solid. LC-MS: m / z = 494.5[M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0859] Isomer 2 (Example 18): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one (2.8 mg, 14.6% yield) as off-white solid. LC-MS: m / z = 494.5[M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0860] Isomer 3 (Example 19): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one (0.3 mg, 0.8% yield, 50% purity) as off-white solid. LC-MS: m / z = 494.5[M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0861] Isomer 4 (Example 20): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one (1.5 mg, 7.8% yield) as off-white solid. LC-MS: m / z = 494.5[M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0862] Examples 21 -24: re / -(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel- ( 1 aS *, 7b S *)-7-(2,4-difluorophenyl)-2-methyl-5 - [(2R*)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0863]

[0864] Example 21 Example 22 Example 23 Example 24

[0865]

[0866] To a thin suspension of methyl 2-chloro-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4- carboxylate (obtained in Example 5, Step 1, 950 mg, 2.82 mmol, 1.0 eq) in THF (11.3 mL) was added at rt (2,4-difluorophenyl)boronic acid (467.7 mg, 2.96 mmol, 1.05 eq) followed by Cs₂CO₃ (2.76 g, 8.46 mmol, 3.0 eq). The mixture was purged with Ar for 10 min, before adding PdC12(dtbpf) (91.93 mg, 0.14 mmol, 0.050 eq). After purging the reaction mixture further with Ar, it was stirred at 85 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure, then the residue was taken up in EtOAc and water. The two layers were separated and the organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was triturated in Et2O and dried under reduced pressure to afford methyl 2-(2,4- difluorophenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (756 mg, 58.2% yield) as light brown solid. LC-MS: m / z = 431.2 [M+H]+, ESI pos.

[0867] -4-yl)morpholin-4-

[0868]

[0869] To a solution of methyl 2-(2,4-difluorophenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyridine-4-carboxylate (755 mg, 1.82 mmol, 1.0 eq) in DCM (15.7 mL) was added NBS (356.7 mg, 2.0 mmol, 1.1 eq) in 2 portions over 10 min. The mixture was stirred at rt overnight, after which the volatiles were evaporated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 0 - 50% EtOAc in heptane) to afford methyl 3-bromo-2-(2,4- difluorophenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylate (596 mg, 63.0% yield) as light yellow solid. LC-MS: m / z = 495.0 [M+H]+, ESI pos.

[0870]

[0871] To a suspension of methyl 3-bromo-2-(2,4-difluorophenyl)-6-[2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyridine-4-carboxylate (550 mg, 1.1 mmol, 1.0 eq) in THF (2.5 mL) was added a solution of LiOH·H₂O (187.2 mg, 4.4 mmol, 4.0 eq) in H2O (4.5 mL). The mixture was stirred at 50 °C for 30 min. After addition of MeOH (2.5 mL) in order to fully dissolve the starting material, stirring at 50 °C was continued for 3 h. The mixture was acidified with IM aq. HC1 (550 pl) to a pH of 1-2, diluted with water (10 mL) and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford 3-bromo-2-(2,4-difluorophenyl)- 6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxylic acid (535 mg, quantitative) as off-white solid which was used as such in the next step. LC-MS: m / z = 477.2 [M−H]⁻, ESI neg.

[0872] Step 4: 3-bromo-N-cvclopropyl-2-(2,4-difluorophenyl)-N-methyl-6-r2-(l-methylpyrazol-4- in-4-:-4-carboxamide

[0873]

[0874] To a solution of 3-bromo-2-(2,4-difluorophenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyridine-4-carboxylic acid (200 mg, 0.42 mmol, 1.0 eq) in DMF (4 mL) was added at rt N- methylcyclopropanamine hydrochloride (53.9 mg, 0.50 mmol, 1.2 eq) and HATU (190.4 mg, 0.50 mmol, 1.2 eq) followed by DIPEA (161.8 mg, 218.7 pL, 1.25 mmol, 3.0 eq). The reaction mixture was stirred at rt overnight. The mixture was then treated with aq. sat. NaHCO₃ (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 60% EtOAc / EtOH (3:1) in heptane) to afford 3-bromo-N-cyclopropyl-2-(2,4-difluorophenyl)-N- methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (224 mg, 98.8% yield) as white amorphous solid. LC-MS: m / z = 532.3 [M+H]+, ESI pos.

[0875]

[0876] i-2-methyl-5-r(2S*)-2-(l-methylpyrazol-4- orpholin-4-yl]-la,7b-dihydro-lH-i )parcir2,6]naphthyridin-3-one and rel-

[0877]

[0878] A reaction tube was filled with 3-bromo-N-cyclopropyl-2-(2,4-difluorophenyl)-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (65 mg, 122.09 umol, 1.0 eq), Cs₂CO₃ (59.67 mg, 183.14 umol, 1.5 eq), PCy3(3.42 mg, 12.2 pmol, 0.10 eq) and 1-adamantanecarboxylic acid (6.6 mg, 36.63 umol, 0.30 eq) and toluene (3.5 mL). The mixture was degassed by purging with Ar for 10 min. After addition of Pd(dba)2 (3.51 mg, 6.1 umol, 0.050 eq) degassing was repeated for 5 min. The tube sealed and heated to 120 °C for 1.5 h. Then the mixture was treated with aq. sat. NaHCO₃ (10 mL) and extracted with EtOAc (2 x 10 mL). The organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20 - 70% EtOAc / EtOH (3: 1) in heptane). Repurification by reversed phase HPLC (Gemini NX, 12 nm, 5 pm, 100 x 30 mm; CH3CN in water+0.1% HCOOH) afforded the diastereoisomeric mixture 7-(2,4-difluorophenyl)-2-methyl-5-[2-(l-methylpyrazol-4-yl)morpholino]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (37 mg, 67 % yield, 83% purity) as light yellow oil. LC-MS: m / z = 452.4 [M+H]+, ESI pos. Separation by SFC (chiral OZ, 5 pm, 250 x 20 mm, 35% MeOH + 0,2% DEA in CO2) afforded the separation of both diastereoisomers (as racemic mixtures), fractions A and B. Subsequent separation of both racemic mixtures by chiral SFC (chiral Amylose3, 5 pm, 250x20 mm, 46% resp. 50% EtOH) afforded the 4 single stereoisomers.

[0879] Isomer 1 (Example 21): re / -(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (6 mg, 11% yield) as light yellow oil as first eluting isomer from fraction A. LC-MS: m / z = 452.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0880] Isomer 2 (Example 22): re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (7 mg, 13% yield) as light yellow oil as second eluting isomer from fraction A. LC-MS: m / z = 452.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily. - Ill - Isomer 3 (Example 23): re / -(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (7 mg, 13% yield) as light yellow oil as first eluting isomer from fraction B. LC-MS: m / z = 452.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0881] Isomer 4 (Example 24): re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (8 mg, 15% yield) as light yellow oil as second eluting isomer from fraction B. LC-MS: m / z = 452.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0882] Examples 25 - 28: re / -(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / - (laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5- [(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0883]

[0884] The title compound was prepared in analogy to Example 12, Steps 1-4 using (4-chlorophenyl)boronic acid (510.8 mg, 3.27 mmol, 1.1 eq) in Step 1 to yield 3-bromo-2-(4-chlorophenyl)-N-cyclopropyl-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (165 mg) as light brown oil. LC-MS: m / z = 530.3 [M+H]+, ESI pos.

[0885]

[0886]

[0887] lH- i-2-methyl-5-

[0888]

[0889] A reaction tube was filled with 3-bromo-2-(4-chlorophenyl)-N-cyclopropyl-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (165 mg, 0.31 mmol, 1.0 eq), Cs₂CO₃ (151.9 mg, 0.47 mmol, 1.5 eq), PCy3(8.7 mg, 31.1 pmol, O.l eq), 1 -adamantanecarboxylic acid (16.8 mg, 93.3 pmol, 0.3 eq) and toluene (8.5 mL). The mixture was degassed by purging with argon for 10 min. After addition of Pd(dba)2 (8.9 mg, 15.5 pmol, 0.05 eq) degassing was continued for 5 min. The tube was sealed and heated to 120 °C for 10 h. The mixture was treated with aq. sat. NaHCCf (10 mL) and extracted with EtOAc (2 x 10 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20 - 70% EtOAc / EtOH (3:1) in heptane) followed by reversed phase HPLC (YMC-Triart C18, 12 nm, 5 pm, 100 x 30 mm, CH3CN / Water+0.1% HCOOH) to give 7-(4-chlorophenyl)-2-methyl-5-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (39 mg, 28% yield) as yellow oil as a mixture of 4 stereoisomers. LC-MS: m / z = 450.4 [M+H]+, ESI pos. Separation by SFC (chiral OZ-H, 12 nm, 5 pm, 250 x 4.6 mm, 43% MeOH in CO2) afforded the separation of both diastereoisomers (as racemic mixtures) as fractions A and B. Subsequent separation of both racemic mixtures by chiral SFC (fraction A: chiral Amylose-3, 5 pm, 250 x 20 mm, 50% EtOH in CO2 and fraction B: chiral OJ, 5 pm, 250 x 20 mm, 26% MeOH in CO2) afforded the 4 single stereoisomers.

[0890] Isomer 1 (Example 25): re / -(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (13.7 mg, 5.5% yield) as yellow solid as first eluting isomer from fraction A. LC-MS: m / z = 450.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0891] Isomer 2 (Example 26): re / -(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (13.9 mg, 5.5% yield) as yellow solid second eluting isomer from fraction A. LC-MS: m / z = 450.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily. Isomer 3 (Example 27): re / -(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (11.9 mg, 4.6% yield) as yellow solid first eluting isomer from fraction B. LC-MS: m / z = 450.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0892] Isomer 4 (Example 28): re / -(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (11.4 mg, 4.5% yield) as yellow solid second eluting isomer from fraction B. LC-MS: m / z = 450.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0893] Examples 29 and 30: re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one

[0894]

[0895] yl]pyridine-4-carboxylic acid

[0896]

[0897] 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholino]isonicotinic acid (obtained in Example 11, Step 1, 164.0 mg, 0.31 mmol, 1.0 eq) was dissolved in DMF (2.7 mL). DIPEA (121.9 mg, 163 pL, 0.94 mmol, 3.0 eq) and methyl-(l-methylcyclopropyl)amine (53.5 mg, 0.63 mmol, 2.0 eq) were added. The reaction mixture was stirred for a few minutes and HATU (143.4 mg, 0.37 mmol, 1.2 eq) was added. After Ih a second portion of methyl-(l-methylcyclopropyl)amine (53.5 mg, 0.63 mmol, 2.0 eq), DIPEA (121.9 mg, 163 pL, 942.85 pmol, 3.0 eq) and HATU (143.4 mg, 0.37 mmol, 1.2 eq) were added and the reaction stirred for another 40 min. The reaction mixture was then diluted with EtOAc and water, and the two layers separated. The aqueous layer was further washed with EtOAc (3 times). The organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was then purified by flash chromatography to afford 3-bromo-2-(4-3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-methyl-N-(l-methylcyclopropyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (132.9 mg, 71.4% yield) as light brown solid. LC-MS: m / z = 564.1[M+H]+, ESI pos.

[0898] Step 2: re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-l(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1-E7b-dihydrocyclopropalcir2,61naphthyridin-3-one and rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-l(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1-l Jb-dihydrocy cl opropalcir2,61naphthyri din-3 -one

[0899] A sealed vial was charged with 3-bromo-2-(4-3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-methyl-N-(l-methylcyclopropyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyridine-4-carboxamide (96 mg, 0.17 mmol, 1.0 eq), ('Bu)2PMeHBF4 (8.46 mg, 34.11 pmol, 0.20 eq), K3PO4 (8.46 mg, 34.11 pmol, 0.20 eq) and cesium pivaloate (12.0 mg, 51.2 pmol, 0.30 eq). All solids were dissolved in toluene (3.4 mL). The mixture was then purged with Ar for 5 min before adding Pd(OAc)2 (3.8 mg, 17.1 pmol, 0.10 eq). Then the reaction mixture was purged again with Ar, the viale was sealed, and the reaction was stirred at 120 °C overnight. The resulting mixture was filtered and the filtrate diluted with EtOAc and water. The two layers were separated and the aqueous phase washed twice with DCM. The organic phases were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was purified by flash chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford 7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[2-(l-methylpyrazol-4-yl)morpholino]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one (74.5 mg, 86.1% yield) as light yellow solid. LC-MS: m / z = 482.2 [M+H]+, ESI pos. Chiral SFC (chiral OZ-H, 5 pm, 250 x 20 mm, 30% MeOH in CO2) afforded two major stereoisomers:

[0900] Isomer 1 (Example 29): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one (22.1 mg, 30.6% yield, 97% purity) as light yellow powder as first eluting isomer. LC-MS: m / z = 482.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0901] Isomer 2 (Example 30): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin-3-one (22.3 mg, 29.3% yield, 92% purity) as light yellow powder as second eluting isomer. LC-MS: m / z = 482.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily. Example 31: (lRS,laSR,7bRS)-7-(4-chloro-2-fhioro-phenyl)-2-methyl-5-[(2SR)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-l-(trifluoromethyl)-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[0902]

[0903] -4-yl)morpholin-4-yl]-N-r2-:-4-carboxamide

[0904]

[0905] 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholino]isonicotinic acid (obtained in Example 11, Step 1, 85 mg, 0.16 mmol, 1.0 eq) was dissolved in DMF (1.4 mL). DIPEA (126.3 mg, 169.1 pL, 0.98 mmol, 6.0 eq) and [2-(trifluoromethyl)cyclopropyl]amine hydrochloride (31.6 mg, 0.20 mmol, 1.2 eq) were added. The reaction mixture was stirred for a few minutes at rt and HATU (2.45 g, 6.44 mmol, 1.0 eq) was added, and the reaction mixture was stirred further at rt until completion. EtOAc / H₂O was added and the two layers separated. The aqueous layers was further washed 3 times with EtOAc. All organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-[2-(trifluoromethyl)cyclopropyl]pyridine-4-carboxamide (126 mg, 89.8% yield) as light yellow solid used as such without further purification in the next step. LC-MS: m / z = 301.6 [M+2H]2+.

[0906]

[0907] :-4-carboxamide

[0908]

[0909] In a 5 mL round-bottomed flask, 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-[2-(trifluoromethyl)cyclopropyl]pyridine-4-carboxamide (64.9 mg, 0.11 mmol, 1.0 eq) was suspended in DMF (2 mL), followed by the addition of NaH (60% dispersion in mineral oil, 12 mg, 0.30 mmol, 2.79 eq), and the resulting suspension was stirred at rt. After 30 min, Mel (152.8 mg, 67.3 pL, 1.08 mmol, 10.0 eq) was added. The reaction mixture was further stirred at rt until reaction completion. The reaction mixture was then quenched with water and diluted with EtOAc. The layers were separated and the aqueous layer washed twice with EtOAc. All organic layers were combined, washed with brine and dried over Na2SO4, then concentrated under reduced pressure. The residue was then purified by flash column chromatography (4g SiO₂) using 0-100% EtOAc in heptane as eluent to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-[2-(trifluoromethyl)cyclopropyl]pyridine-4-carboxamide (35 mg, 47.4% yield) as off-white solid. LC-MS: m / z = 618.2 [M+H]+, ESI pos.

[0910] Step 3: (lRS,laSR,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-r(2SR)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1-l-(trifluoromethyl)-la,7b-dihydro-lH-cycloproparcir2,61naphthyridin-3-one

[0911] A vial was charged with 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-[2-(trifluoromethyl)cyclopropyl]pyridine-4-carboxamide (35 mg, 56.7 pmol, 1.0 eq), PCy3(3.2 mg, 11.4 pmol, 0.20 eq), Cs₂CO₃ (27.7 mg, 85.1 pmol, 1.5 eq), 1-adamantanecarboxylic acid (2.05 mg, 11.35 pmol, 0.200 eq) and toluene (1.1 mL). The resulting mixture was purged with Ar for several minutes before adding Pd2(dba)3(5.2 mg, 5.67 pmol, 0.10 eq). The vial was sealed and the reaction mixture was stirred at 120 °C overnight. The reaction mixture was then diluted with EtOAc and water. The two layers were separated and the aqueous layer further washed with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was then purified by flash column chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(l-methylpyrazol-4-yl)morpholino]-l-(trifluoromethyl)-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (15.6 mg, 41.0% yield) as light yellow lyoph powder as a complex mixture of stereoisomers. LC-MS: m / z = 536.3 [M+H]+, ESI pos.

[0912] Example 32: ( 1 aSR,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [(2 SR)-2-( 1 -methylpyrazol-4-yl)morpholin-4-yl] spirof 1 a,7b-dihydrocyclopropa[c] [2,6]naphthyridine- 1,1'-cy clopropane] -3 -one

[0913]

[0914] in-4-yll-N- ine-4-carboxamide

[0915]

[0916] To a round-bottom flask was added 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholino]isonicotinic acid (obtained in Example 11, Step 1, 150 mg, 0.30 mmol, 1.0 eq), HATU (138.1 mg, 0.36 mmol, 1.2 eq), DIPEA (234.6 mg, 314.1 pL, 1.82 mmol, 6.0 eq) and DMF (2.6 mL). The resulting mixture was cooled to 0 °C and stirred at this temperature for 30 min. Then spiro[2.2]pentan-2-ylamine hydrochloride (54.3 mg, 0.45 mmol, 1.5 eq) was added and the resulting mixture was stirred for 2 h at rt. The reaction mixture was then diluted in EtOAc and water and the two layers were separated. The aqueous layer was further washed 3 times with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was then purified by flash chromatography to afford (silica gel, 0 - 100% EtOAc in heptane) to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-spiro[2.2]pentan-2-yl-pyridine-4-carboxamide (116 mg, 62.9% yield) as off-white solid. LC-MS: m / z = 562.3 [M+H]+, ESI pos.

[0917] 2: 3-bromo-2-(4-chloro-2-fluoro- i-N-methvl-6-12-( 1 -:

[0918]

[0919] 4-yl]-N-spiroF2.2]pentan-2-yl-Dyridine-4-carboxamide

[0920]

[0921] In a 5 mL round-bottom flask was added 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-spiro[2.2]pentan-2-yl-pyridine-4-carboxamide (101.5 mg, 0.18 mmol, 1.0 eq) to a suspension of NaH (60% dispersion in mineral oil, 10.9 mg, 0.27 mmol, 1.5 eq) in DMF (1.8 mL) and the resulting mixture was cooled down to 0 °C. After 60 min, Mel (256.9 mg, 113.2 pL, 1.81 mmol, 10.0 eq) was added. The reaction mixture was then stirred at rt until reaction completion after which it was quenched with water and diluted with EtOAc. The layers were separated and the aqueous layer was washed twice with EtOAc. The organic layers were combined, washed with brine and dried over Na2SO4and concentrated under reduced pressure. The residue was then purified by flash chromatography to afford 3-bromo-2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-spiro[2.2]pentan-2-yl-pyridine-4-carboxamide (86.6 mg, 66.6% yield) as off-white solid. LC-MS: m / z = 576.1[M+H]+, ESI pos.

[0922] 4-chloro-2-fluoro-

[0923]

[0924] i-2-methvl-5-|

[0925]

[0926] -4-

[0927]

[0928] a, 7b -di

[0929]

[0930] -3 -one A vial was charged with 3-bromo-2-(4-chloro-2-fhioro-phenyl)-N-methyl-6-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]-N-spiro[2.2]pentan-2-yl-pyridine-4-carboxamide (81 mg, 0.14 mmol, 1.0 eq) in toluene (2.8 mL) and purged with Ar for a few minutes. 1 -adamantanecarboxylic acid (5.1 mg, 28.2 pmol, 0.2 eq), Cs₂CO₃ (68.9 mg, 0.21 mmol, 1.5 eq), PCy3(7.9 mg, 28.2 pmol, 0.2 eq) were then added at once. Then the resulting mixture was purged with Ar for a few more seconds before adding Pd2(dba)3(12.9 mg, 14.1 pmol, 0.1 eq). The resulting mixture was heated to 120 °C and stirred at this temperature overnight. The reaction mixture was diluted with EtOAc and water. The two layers were separated and the aqueous layer further washed with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude was then purified by flash chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford (laSR,7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2SR)-2-(l-methylpyrazol-4-yl)morpholin-4-yl] spirof 1 a,7b-dihydrocyclopropa[c] [2,6]naphthyridine- 1,1'-cyclopropane]-3-one (4.6 mg, 5.3% yield) as off-white lyoph solid as a complex mixture of stereoisomers. LC-MS: m / z = 494.17 [M+H]+, ESI pos.

[0931] Examples 33-36: re / -(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one and re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one and rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one and rel- (2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one

[0932]

[0933] Example 33 Example 34 Example 35 Example 36 1: methyl 2-chloro-6-(4-chloro-2-fluoro-

[0934]

[0935] :-4-carboxylate

[0936]

[0937] methyl 2,6-dichloropyrimidine-4-carboxylate (1.0 g, 4.8 mmol, 1.0 eq) was dissolved in 1,4-dioxane (32 mL) and (4-chloro-2-fluoro-phenyl)boronic acid (842.3 mg, 4.83 mmol, 1.0 eq) and Cs₂CO₃ (4.7 g, 14.5 mmol, 3.0 eq) were added at rt. The mixture was degassed before PdCl₂(dppf)·CH₂Cl₂ (394.5 mg, 483.1 pmol, 0.10 eq) was added. Then, the reaction was stirred for 2 hours at rt. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layers were dried over MgSO₄ and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 0 - 50 % EtOAc in heptane) to obtain the title compound methyl 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate (983 mg, 59.7% yield) as light yellow solid. LC-MS: m / z = 301.02 [M+H]+, ESI pos.

[0938] 2: methyl 6-(4-chloro-2-fluoro-

[0939]

[0940] yl]pyrimidine-4-carboxylate

[0941]

[0942] 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate (812 mg, 2.7 mmol, 1.0 eq) was dissolved in DMF (13.4 mL), racemic 2-(l-methylpyrazol-4-yl)morpholine (Intermediate Al, 496.0 mg, 2.97 mmol, 1.1 eq) and DIPEA (697.1 mg, 942.0 pL, 5.39 mmol, 2.0 eq) were added at rt. The reaction mixture was stirred for 2 hours at 110 °C. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layers were dried over MgSO₄ and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 0 -50% EtOAc in heptane) to afford methyl 6-(4-chloro-2-fluoro-phenyl)-2-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (630 mg, 54.1% yield) as light yellow solid. LC-MS: m / z = 432.17 [M+H]+, ESI pos.

[0943] mo-6-(4-chloro-2-fluoro-

[0944]

[0945] -4-vl)morpholin-4- oxylate

[0946]

[0947] methyl 6-(4-chloro-2-fluoro-phenyl)-2-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (630 mg, 1.46 mmol, 1.0 eq) was dissolved in DCM (10 mL) andNBS (285.6 mg, 1.6 mmol, 1.1 eq) was added and the mixture was stirred overnight at rt. The reaction mixture was diluted with aq. sat. NaHCO3and the aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 0 - 100% EtOAc in heptane) to afford methyl 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (609 mg, 69.5% yield) as light yellow solid. LC-MS: m / z = 512.1 [M+H]+, ESI pos.

[0948] Step 4: 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[2-(l-methylpyrazol-4-vl)morpholin-4-vl]pvrimidine-4-carboxamide

[0949]

[0950] To a solution of methyl 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (300 mg, 0.59 mmol, 1.0 eq) in THF (5 mL) was added at rt a solution of LiOH·H₂O (37.0 mg, 0.88 mmol, 1.5 eq) in water (0.5 mL) and the mixture was stirred at rt for 1.5 h, and then warme to 50 °C for 2 h. Additional LiOH·H₂O (24.7 mg, 0.59 mmol, 1.0 eq) in water (0.35 mL) was added and stirring at 50 °C was continued for 1 h to give complete conversion. The mixture was concentrated in vacuo to give crude lithium salt as yellow solid. The crude intermediate was dissolved in DMF (5 mL) and treated with DIPEA (227.7 mg, 307.8 pL, 1.76 mmol, 3.0 eq), HATU (290.4 mg, 0.76 mmol, 1.3 eq) and N-methylcyclopropanamine hydrochloride (94.8 mg, 0.88 mmol, 1.5 eq) and the resulting mixture was stirred at rt for 16 h. Further N-methylcyclopropanamine hydrochloride (9.5 mg, 88.1 pmol, 0.15 eq), DIPEA (22.8 mg, 30.8 pL, 0.18 mmol, 0.3 eq) and HATU (33.5 mg, 88.1 pmol, 0.15 eq) was added and stirring was continued for 2 h. The reaction mixture was treated with aq. sat. NaHCO₃ (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 70% EtOAc / EtOH (3:1) in heptane) to give 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide (148 mg, 45.8% yield) as light yellow foam. LC-MS: m / z = 549.3 [M+H]+, ESI pos.

[0951] Step 5: re / -(2R*,4R*)-H-(4-chloro-2-fluoro-phenyl)-5-methyl-9-r(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclor5.4.0.02’4]undeca-l(l l\7,9-trien-6-one and rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-r(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclor5.4.0.02’4]undeca-l(l l\7,9-trien-6-one and re / -(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-r(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl1-5,8,10-triazatricyclor5.4.0.02’4]undeca-l(l l\7,9-trien-6-one and re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-r(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclor5.4.0.02’4]undeca-l(l l\7,9-trien-6-one

[0952] A reaction tube was filled with 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide (138 mg, 0.25 mmol, 1.0 eq), Cs₂CO₃ (122.7 mg, 0.38 mmol, 1.5 eq), PCy3(7.0 mg, 25.1 pmol, 0.1 eq) and 1-adamantanecarboxylic acid (13.6 mg, 75.3 pmol, 0.3 eq) and toluene (4 mL). The mixture was degassed for 10 min by bubbling argon through the mixture. After addition of Pd(dba)2 (7.2 mg, 12.6 pmol, 0.05 eq) degassing was repeated for 5 min. The tube was sealed and heated to 120 °C for 6 h. Another portion of PCy3(7. 0 mg, 25.1 pmol, 0.1 eq), 1 -adamantanecarboxylic acid (13.6 mg, 75.3 pmol, 0.3 eq), Cs₂CO₃ (122.7 mg, 0.38 mmol, 1.5 eq) and Pd(dba)2 (7.2 mg, 12.6 pmol, 0.05 eq) was added. The mixture was degassed once more as described and the tube was resealed and heated to 120 °C for an additional 16 h. The mixture was treated with aq. sat. NaHCO₃ (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10-70% EtOAc / EtOH (3:1) in heptane) to yield 1 l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[2-(l-methylpyrazol-4-yl)morpholino]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one (35.6 mg, 30.3% yield ) as yellow oil as a mixture of stereoisomers. LC-MS: m / z = 469.4 [M+H]+, ESI pos. Chiral SFC (Chiral AD-H, 5 pm, 250x20 mm, 30% EtOH in CO2) afforded the 4 separated stereoisomers.

[0953] Isomer 1 (Example 33): re / -(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one (6.4 mg, 18% yield) as yellow oil as first eluting isomer. LC-MS: m / z = 469.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0954] Isomer 2 (Example 34): re / -(2S*,4S*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one (7.1 mg, 20% yield) as yellow oil as second eluting isomer. LC-MS: m / z = 469.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0955] Isomer 3 (Example 35): re / -(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one (6.6 mg, 19% yield) as yellow oil as third eluting isomer. LC-MS: m / z = 469.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0956] Isomer 4 (Example 36): re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one (8.1 mg, 23% yield) as yellow oil as fourth eluting isomer. LC-MS: m / z = 469.4 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0957] Example 37 and 38: re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one and re / -(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one

[0958]

[0959] Example 37 Example 38 i-2-hydroxy-4-oxo-but-2-enoate

[0960]

[0961] To a solution of l-(4-chloro-2-fluoro-phenyl)ethanone (2.00 g, 11.6 mmol, 1.0 eq) in TBME (20 mL) was added at 5 °C dropwise over the course of 15 min, 1 M LiHMDS (IM in THF / ethylbenzene, 11.6 mL, 11.6 mmol, 1.0 eq). Gas evolution started immediately and stirring at 5 °C was continued for 30 min. Then dimethyl oxalate (1.71 g, 14.49 mmol, 1.250 eq) was added at 5 °C in 2 portions resulting in a temperature increase to 6 °C. The resulting mixture was tehn allowed to warm to rt and stirred for 1.5 h. The mixture was acidified with 1 M aq. HC1 (23 mL) while cooling with an ice / water-bath to keep temperature below 30 °C. The thick mixture was vigorously stirred for 5 min, the solids filtered off, washed with water (1 x 10 mL) and TBME (2 x 15 mL) and dried under reduced pressure to give 4-(4-chloro-2-fhioro-phenyl)-2-hydroxy-4-oxo-but-2-enoate (1.15 g, 38.4% yield) as light yellow solid. The filtrate was transferred into a separation funnel and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a second crop of methyl 4-(4-chloro-2-fhioro-phenyl)-2 -hydroxy -4-oxo-but-2-enoate (1.65 mg, 55% yield) as yellow waxy solid. LC-MC: m / z = 259.1 [M+H]+, ESI pos.

[0962] Step 2: 4-(4-chloro-2-fluoro-phenyl)-2-hydroxy-4-keto-but-2-enoic acid

[0963]

[0964] To a solution of methyl 4-(4-chloro-2-fluoro-phenyl)-2-hydroxy-4-oxo-but-2-enoate (1.65 g, 6.38 mmol, 1.0 eq) in MeOH (25 mL) and THF (25 mL) was added at rt LiOH·H2O (803.2 mg, 19.14 mmol, 3.0 eq) in H2O (5 mL). The mixture was stirred at rt for 30 min after which the mixture was concentrated in vacuo. The aqueous residue was diluted with aq. 0.1 N NaOH (50 mL) and washed with EtOAc (2 x 50 mL). The aqueous layer was acidified with with 1 M HC1 (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 4-(4-chloro-2-fluoro-phenyl)-2-hydroxy-4-keto-but-2-enoic acid (1.09 g, 69.9% yield) as yellow solid. LC-MS: 100 m / z = 243.1 [M-H]', ESI neg. Step 3: 6-(4-chloro-2-fluoro-phenyl)-2-hydroxy-pynmidine-4-carboxyhc acid

[0965]

[0966] To a suspension of 4-(4-chloro-2-fluoro-phenyl)-2-hydroxy-4-keto-but-2-enoic acid (1.05 g, 4.29 mmol, 1.0 eq) in toluene (110 mL) was added urea (644.5 mg, 10.73 mmol, 2.5 eq) followed by the addition of H2SO4 (168.4 mg, 92.03 pL, 1.72 mmol, 0.40 eq). The suspension was heated to 110 °C overnight. The precipitate was filtered off, washed with cold MeOH (2x 15 mL) and dried in vacuo to yield 6-(4-chloro-2-fluoro-phenyl)-2-hydroxy-pyrimidine-4-carboxylic acid (720 mg, 50% yield) as an off-white solid. LC-MS: m / z = 269.1 [M+H]+, ESI pos.

[0967] Step 4: 6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carb oxami de

[0968]

[0969] To a suspension of 6-(4-chloro-2-fluoro-phenyl)-2-hydroxy-pyrimidine-4-carboxylic acid (100 mg, 0.37 mmol, 1.0 eq) in DMF (2 mL) was added N-methylcyclopropanamine hydrochloride (48.1 mg, 0.45 mmol, 1.2 eq), DIPEA (144.3 mg, 195.0 pL, 1.12 mmol, 3.0 eq) followed by TBTU (179.3 mg, 0.56 mmol, 1.5 eq) and the reaction mixture was stirred for 30 min at rt. Further DIPEA (48.1 mg, 65.0 pL, 0.37 mmol, 1.0 eq), N-methylcyclopropanamine hydrochloride (16.0 mg, 0.15 mmol, 0.4 eq) and TBTU (59.8 mg, 0.19 mmol, 0.50 eq) was added and stirring was continued for Ih. A third portion of DIPEA (33.7 mg, 45.5 pL, 0.26 mmol, 0.70 eq) and N-methylcyclopropanamine hydrochloride (14.0 mg, 0.13 mmol, 0.35 eq) was added and stirring was continued for 30 min. The mixture was diluted with 0.5 M aq. HC1 (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 70% EtOAc / EtOH (3:1) in heptane) to yield 6-(4-chloro-2-fhioro-phenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (20 mg, 16.7% yield) as a white solid. LC-MS: m / z = 322.2 [M+H]+, ESI pos. Step 5: 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide

[0970]

[0971] To a suspension of 6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (145 mg, 0.45 mmol, 1.0 eq) in DMF (2.9 mL) was added at 5 °C NBS (96.3 mg, 0.54 mmol, 1.20 eq). The mixture was stirred for 15 min at 5 °C, then the ice bath was removed and the reaction mixture was further stirred for 1.5 h at rt. The mixture was treated with 0.1 M aq. HC1 (40 mL) and extracted with EtOAc (4 x 40 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The light yellow sticky residue was suspended in CH3CN (3 mL), the solid was filtered off, washed with CH3CN (2 x 1 mL) and dried to give 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (113 mg, 58.8% yield) as off-white solid. LC-MS: m / z = 400.1 [M+H]+, ESI pos.

[0972] Step 6: 5-bromo-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carb oxami de

[0973]

[0974] In a reaction tube, 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (587 mg, 1.47 mmol, 1.0 eq) was treated POCI3 (22.47 g, 13.66 mL, 146.5 mmol, 100.0 eq). The tube was inerted, sealed and heated to 110 °C for 30 min. Then, the reaction mixture was concentrated in vacuo. The residue was treated with aq. sat. NaHCO₃ (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 - 25 % EtOAc / EtOH (3: 1) in heptane) to give 5-bromo-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (288 mg, 42.7% yield) as light yellow oil. LC-MS: m / z = 418.0 [M+H]+, ESI pos. Step 7: 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-<2R,4S)-2-(l-

[0975]

[0976] methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide

[0977]

[0978] A reaction tube was charged with 5-bromo-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (183 mg, 0.45 mmol, 1.0 eq) and XantPhos-Pd-G3 (45.12 mg, 44.6 pmol, 0.10 eq). The tube was sealed with a septum and degassed by evacuation and backfilling with nitrogen (3 x). Then was added THF (0.65 mL) and degassing was done for 5 min by bubbling nitrogen through the mixture after a freshly prepared bromo-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc solution (Intermediate A3, ca. 0.36 M in THF, 1.7 mL, 0.61 mmol, 1.4 eq) was added. The reaction mixture was heated to 50 °C for 30 min and then allowed to be stirred at rt for 16 h. The mixture was siluted with sat. aq. NaHCO₃ (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 70% EtOAc / EtOH (3:1) in heptane) to give 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (178 mg, 73.7% yield) as light yellow foam as a mixture of stereoisomers. LC-MS: m / z = 548.2 [M+H]+, ESI pos. Separation of the stereoisomers by chiral SFC (chiral OJ-H, 5 pm, 250 x 20 mm, 10% MeOH in CO2) yielded both cis-configured enantiomers.

[0979] Isomer 1: 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (66 mg, 37.1% yield) as colorless oil as first eluting isomer. LC-MS: m / z = 548.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0980] Isomer 2: 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (58.4 mg, 32.1% yield) as colorless oil as second eluting isomer. LC-MS: m / z = 548.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0981] Step 8: re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-rre / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclor5.4.0.02’4]undeca-l(l l\7,9-tri end-one and re / -(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-rre / -(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl1-5,8,10-triazatricyclol5.4.0.02’41undeca-l(l 117,9-trien-6-one

[0982] A reaction tube was filled with 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[ / 'c -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (Isomer 1 from Step 7, 110 mg, 0.20 mmol, 1.0 eq), Cs₂CO₃ (98.0 mg, 0.30 mmol, 1.50 eq), PCy3(5.6 mg, 20.0 pmol, 0.10 eq) and 1 -adamantanecarboxylic acid (10.8 mg, 0.061 pmol, 0.30 eq) and toluene (5.4 mL). The resulting mixture was degassed for 10 min by bubbling argon. After addition of Pd(dba)2 (5.8 mg, 10.0 pmol, 0.05 eq) degassing was repeated for 5 min. The tube was sealed and heated to 120 °C for 5 h. A second portion of Cs₂CO₃ (98.0 mg, 0.30 mmol, 1.50 eq), PCy3 (5.6 mg, 20.0 pmol, 0.10 eq) and 1 -adamantanecarboxylic acid (10.8 mg, 0.061 pmol, 0.30 eq) and Pd(dba)2 (5.8 mg, 10.0 pmol, 0.05 eq) was added, the tube degassed with argon, sealed and heated to 120 °C for an additional 16 h. The reaction mixture was then treated with aq. sat. NaHCO₃ (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20 - 100% EtOAc / EtOH (3:1) in heptane) to give ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S,4R)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one (25 mg, 27% yield) as colorless oil as a mixture of diastereoisomers. LC-MS: m / z = 468.2 [M+H]+, ESI pos. Separation of the diastereoisomers by chiral SFC (chiral SZ, 5 pm, 250 x 20 mm, 35% MeOH in CO2) yields: Isomer 1 (Example 37): re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one (11 mg, 44% yield) as off-white foam as first eluting isomer. LC-MS: m / z = 468.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0983] Isomer 2 (Example 38): re / -(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one (10.6 mg, 42.4% yield) as off-white foam as second eluting isomer. LC-MS: m / z = 468.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0984] Example 39 and 40: re / -(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one and re / -(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l 1), 7, 9-tri end-one

[0985]

[0986] Example 39 Example 40

[0987] The title compounds were obtained in analogy to Examples 37 and 38, Step 8 using 5-bromo-6-(4-chloro-2-fluoro-phenyl)-N-cyclopropyl-N-methyl-2-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (Isomer 2 from Step 7). Chiral separation by SFC (chiral SZ, 5 pm, 250 x 20 mm, 40% MeOH in CO₂) afforded two stereoisomers:

[0988] Isomer 1 (Example 39): re / -(2S*,4S*)-ll-(4-chloro-2-fhioro-phenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one (14.6 mg, 34.8% yield) as off-white foam as first eluting isomer. LC-MS: m / z = 468.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0989] Isomer 2 (Example 40): reZ-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[reZ-(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one (14.5 mg, 34.5% yield) as off-white foam as second eluting isomer. LC-MS: m / z = 468.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[0990] Examples 41 and 42: re / -(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one and rel-(2R*,4R*)-1 l-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-tri azatri cyclo[5.4.0.02,4]undeca- 1 (7), 8, 10-trien-6-one

[0991]

[0992] Example 41 Example 42 Step 1: 4-(4-chlorophenyl)-2-hydroxy-4-keto-but-2-enoic acid methyl ester

[0993]

[0994] At 5 °C, NaH (60% dispersion in mineral oil, 1.94 g, 48.52 mmol, 1.5 eq) was suspended in THF (45 mL) and dimethyl oxalate (4.2 g, 35.58 mmol, 1.1 eq) was added in portions. The resulting mixture was stirred for 15 min at 5 °C, followed by slow addition of l-(4-chlorophenyl)ethanone (5 g, 4.2 mL, 32.34 mmol, 1.0 eq) in THF (15 mL). After stirring at 70 °C overnight, the reaction mixture was treated with 1 M aq. HC1 (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0 - 25% EtOAc in heptane) to afford 4-(4-chlorophenyl)-2-hydroxy-4-keto-but-2-enoic acid methyl ester (3.16 g, 39% yield) as yellow solid. LC-MS: m / z = 241.1 [M+H]+, ESI pos.

[0995] Step 2: 4-(4-chlorophenyl)-2-hydroxy-4-keto-but-2-enoic acid

[0996]

[0997] To a suspension of 4-(4-chlorophenyl)-2-hydroxy-4-keto-but-2-enoic acid methyl ester (3.11 g, 12.92 mmol, 1.0 eq) in MeOH (30 mL) was added LiOH-H2O (1.63 g, 38.77 mmol, 3.0 eq) in H2O (10 mL). After stirring at rt for 5 h, the reaction mixture was treated with 0.5 M aq. HC1 (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 4-(4-chlorophenyl)-2-hydroxy-4-keto-but-2-enoic acid (2.86 g, 96% yield) as yellow solid. LC-MS: m / z = 225.0 [M-H]", ESI neg. Step 3: 6-(4-chlorophenyl)-2-hydroxy-pyrimidine-4-carboxylic acid

[0998]

[0999] To a suspension of 4-(4-chlorophenyl)-2-hydroxy-4-keto-but-2-enoic acid (2.8 g, 12.36 mmol, 1.0 eq) in toluene (140 mL), urea (1.86 g, 30.89 mmol, 2.5 eq) was added, followed by the addition of H2SO4 (485 mg, 265 pL, 4.94 mmol, 0.4 eq). The reaction mixture was stirred at 110 °C overnight. The precipitate was filtered off, washed with cold MeOH (2 x 70 mL) and dried in vacuo to afford 6-(4-chlorophenyl)-2-hydroxy-pyrimidine-4-carboxylic acid (3.15 g, 76% yield, 75% purity) as light yellow solid. LC-MS: m / z = 251.1 [M+H]+, ESI pos.

[1000] i-N-cvclopropvl-2-hvdroxv-N-methvl-pvrimidine-4-carboxamide

[1001]

[1002] To a suspension of 6-(4-chlorophenyl)-2-hydroxy-pyrimidine-4-carboxylic acid (1.82 g, 7.25 mmol, 1.0 eq) in DMF (36 mL), DIPEA (4.21 g, 5.7 mL, 32.6 mmol, 4.5 eq) was added, followed by addition ofN-methylcyclopropanamine hydrochloride (935 mg, 8.69 mmol, 1.2 eq). T3P (50% solution in DMF, 9.22 g, 14.49 mmol, 2.0 eq) was added dropwise, resulting in a temperature rise to 35 °C, which was stabilized with the help of a water bath. The reaction mixture was stirred at rt for 30 min, then quenched with 0.5 M aq. HC1 (200 mL) and extracted with EtOAc (5 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was suspended in 30 mL of Et2O, filtered and the mother cake was washed with Et2O (3 x 10 mL) and dried in vacuo to afford 6-(4-chlorophenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (1.81 g, 74% yield) as light yellow solid. LC-MS: m / z = 304.1 [M+H]+, ESI pos.

[1003] Step 5: 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carb oxami de

[1004]

[1005] To a suspension of 6-(4-chlorophenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (1.81 g, 5.96 mmol, 1.0 eq) in DMF (36 mL) was added NBS (1.27 g, 7.15 mmol, 1.2 eq) at 5 °C. The reaction mixture was stirred for 15 min at 5 °C. The cooling bath was removed and the reaction allowed to stir at rt for 30 min. The reaction was then treated with 0.1 M aq. HC1 (250 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was suspended in CH3CN (20 mL), filtered, and the solid was washed with CH3CN (3 x 6 mL) and dried in vacuo to afford 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (1.41 g, 62% yield) as light yellow solid. LC-MS: m / z = 382.1 [M+H]+, ESI pos.

[1006] Step 6: 5-bromo-2-chloro-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carb oxami de

[1007]

[1008] To a reaction tube were added 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-2-hydroxy-N-methyl-pyrimidine-4-carboxamide (700 mg, 1.83 mmol, 1.0 eq) and POCI3 (14.03 g, 8.53 mL, 91.47 mmol, 50.0 eq). The reaction tube was inerted with argon and sealed. The reaction mixture was stirred at 110 °C for 2 h and then concentrated under reduced pressure. The resulting residue was treated with saturated aqueous NaHCO₃ (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0 - 30% EtOAc / EtOH (3:1) in heptane) to afford 5-bromo-2-chloro-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (635 mg, 83% yield) as light brown solid. LC-MS: m / z = 400.1 [M+H]+, ESI pos.

[1009] Step 7: 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-r(2S)-2-(l-methylpyrazol-4-yl)morpholino]pyrimidine-4-carboxamide

[1010]

[1011] In a reaction tube, to a suspension of 5-bromo-2-chloro-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (200 mg, 0.50 mmol, 1.0 eq) in 1,4-dioxane (8 mL), were added (2S)-2-(l-methylpyrazol-4-yl)morpholine (Intermediate (+)-Al, 100 mg, 0.60 mmol, 1.2 eq) and Cs₂CO₃ (487 mg, 1.5 mmol, 3.0 eq). The reaction mixture was degassed by bubbling argon through for 10 min. Then, Pd2(dba)3(22.8 mg, 24.9 pmol, 0.05 eq) and XantPhos (28.9 mg, 49.9 pmol, 0.1 eq) were added and degassing was repeated for 5 min. The tube was sealed and the reaction mixture was stirred at 100 °C for 1 h. The mixture was then treated with saturated aqueous NaHCO₃ (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by flash column chromatography (silica gel, 0 - 40% EtOAc / EtOH (3:1) in heptane) to afford 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]pyrimidine-4-carboxamide (250 mg, 88% yield) as light yellow foam. LC-MS: m / z = 531.2 [M+H]+, ESI pos.

[1012]

[1013] 5-Bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]pyrimidine-4-carboxamide (100 mg, 0.19 mmol, 1.0 eq), Cs₂CO₃ (92 mg, 0.28 mmol, 1.5 eq), PCy3 (5.3 mg, 18.8 pmol, 0.1 eq) and 1 -adamantanecarboxylic acid (10.2 mg, 56.4 pmol, 0.3 eq) were placed to reaction tube. Toluene (3 mL) was added and reaction mixture was degassed by bubbling argon through for 10 min. Pd(dba)2 (5.4 mg, 9.4 pmol, 0.05 eq) was added and degassing was repeated for 5 min. Reaction tube was sealed and reaction mixture was stirred at 120 °C for 5 h. A second portion of Cs₂CO₃ (92 mg, 0.28 mmol, 1.5 eq), PCy3 (5.3 mg, 18.8 pmol, 0.1 eq) and 1 -adamantanecarboxylic acid (10.2 mg, 56.4 pmol, 0.3 eq) were added. The reaction mixture was degassed by bubbling argon through for 10 min, Pd(dba)2 (5.4 mg, 9.4 pmol, 0.05 eq) was added and degassing was repeated for 5 min. The reaction tube was sealed and the reaction mixture was stirred at 120 °C overnight. Then the reaction mixture was treated with sat. aq. NaHCO₃ (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 20 - 90 % EtOAc / EtOH (3:1) in heptane). A second purification by reversed-phase chromatography (Cl 8, 20 - 90% CH3CN in H2O) afforded 11 -(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]-5,8,10-triazatri cyclo[5.4.0.02,4]undeca- 1(7), 8, 10-trien-6-one (6 mg, 7% yield) as a yellow oil as a mixture of stereoisomers. LC-MS: m / z = 451.3 [M+H]+, ESI pos. Separation of the diastereoisomeric mixture by chiral SFC (chiral OJ-H, 5 pm, 250 x 20 mm, 20% MeOH in CO2) yielded: Isomer 1 (Example 41): re / -(2S*,4S*)-l l-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (8.5 mg, 33%) as yellow solid as first eluting isomer (8.3 mg, 32% yield) as yellow solid. LC-MS: m / z = 451.2 [M+H]+, ESI pos. 'HNMR (300 MHz, CDC13) 8 = 0.47 - 0.55 (m, 1 H), 1.32 - 1.45 (m, 1 H), 2.14 (td, J = 8.92, 6.15 Hz, 1 H), 3.10 - 3.30 (m, 3 H), 3.26 (s, 3H), 3.75 (td, J = 11.48, 2.62 Hz, 1 H), 3.88 (s, 3 H), 4.05 (br d, J = 10.07 Hz, 1 H), 4.55 (dd, J = 10.28, 2.62 Hz, 1 H), 4.69 (br d, J= 12.89 Hz, 1 H), 4.84 (br d, J = 13.10 Hz, 1 H), 7.42 (s, 1 H), 7.47 (d, J = 8.46 Hz, 2 H), 7.53 (s, 1 H), 7.83 (d, J = 8.66 Hz, 2 H). *The stereochemistry was assigned arbitrarily. Isomer 2 (Example 42): re / -(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (8.5 mg, 33%) as yellow solid as second eluting isomer. LC-MS: m / z = 451.2 [M+H]+, ESI pos. 'HNMR (300 MHz, CDCl3) 6 = 0.52 (ddd, J=5.89, 4.99, 4.03 Hz, 1 H), 1.32 - 1.45 (m, 1 H), 2.14 (td, J = 8.97, 6.04 Hz, 1 H), 3.10 - 3.30 (m, 3 H), 3.26 (s, 3H), 3.76 (td, J = 11.48, 2.82 Hz, 1 H), 3.89 (s, 3 H), 4.03 - 4.10 (m, 1 H), 4.53 (dd, J= 10.28, 2.82 Hz, 1 H), 4.69 (br d, J= 13.10 Hz, 1 H), 4.84 (br d, J = 13.10 Hz, 1 H), 7.42 (s, 1 H), 7.43 - 7.51 (m, 2 H), 7.53 (s, 1 H), 7.79 - 7.86 (m, 2 H). *The stereochemistry was assigned arbitrarily.

[1014] Examples 43 and 44: re / -(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one and re / -(2R*,4R*)-l l-(4-chlorophenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one

[1015]

[1016] -N-methvl-2-lre / -(2R*,4S*)-2-(l-i

[1017]

[1018] -4-vl)tetrahvdropvran-4-yllpyrimidine-4-carboxamide

[1019]

[1020] A reaction tube was charged with 5-bromo-2-chloro-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (prepared in Examples 41 - 42, Step 6, 300 mg, 0.75 mmol, 1.0 eq) and XantPhos-Pd-G3 (77.3 mg, 74.8 pmol, 0.1 eq). The tube was sealed with a septum and purged with N2. THF (1 mL) was added and the reaction mixture was degassed by bubbling N2 through for 5 min. Freshly prepared bromo-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc (Intermediate A3, ca. 0.36 M solution in THF, 2.9 mL, 1.05 mmol, 1.4 eq) was added via syringe. The reaction mixture was stirred at 50 °C for 30 min and then at rt overnight. Sat. aq. NaHCO₃ (25 mL) was added and the product extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 70 % EtOAc / EtOH (3:1) in heptane) to afford 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (235 mg, 53% yield) as light yellow foam as a mixture of stereoisomers. LC-MS: m / z = 530.2 [M+H]+, ESI pos. Separation of the stereoisomers by chiral SFC (chiral IA, 5 pm, 250 x 20 mm, 25% MeOH in CO2 + 0.2% DEA) yielded both cis-enanti omers:

[1021] Isomer 1: 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (86 mg, 22% yield) as light yellow foam as first eluting isomer, m / z = 530.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1022] Isomer 2: 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (84 mg, 21% yield) as light yellow foam as second eluting isomer. LC-MS: m / z = 530.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1023] Step 2: re / -(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-lre / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl1-5,8,10-triazatricyclol5.4.0.02’41undeca-l(7),8,10-trien-6-one and rel- -4-

[1024]

[1025] -6-one

[1026] The title compound was prepared in analogy to ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (Examples 25 and 26, Step 8) using 5-bromo-6-(4-chlorophenyl)-N-cyclopropyl-N-methyl-2-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidine-4-carboxamide (Isomer 1 from Step 1, 50 mg, 94.2 pmol, 1.0 eq), Cs₂CO₃ (46 mg, 0.14 mmol, 1.5 eq), PCy3(2.6 mg, 9.4 pmol, 0.1 eq), 1 -adamantanecarboxylic acid (5.1 mg, 28.3 pmol, 0.3 eq) and toluene (2.5 mL) yielding 1 l-(4-chlorophenyl)-5-methyl-9-[(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (6.5 mg, 15% yield) as yellow oil as a mixture of diastereoisomers. LC-MS: m / z = 450.3 [M+H]+, ESI pos. Separation of the diastereoisomers by chiral SFC (chiral OJ-H, 5 pm, 250 x 20 mm, 15% MeOH in CO2) yielded:

[1027] Isomer 1 (Example 43): re / -(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5, 8,10-tri azatricyclo[5.4.0.02,4]undeca- 1(7), 8,10-tri en-6-one (6.5 mg, 33% yield) as light yellow oil as first eluting isomer. LC-MS: m / z = 450.2 [M+H]+, ESI pos. 'H NMR (300 MHz, CDCI3) 8 = 0.64 (td, J = 5.54, 4.23 Hz, 1 H), 1.54 (ddd, J = 9.72, 6.40, 5.24 Hz, 1 H), 1.97 - 2.16 (m, 3 H), 2.23 - 2.35 (m, 2 H), 3.19 - 3.27 (m, 1 H), 3.31 (s, 3 H), 3.50 (tt, J= 11.91, 3.80 Hz, 1 H), 3.75 (td, J= 11.79, 2.62 Hz, 1 H), 3.87 (s, 3 H), 4.17 - 4.24 (m, 1 H), 4.52 (dd, J = 11.38, 1.91 Hz, 1 H), 7.38 (s, 1 H), 7.48 (s, 1 H), 7.49 - 7.55 (m, 2 H), 7.83 -7.93 (m, 2 H). *The stereochemistry was assigned arbitrarily.

[1028] Isomer 2 (Example 44): re / -(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5, 8,10-tri azatri cyclo[5.4.0.02,4]undeca- 1(7), 8,10-tri end-one (5.8 mg, 29% yield) as light yellow oil as second eluting isomer. LC-MS: m / z = 450.2 [M+H]+, ESI pos. 'HNMR (300 MHz, CDCI3) 6 = 0.64 (td, J = 5.49, 4.13 Hz, 1 H), 1.49 - 1.58 (m, 1 H), 1.96 - 2.19 (m, 3 H), 2.22 - 2.34 (m, 2 H), 3.20 - 3.27 (m, 1 H), 3.31 (s, 3 H), 3.50 (tt, J = 11.86, 3.75 Hz, 1 H), 3.76 (td,.7 = 11.89, 2.42 Hz, 1 H), 3.84 (s, 3 H), 4.18 - 4.26 (m, 1 H), 4.51 (dd, J = 11.28, 2.01 Hz, 1 H), 7.36 (s, 1 H), 7.45 (s, 1 H), 7.46 - 7.54 (m, 2 H), 7.85 - 7.91 (m, 2 H). *The stereochemistry was assigned arbitrarily.

[1029] Examples 45 and 46: re / -(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5, 8,10-tri azatri cyclo[5.4.0.02,4]undeca- 1(7), 8,10-tri end-one and re / -(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5, 8,10-tri azatri cyclo[5.4.0.02,4]undeca- 1(7), 8,10-tri en-6-one

[1030]

[1031] Example 45 Example 46

[1032] The two title compounds were prepared in analogy to Examples 43 and 44, Step 2 using rel-(2R*,4R*)-1 l-(4-chlorophenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (Isomer 2 from Step 1). Separation of the diastereoisomers by chiral SFC (chiral OJ-H, 5 pm, 250 x 20 mm, 15% MeOH in CO2) yielded:

[1033] Isomer 1 (Example 45): re / -(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5, 8,10-tri azatricyclo[5.4.0.02,4]undeca- 1(7), 8,10-tri en-6-one (6.5 mg, 33% yield) as light yellow oil as first eluting isomer. LC-MS: m / z = 450.2 [M+H]+, ESI pos. 'H NMR (300 MHz, CDCI3) 8 = 0.64 (td, J = 5.54, 4.23 Hz, 1 H), 1.54 (ddd, J = 9.72, 6.40, 5.24 Hz, 1 H), 1.97 - 2.16 (m, 3 H), 2.23 - 2.35 (m, 2 H), 3.19 - 3.27 (m, 1 H), 3.31 (s, 3 H), 3.50 (tt, J= 11.91, 3.80 Hz, 1 H), 3.75 (td, J= 11.79, 2.62 Hz, 1 H), 3.87 (s, 3 H), 4.17 - 4.24 (m, 1 H), 4.52 (dd, J = 11.38, 1.91 Hz, 1 H), 7.38 (s, 1 H), 7.48 (s, 1 H), 7.49 - 7.55 (m, 2 H), 7.83 -7.93 (m, 2 H). *The stereochemistry was assigned arbitrarily.

[1034] Isomer 2 (Example 46): re / -(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5, 8,10-tri azatri cyclo[5.4.0.02,4]undeca- 1(7), 8,10-tri end-one (5.8 mg, 29% yield) as light yellow oil as second eluting isomer. LC-MS: m / z = 450.2 [M+H]+, ESI pos. 'HNMR (300 MHz, CDCI3) 6 = 0.64 (td, J = 5.49, 4.13 Hz, 1 H), 1.49 - 1.58 (m, 1 H), 1.96 - 2.19 (m, 3 H), 2.22 - 2.34 (m, 2 H), 3.20 - 3.27 (m, 1 H), 3.31 (s, 3 H), 3.50 (tt, J = 11.86, 3.75 Hz, 1 H), 3.76 (td,.7 = 11.89, 2.42 Hz, 1 H), 3.84 (s, 3 H), 4.18 - 4.26 (m, 1 H), 4.51 (dd, J = 11.28, 2.01 Hz, 1 H), 7.36 (s, 1 H), 7.45 (s, 1 H), 7.46 - 7.54 (m, 2 H), 7.85 - 7.91 (m, 2 H). *The stereochemistry was assigned arbitrarily.

[1035] Examples 47 and 48: re / -(2R*,4R*)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-ll-[3-(trifhioromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-1(7), 8,10-tri en-6-one and re / -(2S*,4S*)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-ll-[3-(trifhioromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-1(7), 8,10-tri en-6-one

[1036]

[1037] To a suspension of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (5 g, 20.07 mmol, 1.0 eq) in EtOAc (100 mL) was added DIPEA (10.38 g, 14 mL, 80.3 mmol, 4.0 eq). The reaction mixture was cooled to 0°C, HATU (11.45 g, 30.11 mmol, 1.5 eq) was added and the reaction mixture was stirred at 0°C for 45 min before N-methylcyclopropanamine hydrochloride (3.24 g, 30.11 mmol, 1.5 eq) was added and stirring was continued overnight. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in heptane) to afford 5-bromo-N-cyclopropyl-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (5.1 g, 80% yield) as light yellow solid. LC-MS: m / z = 302.1 [M+H]+, ESI pos.

[1038] -1(1 l),7,9-trien-6-one

[1039]

[1040] A reaction vial was loaded with 5-bromo-N-cyclopropyl-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (1.9 g, 6.29 mmol, 1.0 eq), (-Bu)2PMeHBF4(312 mg, 1.26 mmol, 0.2 eq), cesium pivaloate (441 mg, 1.89 mmol, 0.3 eq) and K3PO4 (2 g, 9.43 mmol, 1.5 eq). Toluene (58 mL) was added and reaction mixture was degassed by bubbling argon through for 10 min. Then Pd(OAc)2 (141 mg, 0.63 mmol, 0.1 eq) was added and degassing was repeated for 5 min. The tube was sealed and the reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was then treated with sat. aq. NaHCO₃ (200 mL) and the product was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10 - 70% EtOAc / EtOH (3:1) in heptane) to afford 5-methyl-9-(methylthio)-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one (500 mg, 36% yield) as light brown solid. LC-MS: m / z = 222.1 [M+H]+, ESI pos. Step 3: 9-mesyl-5-methyl-5,8,10-triazatricyclor5.4.0.02’4]undeca-l(l l\7,9-trien-6-one

[1041]

[1042] To a solution of 5-methyl-9-(methylthio)-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(l l),7,9-trien-6-one (500 mg, 2.26 mmol, 1.0 eq) in DCM (20 mL) was added 3 -chloroperoxybenzoic acid (1.39 g, 5.65 mmol, 2.5 eq) at 0 °C. After 5 minutes, the reaction mixture was allowed to warm to rt and stirred for 1 h. The suspension was filtered, and the solid was washed with DCM (20 mL). The filtrate was treated with sat. aq. NaHCO₃ (25 mL) and H2O (25 mL). The aqueous layer was separated and extracted with DCM (4 x 50 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 9-mesyl-5-methyl-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(ll),7,9-trien-6-one (608 mg, 96% yield, 90% purity) as off-white foam. LC-MS: m / z = 254.1 [M+H]+, ESI pos.

[1043] Step 4: 9-mesyl-5-methyl-ll-r3-(trifluoromethyl)-l-bicyclori. L11pentanyl1-5,8,10-tri azatri cyclop, 4, 0.02’4]undeca-l(7\8,10-trien-6-one

[1044]

[1045] To a reaction tube were added 9-mesyl-5-methyl-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (15 mg, 59.2 pmol, 1.0 eq) and 3 -(trifluoromethyl)bicyclo[l.l.l]pentane-l -carboxylic acid (42.7 mg, 0.23 mmol, 4.0 eq). The reaction tube was filled with argon, and a degassed mixture of DMSO (600 pL) and H2O (1 pL) was added. Then, a degassed solution of (NH4)2S2O8(33.8 mg, 0.15 mmol, 2.5 eq) in DMSO (1.2 mL) and H2O (2 pL) was added. Argon was bubbled through the reaction mixture for 5 min, the tube was sealed and heated 45 °C under stirring for 3 h. The reaction mixture was then treated with sat. aq. NaHCO₃ (10 mL) and extracted with EtOAc (2x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (Cl 8, 5 -80% CH3CN in H2O) to afford 9-mesyl-5-methyl-ll-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (2 mg, 8% yield) as off-white solid. LC-MS: m / z = 388.2 [M+H]+, ESI pos.

[1046]

[1047] -4-yl)morpholin-4-yl]-l 1-F3- (trifluorom ethyl)- 1 -bi

[1048]

[1049] .1.

[1050]

[1051] 1-5,8, 10-tri;

[1052]

[1053] .- 1(7), 8,10-trien-6-one and re / -(2S*,4S*)-5-methyl-9-F(2S)-2-(l-i

[1054]

[1055] in-4-yll-l 1-F3- (trifluoromethyl)- 1-bicycloF 1.1. l]pentanyl]-5, 8, 10-tri;

[1056]

[1057] .- 1(7), 8,10-trien-6-one

[1058] To a solution of 9-mesyl-5-methyl-ll-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (19.5 mg, 50.3 pmol, 1.0 eq)inDMSO (250 pL) were added (2S)-2-(l-methylpyrazol-4-yl)morpholine (Intermediate (+)-Al, 10.1 mg, 60.4 pmol, 1.2 eq) and DIPEA (19.5 mg, 26.4 pL, 0.15 mmol, 3.0 eq). The reaction mixture was stirred at 120 °C for overnight under inert atmosphere. The resulting solution was directly purified by reversed-phase chromatography (Cl 8, 20 - 80% CH3CN in H2O) to afford 5-methyl-9-[(2S)-2-( 1 -methylpyrazol-4-yl)morpholino]- 11 -[3 -(trifluoromethyl)- 1 -bicyclo[ 1.1.1 ]pentanyl]-5, 8, 10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (14.7 mg, 62% yield) as light brown solid as a mixture of diastereoisomers. LC-MS: m / z = 475.3 [M+H]+, ESI pos. Separation of the diastereoisomeric mixture of by chiral SFC (chiral NR, 5 pm, 250 x 20 mm, 42% MeOH in CO2) yielded:

[1059] Isomer 1 (Example 47): re / -(2R*,4R*)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-ll-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (7.3 mg, 37% yield) as off-white solid as first eluting isomer. LC-MS: m / z = 475.3 [M+H]+, ESI pos. 'HNMR (300 MHz, CDCI3) 8 = 0.33 (td, J = 5.49, 4.13 Hz, 1 H), 1.29 - 1.38 (m, 1 H), 2.28 (td, J= 8.97, 5.84 Hz, 1 H), 2.39 - 2.50 (m, 6 H), 3.07 - 3.27 (m, 3H), 3.24 (s, 3H), 3.73 (td, J= 11.38, 2.82 Hz, 1 H), 3.90 (s, 3 H), 4.05 (dq, J= 11.48, 1.70 Hz, 1 H), 4.52 (dd, J= 10.17, 2.72 Hz, 1 H), 4.62 (br d, J= 13.30 Hz, 1 H), 4.76 (br d, J = 13.50 Hz, 1 H), 7.42 (s, 1 H), 7.52 (s, 1 H). *The stereochemistry was assigned arbitrarily.

[1060] Isomer 2 (Example 48): re / -(2S*,4S*)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]-ll-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-5,8,10-triazatricyclo[5.4.0.02’4]undeca-l(7),8,10-trien-6-one (7.6 mg, 38% yield) as off-white solid as second eluting isomer. LC-MS: m / z = 475.3 [M+H]+, ESI pos. 'HNMR (300 MHz, CDCI3) 6 = 0.33 (td, J = 5.49, 4.13 Hz, 1 H), 1.29 - 1.38 (m, 1 H), 2.29 (td, J= 8.92, 5.94 Hz, 1 H), 2.40 - 2.50 (m, 6 H), 3.07 - 3.27 (m, 3H), 3.24 (s, 3H), 3.73 (td, J = 11.48, 2.82 Hz, 1 H), 3.90 (s, 3 H), 4.05 (dq, J = 11.48, 1.70 Hz, 1 H), 4.52 (dd, J= 10.28, 2.82 Hz, 1 H), 4.62 (br d, J = 13.70 Hz, 1 H), 4.77 (br d, J = 13.70 Hz, 1 H), 7.42 (s, 1 H), 7.53 (s, 1 H). *The stereochemistry was assigned arbitrarily. Examples 49 - 52: re / -(laR*,7bR*)-7-(2,4-dinuorophenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and rel- (laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1061]

[1062] Example 49 Example 50 Example 51 Example 52 Step 1: 5-chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropalcir2,61naphthyri din-3 -one

[1063]

[1064] The title compound has been prepared in analogy to Intermediate Bl using 2,4-difluorobenzeneboronic acid instead of 4-chloro-2-fluorobenzeneboronic acid in step 1 5-chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (450.0 mg) as yellow solid. LC-MS: m / z = 321.1 [M+H]+, ESI pos.

[1065] Step 2: 5-16-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl1-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropalcir2,61naphthyridin-3-one

[1066]

[1067] To a solution of 5-chloro-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (300.0 mg, 0.94 mmol, 1.0 eq) in 1,4-dioxane (3 mL) and H2O (0.3 mL) was added l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (Intermediate A4, 384.5 mg, 1.22 mmol, 1.3 eq), Cs₂CO₃ (609.5 mg, 1.87 mmol, 2.0 eq) and PdCl₂(dppf)·CH₂Cl₂ (76.4 mg, 0.09 mmol, 0.1 eq). Then the reaction was purged three times with N2 and the reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and water (20 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and the volatiles removed under reduced pressure. The residue was purified by preparative HPLC (spherical C18, 20 – 45 mm, 100 Å, CH3CN in water with 0.1% formic acid) to yield 5-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihy dro-2H-pyran-4-yl] -7-(2,4-difluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1H-cyclopropa[c][2,6]naphthyridin-3-one (450.0 mg, quant.) as a yellow solid. LC-MS: m / z = 475.3 [M+H]+, ESI pos.

[1068]

[1069] To a suspension of Pd / C (89.7 mg, 0.08 mmol, 0.2 eq) in EtOAc (5 mL) and MeOH (1 mL) under argon was added a solution of 5-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (200.0 mg, 0.42 mmol, 1.0 eq) in EtOAc (5 mL). The reaction was purged three times with H2 and then stirred for 12 h under H2 (15 Psi) at rt. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex luna C18, 10 pm, 150 mm x 25 mm), 45 - 75% CH3CN in H2O with 0.225% formic acid) to yield 7-(2,4-difluorophenyl)-2-methyl-5-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (70.0 mg, 34.85% yield) was obtained as yellow solid as a mixture of stereoisomers. LC-MS: m / z = 477.2 [M+H]+, ESI pos. Chiral SFC (Chiralpak AD, 10 pm, 250 mm x 30 mm, 40 % EtOH (0.1% NH4OH) in CO2) afforded four stereoisomers.

[1070] Isomer 1 (Example 49): re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (5.4 mg, 9.0% yield) as white solid as first eluting isomer. LC-MS: m / z = 477.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 8 = 7.96 (s, 1H), 7.55 - 7.49 (m, 1H), 7.46 (d, J = 1.6 Hz, 2H), 7.04 (dt, J = 2.4, 8.0 Hz, 1H), 6.95 (dt, J = 2.4, 9.2 Hz, 1H), 4.49 (dd, J = 2.0, 11.2 Hz, 1H), 4.22 (td, J = 3.2, 11.2 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.55 (tt, J = 3.6, 7.2 Hz, 1H), 3.28 (s, 3H), 3.25 - 3.15 (m, 1H), 3.15 - 3.07 (m, 1H), 2.21 (br d, J = 13.6 Hz, 1H), 2.06 - 1.89 (m, 4H), 1.46 - 1.39 (m, 1H), 1.14 - 1.04 (m, 2H), 1.04 - 0.95 (m, 2H), 0.46 - 0.38 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1071] Isomer 2 (Example 50): re / -(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (4.9 mg, 8.0% yield) as white solid as second eluting isomer. LC-MS: m / z = 477.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.96 (s, 1H), 7.55 - 7.49 (m, 1H), 7.46 (d, J = 1.6 Hz, 2H), 7.04 (dt, J = 2.4, 8.0 Hz, 1H), 6.95 (dt, J = 2.4, 9.2 Hz, 1H), 4.49 (dd, J= 2.0, 11.2 Hz, 1H), 4.22 (td, J = 3.2, 11.2 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.55 (tt, J= 3.6, 7.2 Hz, 1H), 3.28 (s, 3H), 3.25 - 3.15 (m, 1H), 3.15 - 3.07 (m, 1H), 2.21 (br d, J = 13.6 Hz, 1H), 2.06 - 1.89 (m, 4H), 1.46 - 1.39 (m, 1H), 1.14 - 1.04 (m, 2H), 1.04 - 0.95 (m, 2H), 0.46 -0.38 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1072] Isomer 3 (Example 51): re / -(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (4.8 mg, 8.0% yield) as white solid as third eluting isomer. LC-MS: m / z = 477.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.96 (s, 1H), 7.55 - 7.49 (m, 1H), 7.46 (d, J = 1.6 Hz, 2H), 7.04 (dt, J = 2.4, 8.0 Hz, 1H), 6.95 (dt, J = 2.4, 9.2 Hz, 1H), 4.49 (dd, J = 2.0, 11.2 Hz, 1H), 4.22 (td, J = 3.2, 11.2 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.55 (tt, J = 3.6, 7.2 Hz, 1H), 3.28 (s, 3H), 3.25 - 3.15 (m, 1H), 3.15 - 3.07 (m, 1H), 2.21 (br d, J = 13.6 Hz, 1H), 2.06 - 1.89 (m, 4H), 1.46 - 1.39 (m, 1H), 1.14 - 1.04 (m, 2H), 1.04 - 0.95 (m, 2H), 0.46 - 0.38 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1073] Isomer 4 (Example 52): re / -(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (8.7 mg, 14.2% yield) as white solid as fourth eluting isomer. LC-MS: m / z = 477.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.96 (s, 1H), 7.55 - 7.49 (m, 1H), 7.46 (d, J = 1.6 Hz, 2H), 7.04 (dt, J = 2.4, 8.0 Hz, 1H), 6.95 (dt, J = 2.4, 9.2 Hz, 1H), 4.49 (dd, J= 2.0, 11.2 Hz, 1H), 4.22 (td, J = 3.2, 11.2 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.55 (tt, J= 3.6, 7.2 Hz, 1H), 3.28 (s, 3H), 3.25 - 3.15 (m, 1H), 3.15 - 3.07 (m, 1H), 2.21 (br d, J = 13.6 Hz, 1H), 2.06 - 1.89 (m, 4H), 1.46 - 1.39 (m, 1H), 1.14 - 1.04 (m, 2H), 1.04 - 0.95 (m, 2H), 0.46 -0.38 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1074] Examples 53 - 56: re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(1 -methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-l a,7b-dihydro- 1H-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1075]

[1076] Step 1: 7-(4-chloro-2-fluoro-phenyl)-5-r6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl1-2-methyl-la,7b-dihydro-lH-cycloproparcir2,61naphthyridin-3-one

[1077]

[1078] To a solution of 5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (Intermediate Bl, 350.0 mg, 1.04 mmol, 1.0 eq) in 1,4-dioxane (5 mL) and water (0.500 mL) was added 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (Intermediate A5, 428.0 mg, 1.35 mmol, 1.3 eq), Cs₂CO₃ (676.4 mg, 2.08 mmol, 2.0 eq) and PdCl₂(dppf)·CH₂Cl₂ (84.76 mg, 0.1 mmol, 0.1 eq). The reaction was degassed three times with N2 and then stirred at 90 °C for 12 h. The mixture was then poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The mixture was purified by flash chromatography (silica gel, 48 - 50% EtOAc in PE to yield 7-(4-chloro-2-fluoro-phenyl)-5-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (460.0 mg, 90.1% yield) as a yellow solid. LC-MS: m / z = 492.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 8.21 -8.06 (m, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.22 (dd, J = 2.0, 9.6 Hz, 1H), 6.95 (d, J= 5.2 Hz, 1H), 6.85 - 6.78 (m, 2H), 5.37 - 5.26 (m, 1H), 4.25 - 4.16 (m, 1H), 3.93 (d, J= 2.8 Hz, 3H), 3.28 (s, 3H), 3.17 - 3.07 (m, 1H), 2.91 - 2.76 (m, 1H), 2.75 - 2.59 (m, 1H), 2.05 (s, 1H), 1.98 (s, 1H), 1.48 - 1.39 (m, 1H), 0.42 (quin, J = 5.2 Hz, 1H).

[1079] Step 2: 7-(4-chloro-2-fluoro-phenyl)-5-12-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl1-2-methyl- 1 a,7b-dihydro- IH-cyclopropal c] 12, 6]naphthyri din-3 -one

[1080]

[1081] A solution of 7-(4-chloro-2-fluoro-phenyl)-5-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (400.0 mg, 0.81 mmol, 1.0 eq) in THF (40 mL) was hydrogenated in a flow reactor (5 mL fixed bed 6.35 mm packed with granular 5% Ru / Al₂O₃ (3.0 g), 0.5 Mpa H2 back-pressure, flow rate H₂ 20 mL / min) at a flow rate 0.4 mL / min at 35 °C. The mixture was concentrated under vacuum and purified by preparative HPLC (Welch Xtimate C 18, 15 pm, 150 mm x 40 mm, 55 - 85% CH3CN in H2O with 0.225% formic acid) to give 7-(4-chloro-2-fluoro-phenyl)-5-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (160.0 mg, 39.8% yield) as a yellow solid. LC-MS: m / z = 494.3 [M+H]+, ESI pos.

[1082] Step 3: 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-12-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cyclopropalc112,61naphthyridin-3-one

[1083]

[1084] To a yellow solution of 7-(4-chloro-2-fluoro-phenyl)-5-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (160.0 mg, 0.32 mmol, 1.0 eq) in CH3CN (4 mL) was added TMSI (129.6 mg, 0.65 mmol, 2.0 eq) at 0 °C under nitrogen atmosphere. The reaction mixture was heated to 70 °C and stirred for 2 h. The mixture was purified by reversed phase column chromatography (spherical C18, 20-45 mm x 100 Å; 30 - 42% CH3CN in H2O (0.1% formic acid)) to yield 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (130.0 mg, 83.6% yield) as a yellow solid. LC-MS: m / z = 480.2 [M+H]+, ESI pos.

[1085] -methvl-2- -3 -one

[1086]

[1087] ethyl-2-oxo-4-

[1088]

[1089] -4-yll- 1 a,7b-dihydro- IH-i

[1090]

[1091] in-3-one and re / -( 1 aS *,7b S *)-7-(4-chloro-2-fluoro-i

[1092]

[1093] i-2-methyl-5-| Z-(2R*,4S*)-2-(l -methyl -2-oxo-4-

[1094]

[1095] -4-yll- 1 a,7b-dihydro- IH-i

[1096]

[1097] -3 -one and re / -( 1 aS *,7b S *)-7-(4-chloro-2-fluoro-i

[1098]

[1099] i-2-methyl-5-| Z-(2S*,4R*)-2-(l-methyl-2-oxo-4-

[1100]

[1101] -4-yll- 1 a,7b-dihydro- IH-i

[1102]

[1103] in-3-one To a solution of 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (130.0 mg, 0.27 mmol, 1.0 eq) and Cs₂CO₃ (264.76 mg, 0.81 mmol, 3.0 eq) in DMF (3 mL) was added Mel (0.05 mL, 0.81 mmol, 3.0 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction mixture was filtered to give a solution and the filtrate was purified by reversed phase (spherical C18, 20-45 mm x 100 Å; 30 - 42% CH3CN in H2O (0.1% formic acid)) to yield (7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (60.0 mg, 44.8% yield) as a light yellow solid as a mixture of stereoisomers. LC-MS: m / z = 494.3 [M+H]+, ESI pos. Chiral SFC (Chiralpak AD, 10 pm, 250 mm x 30 mm, 60 % EtOH (0.1% NH4OH) in CO2) afforded four stereoisomers.

[1104] Isomer 1 (Example 53): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (7.3 mg, 12.1% yield) as a yellow solid as first eluting isomer. LC-MS: m / z = 494.3 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 8 = 7.93 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.29 (dd, J= 1.6, 8.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.54 (s, 1H), 6.27 (dd, J = 1.6, 7.2 Hz, 1H), 4.38 - 4.22 (m, 2H), 3.72 (dt, J = 4.0, 11.2 Hz, 1H), 3.52 (s, 3H), 3.27 (s, 3H), 3.25 - 3.17 (m, 1H), 3.14 - 3.08 (m, 1H), 2.16 (br d, J = 13.6 Hz, 1H), 2.03 - 1.92 (m, 3H), 1.81 - 1.73 (m, 1H), 1.42 (td, J = 6.0, 10.0 Hz, 1H), 0.47 - 0.37 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1105] Isomer 2 (Example 54): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (5.4 mg, 9.0% yield) as a yellow solid as second eluting isomer. LC-MS: m / z = 494.3 [M+H]+, ESI pos. 'HNMR (400 MHz, CDC13) 8 = 7.93 (s, 1H), 7.47 (t, J= 8.0 Hz, 1H), 7.30 (s, 1H), 7.26 - 7.20 (m, 2H), 6.54 (s, 1H), 6.26 (dd, J= 1.6, 6.8 Hz, 1H), 4.35 - 4.25 (m, 2H), 3.76 - 3.69 (m, 1H), 3.52 (s, 3H), 3.27 (s, 3H), 3.25 - 3.17 (m, 1H), 3.11 (ddd, J = 4.0, 6.4, 8.0 Hz, 1H), 2.14 (br d, J = 13.6 Hz, 1H), 2.02 - 1.93 (m, 3H), 1.77 (br d, J= 12.4 Hz, 1H), 1.42 (td, J = 6.0, 10.0 Hz, 1H), 0.45 - 0.37 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1106] Isomer 3 (Example 55): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (8.4 mg, 13.8% yield) as a yellow solid as third eluting isomer. LC-MS: m / z = 494.3 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.93 (s, 1H), 7.51 - 7.43 (m, 1H), 7.29 (dd, J= 1.6, 8.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.54 (s, 1H), 6.26 (dd, J= 1.6, 7.2 Hz, 1H), 4.35 - 4.24 (m, 2H), 3.77 - 3.68 (m, 1H), 3.52 (s, 3H), 3.27 (s, 3H), 3.25 - 3.17 (m, 1H), 3.11 (ddd, J= 4.0, 6.4, 8.0 Hz, 1H), 2.14 (br d, J= 13.2 Hz, 1H), 2.03 - 1.91 (m, 3H), 1.83 - 1.74 (m, 1H), 1.42 (td, J = 6.0, 10.0 Hz, 1H), 0.46 - 0.36 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1107] Isomer 4 (Example 56): reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (7.3 mg, 12.2% yield) as a yellow solid as fourth eluting isomer. LC-MS: m / z = 494.3 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.93 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.29 (br d, J = 8.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.54 (s, 1H), 6.30 - 6.23 (m, 1H), 4.36 - 4.23 (m, 2H), 3.72 (dt, J= 3.6, 11.2 Hz, 1H), 3.52 (s, 3H), 3.27 (s, 3H), 3.25 - 3.17 (m, 1H), 3.14 - 3.08 (m, 1H), 2.20 - 2.12 (m, 1H), 2.03 - 1.91 (m, 3H), 1.82 - 1.71 (m, 1H), 1.45 - 1.38 (m, 1H), 0.42 (q, J = 5.2 Hz, 1H). *The stereochemistry was assigned arbitrarily.

[1108] Examples 57 -60: re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2- methyl-5-[re / -(2R*,4S*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1109]

[1110] Example 57 Example 58 Example 59 Example 60 The title compounds were prepared in analogy to Examples 53 - 56 using 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2J / -pyran-6-yl]pyridine (Intermediate A6) instead of 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2J / -pyran-6-yl]pyridine in step 1 yielding 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (80.0 mg) as yellow solid as a mixture of stereoisomers. LC-MS: m / z = 494.2 [M+H]+, ESI pos. Separation by chiral SFC (Chiralpak AS, 10 pm, 250 mm x 30 mm, 60% PrOH (0.1% NH4OH) in CO2) yielded four stereoisomers:

[1111] Isomer 1 (Example 57): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (4.4 mg, 5.5% yield) as yellow solid a first eluting isomer. LC-MS: m / z = 494.2 [M+H]+, ESI pos.1H NMR (400 MHz, CDCI3) 8 = 7.95 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 10.4 Hz, 1H), 4.30 - 4.23 (m, 2H), 3.77 - 3.69 (m, 1H), 3.55 (s, 3H), 3.28 (s, 3H), 3.25 - 3.17 (m, 1H), 3.12 (ddd, J= 4.0, 6.4, 8.0 Hz, 1H), 2.15 (br d, J= 13.2 Hz, 1H), 2.04 - 1.95 (m, 3H), 1.85 -1.76 (m, 1H), 1.47 - 1.42 (m, 1H), 0.45 - 0.40 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1112] Isomer 2 (Example 58): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (18.7 mg, 23.3% yield) as yellow solid a second eluting isomer. LC-MS: m / z = 494.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.95 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.30 (br d, J = 6.4 Hz, 1H), 7.24 (dd, J = 2.0, 9.6 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.34 - 4.24 (m, 2H), 3.79 - 3.70 (m, 1H), 3.54 (s, 3H), 3.28 (s, 3H), 3.24 -3.17 (m, 1H), 3.15 - 3.07 (m, 1H), 2.18 - 2.11 (m, 1H), 2.05 - 1.95 (m, 3H), 1.80 (br d, J = 12.4 Hz, 1H), 1.45 - 1.41 (m, 1H), 0.43 - 0.39 (m, 1H). *The stereochemistry was assigned arbitrarily. Isomer 3 (Example 59): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (6.1 mg, 7.4% yield) as yellow solid a third eluting isomer. LC-MS: m / z = 494.2 [M+H]+, ESI pos.1H NMR (400 MHz, CDC13) 8 = 7.95 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 10.4 Hz, 1H), 4.30 - 4.23 (m, 2H), 3.77 - 3.69 (m, 1H), 3.55 (s, 3H), 3.28 (s, 3H), 3.25 - 3.17 (m, 1H), 3.12 (ddd, J = 4.0, 6.4, 8.0 Hz, 1H), 2.15 (br d, J= 13.2 Hz, 1H), 2.04 - 1.95 (m, 3H), 1.85 - 1.76 (m, 1H), 1.47 - 1.42 (m, 1H), 0.45 - 0.40 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1113] Isomer 4 (Example 60): reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (12.1 mg, 15.1% yield) as yellow solid a fourth eluting isomer. LC-MS: m / z = 494.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.95 (s, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.31 (s, 1H), 7.24 (br d, J = 9.6 Hz, 1H), 6.56 (br d, J = 10.0 Hz, 1H), 4.27 (br dd, J = 6.0, 10.4 Hz, 2H), 3.80 - 3.69 (m, 1H), 3.55 (s, 3H), 3.28 (s, 3H), 3.24 - 3.16 (m, 1H), 3.14 - 3.06 (m, 1H), 2.14 (br d, J = 13.2 Hz, 1H), 2.05 - 1.96 (m, 3H), 1.87 - 1.77 (m, 1H), 1.47 - 1.40 (m, 1H), 0.42 (brd, J= 4.4 Hz, 1H). *The stereochemistry was assigned arbitrarily.

[1114] Examples 61 -64: reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(1 -cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1115]

[1116] Example 61 Example 62 Example 63 Example 64

[1117] A mixture of 7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (which was prepared similarly to Examples 53 - 56, step 3, 160.0 mg, 0.33 mmol, 1.0 eq), Cu(OAc)2 (66.6 mg, 0.37 mmol, 1.1 eq), cyclopropylboronic acid (57.3 mg, 0.67 mmol, 2.0 eq), Na₂CO₃ (70.7 mg, 0.67 mmol, 2.0 eq), 2,2'-bipyridine (57.3 mg, 0.37 mmol, 1.1 eq) in 1,2-di chloroethane (3 mL) and the resulting mixture was stirred for 2 h at 70 °C under 02 atmosphere (15 psi). The reaction mixture was poured into water (10 mL), extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4and the volatiles removed under reduced pressure. The residue was purified by reversed phase flash chromatography (spherical C18, 20 – 45 mm, 100 Å, 50 - 52% CH3CN in water with 0.1% formic acid) to afford 7-(4-chloro-2-fluoro-phenyl)-5-[2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (110.0 mg, 63.5% yield) as a yellow solid as a mixture of stereoisomers. LC-MS: m / z = 520.2 [M+H]+, ESI pos. Separation by chiral SFC (Chiralpak AD, 10 pm, 250 mm x 30 mm, 70% PrOH (0.1% NH4OH) in CO2) yielded four stereoisomers:

[1118] Isomer 1 (Example 61): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (20.8 mg, 20.7% yield) as yellow solid as first eluting isomer. LC-MS: m / z = 520.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 7.94 (s, 1H), 7.52 - 7.41 (m, 1H), 7.33 (qd, J = 2.4, 5.2 Hz, 2H), 7.29 (dd, J = 1.6, 8.0 Hz, 1H), 7.23 (dd, J = 2.0, 9.6 Hz, 1H), 6.57 - 6.49 (m, 1H), 4.25 (br d, J = 11.2 Hz, 2H), 3.81 - 3.64 (m, 1H), 3.35 - 3.29 (m, 1H), 3.28 (s, 3H), 3.25 - 3.15 (m, 1H), 3.12 (ddd, J = 4.4, 6.4, 8.0 Hz, 1H), 2.11 (brd, J= 13.2 Hz, 1H), 2.04 - 1.94 (m, 3H), 1.85 - 1.75 (m, 1H), 1.42 (td, J = 5.6, 10.0 Hz, 1H), 1.16 - 1.09 (m, 2H), 0.90 - 0.86 (m, 2H), 0.45 - 0.38 (m, I H)*7 / ?c stereochemistry was assigned arbitrarily.

[1119] Isomer 2 (Example 62): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (19.3 mg, 19.2% yield) as yellow solid as second eluting isomer. LC-MS: m / z = 520.2 [M+H]+, ESI pos. ‘HNMR (400 MHz, CDCI3) 6 = 7.95 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.30 (dd, J = 2.0, 8.4 Hz, 1H), 7.23 (dd, J = 2.0, 9.6 Hz, 1H), 6.54 (d, J = 10.0 Hz, 1H), 4.26 (br d, J = 10.0 Hz, 2H), 3.72 (dt, J = 3.2, 11.6 Hz, 1H), 3.35 -3.29 (m, 1H), 3.28 (s, 3H), 3.24 - 3.15 (m, 1H), 3.12 (ddd, J = 4.0, 6.4, 8.0 Hz, 1H), 2.18 - 2.08 (m, 1H), 2.05 - 1.91 (m, 3H), 1.86 - 1.74 (m, 1H), 1.43 (td, J = 6.0, 10.0 Hz, 1H), 1.18 - 1.09 (m, 2H), 0.91 - 0.84 (m, 2H), 0.47 - 0.36 (m, 1H). *The stereochemistry was assigned arbitrarily. Isomer 3 (Example 63): reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (18.8 mg, 18.7% yield) as yellow solid as third eluting isomer. LC-MS: m / z = 520.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDC13) 8 =7.95 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.30 (dd, J = 2.0, 8.4 Hz, 1H), 7.23 (dd, J = 2.0, 9.6 Hz, 1H), 6.54 (d, J = 10.0 Hz, 1H), 4.32 - 4.19 (m, 2H), 3.72 (dt, J = 3.2, 11.6 Hz, 1H), 3.35 - 3.29 (m, 1H), 3.28 (s, 3H), 3.20 (tt, J = 4.0, 11.6 Hz, 1H), 3.15 - 3.09 (m, 1H), 2.13 (br dd, J = 2.0, 13.2 Hz, 1H), 2.04 - 1.92 (m, 3H), 1.84 - 1.74 (m, 1H), 1.43 (td, J = 6.0, 10.0 Hz, 1H), 1.17 - 1.09 (m, 2H), 0.93 - 0.85 (m, 2H), 0.46 - 0.36 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1120] Isomer 4 (Example 64): reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (20.7 mg, 20.5% yield) as yellow solid as fourth eluting isomer. LC-MS: m / z = 520.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 6 = 7.94 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.33 (qd, J = 2.4, 5.2 Hz, 2H), 7.29 (dd, J = 2.0, 8.4 Hz, 1H), 7.23 (dd, J = 2.0, 9.6 Hz, 1H), 6.60 - 6.48 (m, 1H), 4.25 (br d, J = 10.8 Hz, 2H), 3.82 - 3.63 (m, 1H), 3.37 - 3.29 (m, 1H), 3.28 (s, 3H), 3.24 - 3.15 (m, 1H), 3.12 (ddd, J = 4.0, 6.4, 8.0 Hz, 1H), 2.11 (brd, J= 13.2 Hz, 1H), 2.05 - 1.93 (m, 3H), 1.84 - 1.75 (m, 1H), 1.42 (td, J = 6.0, 10.0 Hz, 1H), 1.17 - 1.08 (m, 2H), 0.92 - 0.85 (m, 2H), 0.47 - 0.33 (m, 1H). *The stereochemistry was assigned arbitrarily.

[1121] Examples 65 - 68: reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[reZ-(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[reZ-f2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[reZ-(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and reZ-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[reZ-f2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1122]

[1123] Step 1: (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-5-r6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl1-2-methyl-la,7b-dihydro-lH-cycloproparcir2,61naphthyridin-3-one

[1124]

[1125] To a solution of (laRS,7bRS)-5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (Intermediate Bl, 300.0 mg, 0.89 mmol, 1.0 eq) in 1,4-dioxane (5 mL) and water (0.500 mL) was added l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (Intermediate A4, 422.01 mg, 1.33 mmol, 1.5 eq), Cs₂CO₃ (869.6 mg, 2.67 mmol, 3.0 eq) and PdCl₂(dppf)·CH₂Cl₂ (72.7 mg, 0.09 mmol, 0.1 eq). Then the reaction was degassed three times with N2 and the reaction mixture was stirred for 12 h at 90 °C. The reaction mixture was concentrated under vacuum and purified by preparative HPLC (Waters XBridge, 5 pm, 150 x 25 mm, 50 - 80% CH3CN in H2O with 10 mM NH4HCO3) to afford (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-5-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (360 mg, 82.4% yield) as colorless oil. LC-MS: m / z = 491.2 [M+H]+, ESI pos.

[1126] Step 2: re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-rre / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cycloproparcir2,61naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-rre / - 2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cycloproparcir2,61naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-rre / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cycloproparcir2,61naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-rre / - 2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cyclopropalcir2,61naphthyridin-3-one

[1127] The title compounds were prepared in analogy to Examples 53 - 56, Step 2 using (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-5-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (360 mg, 0.73 mmol, 1.0 eq.) to afford (laRS,7bRS)-7-(4-chloro-2-fluoro-phenyl)-5-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (90 mg, 24.9% yield) as a yellow solid as a mixture of four stereoisomers. LC-MS: m / z = 493.2 [M+H]+, ESI pos. Chiral SFC (Chiralpak AD, 10 pm, 250 x 30 mm, 50% EtOH (0.1% NH4OH) in CO2) afforded four stereoisomers:

[1128] Isomer 1 (Example 65): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (11.2 mg, 0.02 mmol, 13.0% yield) as a yellow solid as first eluting isomer. LC-MS: m / z = 493.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1129] Isomer 2 (Example 66): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[re / -(2R*,4S*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (13.3 mg, 0.03 mmol, 15.5% yield) as a yellow solid as second eluting isomer. LC-MS: m / z = 493.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1130] Isomer 3 (Example 67): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one one (15.6 mg, 0.03 mmol, 18.1% yield) as a yellow solid as third eluting isomer. LC-MS: m / z = 493.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1131] Isomer 4 (Example 68): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[re / -(2S*,4R*)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (26.1 mg, 0.05 mmol, 30.4% yield) as a yellow solid as fourth eluting isomer. LC-MS: m / z = 493.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1132] Examples 69- 70: re / -(laS*,7bS*)-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2-fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-5-[re / -(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2-fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1133]

[1134] Example 69 Example 70

[1135] Step 1: 5-12-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl1-7-(2-fluorophenyl)-2-methyl-1 a,7b-dihydro- IH-cyclopropal cl 12, 61naphthyri din-3 -one

[1136]

[1137] The title compound (30.0 mg, 35.4% yield) was obtained as colorless oil as a secondary product from Examples 65 - 68. LC-MS: m / z = 459.4 [M+H]+, ESI pos.

[1138] Step 2: re / -(laS*,7bS*)-5-lre / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl1-7-(2-fluorophenyl)-2-methyl- 1 a,7b-dihydro- IH-cyclopropal cl 12, 61naphthyri din-3 -one and rel- (laS*,7bS*)-5-lre / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl1-7-(2-fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropalc112,61naphthyridin-3-one

[1139]

[1140] Example 69 Example 70

[1141] Chiral SFC (chiral IA, 5 μm, 250 × 20 mmm, 28% MeOH in CO2) afforded 2 stereoisomers:

[1142] Isomer 1 (Example 69): re / -(laS*,7bS*)-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2-fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (16 mg, 40% yield) as white foam as first eluting isomer. LC-MS: m / z = 459.5 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily. Isomer 2 (Example 70): re / -(laS*,7bS*)-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2-fluorophenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one as second eluting isomer. LC-MS: m / z = 459.5 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1143] 71 - 74: re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[re / -(2R*,4S*)-2- (1- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-l a,7b-dihydro- 1H-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-lre / -(2S*.4R*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-lre / -(2R*.4S*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(l aS*, 7bS*)-7-(4-chl oro-2 -fluoro-phenyl)-2-methyl-5-lre / -(2S*.4R*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1144]

[1145] Example 71 Example 72 Example 73 Example 74

[1146]

[1147] i-3, 6-dihy dro-2H-pyran-4-yl] -2- idin-3-one

[1148]

[1149] To a solution of 5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (Intermediate Bl, 350 mg, 1.04 mmol, 1.0 eq.) in 1,4-dioxane (5 ml) and H2O (0.500 ml) were added 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (Intermediate A5, 428 mg, 1.35 mmol, 1.3 eq.), Cs₂CO₃ (676 mg, 2.08 mmol, 2.0 eq.) and PdCl2(dppf)·CH2Cl2(84.8 mg, 0.104 mmol, 0.10 eq.). The mixture was degassed with N2 three times and the reaction mixture was stirred at 90 °C for 12 h. The mixture was poured into H2O (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phase was washed with brine (3 x 20 ml), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 48 - 50% ) to afford 7-(4-chloro-2-fluoro-phenyl)-5-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (460 mg, 90% yield) as a yellow solid. LC-MS: m / z = 492.1 [M+H]+, ESI pos.

[1150] Step 2: 7-(4-chloro-2-fluoro-phenyl)-5-r2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl1-2-methyl- 1 a.7b-di hydro-1 H-cycl opropal c] 12, 6]naphthyri din-3 -one

[1151]

[1152] A solution of 7-(4-chloro-2-fluoro-phenyl)-5-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (400 mg, 0.810 mmol, 1.0 eq.) was pumped at 0.4 ml / min through a fixed bed reactor packed with 5% Ru / Al2O3(3.0 g) at 35 °C. A stream of H2 was flowed concurrently at 20 ml / min with a back pressure of 0.5 MPa. The reaction mixture was collected from the reactor output and purified by prep-HPLC to afford 7-(4-chloro-2-fluoro-phenyl)-5-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (180 mg, 45% yield) as a yellow oil. LC-MS: m / z = 494.1 [M+H]+, ESI pos.

[1153] Step 3: 7-(4-chloro-2-fluoro-phenyl)-5-r2-(2-hydroxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-1 a, 7b-di hydro-1 H-cycl opropal c] 12, 6]naphthyri din-3 -one

[1154]

[1155] To a solution of 7-(4-chloro-2-fluoro-phenyl)-5-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (180 mg, 0.360 mmol, 1.0 eq.) in CH3CN (4 ml) at 0 °C was added TMSI (0.10 ml, 0.73 mmol, 2.0 eq.). The reaction mixture was heated to 70 °C and stirred for 1 h. The reaction mixture was purified by RP chromatography and lyophilized to give 7-(4-chloro-2-fluoro-phenyl)-5-[2-(2-hydroxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (150 mg, 86% yield) as a yellow solid. LC-MS: m / z = 480.1 [M+H]+, ESI pos.

[1156] Step 4: re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-rre / -(2R*,4S*)-2-(l-cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cyclopropalcir2,61naphthyri din-3 -one and re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-lre / -(2S*,4R*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cyclopropalcir2,61naphthyri din-3 -one and re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-lre / -(2R*,4S*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl1-la,7b-dihydro-lH-cyclopropalcir2,61naphthyridin-3-one and re / -(l aS*, 7bS*)-7-(4-chl oro-2 -fluoro-phenyl)-2-methyl-5-lre / --2- l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-

[1157]

[1158] yl1-la,7b-dihydro-lH-cyclopropalcir2,61naphthyridin-3-one

[1159]

[1160] Example 71 Example 72 Example 73 Example 74

[1161] To a suspension of 7-(4-chloro-2-fluoro-phenyl)-5-[2-(2-hydroxy-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (150 mg, 0.310 mmol, 1.0 eq.) in DCE (5 ml) were added copper diacetate (62.4 mg, 0.340 mmol, 1.1 eq.), cyclopropylboronic acid (53.7 mg, 0.630 mmol, 2.0 eq.), Na2CO3(66.3 mg, 0.630 mmol, 2.0 eq.) and [2,2]bipyridinyl (53.7 mg, 0.340 mmol, 1.1 eq.). The resulting mixture was stirred at 70 °C for 2 h under O2 (15 psi). The reaction mixture was poured into H2O (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic phase was washed with brine (10 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by RP chromatography and lyophilized to give 7-(4-chloro-2-fluoro-phenyl)-5-[2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one as a yellow solid. LC-MS: m / z = 520.3 [M+H]+, ESI pos.

[1162] Chiral SFC (Daicel Chiralpak AD, 10 pm, 250mm x 30mm, CH3CN and MeOH (0.1% NH3·H2O) in CO2) afforded four stereoisomers: Isomer 1 (Example 71): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (13.2 mg, 17% yield) as a yellow solid as first eluting isomer. LC-MS: m / z = 520.3 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1163] Isomer 2 (Example 72): re / -(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (13.3 mg, 17% yield) as a yellow solid. LC-MS: m / z = 520.3 [M+H]+, ESI pos as second eluting isomer. *The stereochemistry was assigned arbitrarily.

[1164] Isomer 3 (Example 73): reZ-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2R*,4S*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (5.6 mg, 6.1% yield) as a yellow solid. LC-MS: m / z = 520.3 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1165] Isomer 4 (Example 74): re / -(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[reZ-(2S*,4R*)-2-(l- cyclopropyl -2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (3.2 mg, 3.5% yield) as a yellow solid as third eluting isomer. LC-MS: m / z = 520.3 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1166]

[1167] 75 78: re / -(laR*,7bR*)-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laR*,7bR*)-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one and re / -(laS*,7bS*)-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one

[1168]

[1169] Example 75 Example 76 Example 77 Example 78 (4,4-difluorocyclohexen-

[1170]

[1171] To a solution of 5-chloro-7-(4,4-difluorocyclohexen-l-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one (Intermediate Bll, 700 mg, 2.16 mmol, 1.0 eq.) in 1,4- dioxane (10 ml) and H2O (1 ml) were added l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (Intermediate A4,1.02 g, 3.23 mmol, 1.5 eq.), Cs₂CO₃ (2.11 g, 6.47 mmol, 3.0 eq.) and PdCl2(dppf)·CH2Cl2(176 mg, 0.216 mmol, 0.10 eq.). The mixture was purged and backfilled with nitrogen three times, then stirred at 90 °C for 16 h. The reaction mixture was diluted with H2O and extracted three times with EtO Ac. The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 80 - 95% EtO Ac in PE) to afford 5-[6-(l- cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7-(4,4-difluorocyclohexen-l-yl)-2-methyl- la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (1.00 g, 97% yield) as a yellow solid. LC-MS: m / z = 479.2 [M+H]+, ESI pos.

[1172]

[1173] (4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH-i

[1174]

[1175] idin-3-one and re / -(laS*,7bS*)-5-Fre / -(2R*,4S*)-2-(l-l

[1176]

[1177] -4-yl]-7-(4,4- difluorocyclohexyl)-2-methyl-la,7b-dihydro-lE[-i

[1178]

[1179] idin-3-one and rel- (laR* 7bR*)-5-Fre / -(2R* 4S*)-2-(l-<

[1180]

[1181] -4-yl)tetrahydropyran-4-yl]-7-(4,4- difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH-i

[1182]

[1183] idin-3-one and rel- (laS*,7bS*)-5-Fre / -(2S*,4R*)-2-(l-i

[1184]

[1185] -4-yl)tetrahydropyran-4-yl]-7-(4,4- difluorocyclohexyl)-2-methyl-la,7b-dihydro-lEI-i

[1186]

[1187] in-3 -one

[1188]

[1189] Example 75 Example 76 Example 77 Example 78 To a suspension of Pd / C (89.0 mg, 0.084 mmol, 0.10 eq.) in EtOAc (4 ml) were added 5-[6-(l- cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7-(4,4-difluorocyclohexen-l-yl)-2-methyl- la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one (400 mg, 0.836 mmol, 1.0 eq.), MgO (337 mg, 8.36 mmol, 10 eq.), and Et3N (0.140 ml, 1.00 mmol, 1.2 eq.) in EtOAc (40 ml) at rt. The mixture was purged and backfilled with hydrogen three times, then stirred at rt for 16 h under H2(15 psi). The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by preparative HPLC to afford 5-[2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one (250 mg, 62% yield) as ayellow solid. LC-MS: m / z = 483.3 [M+H]+, ESI pos. Chiral SFC (Column: Phenomenex-Cellulose-2, eluent: EtOH (0.1 % NH3·H2O) in CO2) afforded four stereoisomers:

[1190] Isomer 1 (Example 75): re / -(laR*,7bR*)-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one (24.0 mg, 9.6% yield) as a white solid. LC-MS: m / z = 483.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1191] Isomer 2 (Example 76): re / -(laS*,7bS*)-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one (36.2 mg, 15% yield) as a white solid. LC-MS: m / z = 483.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1192] Isomer 3 (Example 77): re / -(laR*,7bR*)-5-[re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one (28.8 mg, 12% yield) as a white solid. LC-MS: m / z = 483.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1193] Isomer 4 (Example 78): re / -(laS*,7bS*)-5-[re / -(2S*,4R*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one (31.5 mg, 13% yield) as a white solid. LC-MS: m / z = 483.2 [M+H]+, ESI pos. *The stereochemistry was assigned arbitrarily.

[1194]

[1195] re / -(2R*,4R*)-9-[ re / -(2R*,4S*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-ll-(2,4-difluoro...

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:X1and X2are each independently selected from the group consisting of N and CH; A is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl and C3-C10-cycloalkyl;A1is selected from the group consisting of N and CR10;A2is selected from the group consisting of O and CR11R12;R1, R2and R3are each independently selected from the group consisting of halogen, C1-C6-alkyl and halo-C1-C6-alkyl;R4is selected from the group consisting of hydrogen, C1-C6-alkyl, halo-Ci-Ce- alkyl, C3-C10-cycloalkyl, and C3-C10-cycloalkyl-C1-C6-alkyl;R5is selected from the group consisting of hydrogen and C1-C6-alkyl;R6and R7are each independently selected from the group consisting of hydrogen, C1-C6-alkyl, and halo- C1-C6-alkyl; orR6and R7, taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl;R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, C1-C6-alkyl, halo-Ci-Ce- alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10- cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C3-C10- cycloalkyl-C1-C6-alkoxy, C3-C10-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-memberedheterocyclyl-C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo- C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl- C1-C6-alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3-C10-cycloalkyloxy, 3- to 6- membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6- membered heterocyclyl -C1-C6-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce- alkoxy and 3- to 6-membered heterocyclyloxy;R8bis selected from the group consisting of hydrogen and C1-C6-alkyl;R9is selected from the group consisting of hydrogen and C1-C6-alkyl;R10is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci- Ce-alkyl; andR11and R12are each independently selected from the group consisting of hydrogen and halogen.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1and X2are both N.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A1is selected from the group consisting of N and CR10;A2is O; andR10is hydrogen.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl; R1is selected from the group consisting of halogen and halo-C1-C6-alkyl;R2is selected from the group consisting of hydrogen and halogen; andR3is selected from the group consisting of hydrogen and halogen.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A is selected from the group consisting of phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo[l.l.l]pentane;R1is selected from the group consisting of fluoro, chloro, CHF2, and CF3;R2is selected from the group consisting of hydrogen and fluoro; andR3is selected from the group consisting of hydrogen and fluoro.

6. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A is C6-C10-aryl;R1is halogen;R2is selected from the group consisting of hydrogen and halogen; andR3is hydrogen.

7. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A is phenyl;R1is selected from the group consisting of fluoro and chloro;R2is selected from the group consisting of hydrogen and fluoro; andR3is hydrogen.

8. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the group9. The compound of formula (I) according to and one of claims 1 to 8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl.

10. The compound of formula (I) according to and one of claims 1 to 8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of methyl and cyclopropyl.

11. The compound of formula (I) according to and one of claims 1 to 8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is Ci-Ce- alkyl.

12. The compound of formula (I) according to and one of claims 1 to 8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is methyl.

13. The compound of formula (I) according to and one of claims 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R5is selected from the group consisting of hydrogen and methyl.

14. The compound of formula (I) according to and one of claims 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R5is hydrogen.

15. The compound of formula (I) according to and one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R6is selected from the group consisting of hydrogen and halo- C1-C6-alkyl; and R7is hydrogen; orR6and R7, taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl.

16. The compound of formula (I) according to and one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R6is selected from the group consisting of hydrogen and CF3; andR7is hydrogen; orR6and R7, taken together with the carbon atom to which they are attached, form a cyclopropyl.

17. The compound of formula (I) according to and one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R6and R7are both hydrogen.

18. The compound of formula (I) according to and one of claims 1 to 17, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; and wherein said 3- to 6- membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; andR8bis hydrogen.

19. The compound of formula (I) according to and one of claims 1 to 17, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R8ais selected from the group consisting of IH-pyrazolyl, pyrazinyl, 1H- pyridazin-6-one, lH-pyrazin-2-one, and lH-pyridin-2-one, wherein said 1H- pyrazolyl, pyrazinyl, lH-pyridazin-6-one, lH-pyrazin-2-one, and IH-pyridin- 2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; andR8bis hydrogen.

20. The compound of formula (I) according to and one of claims 1 to 17, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:is selected from the group consisting of:R8bis hydrogen.

21. The compound of formula (I) according to and one of claims 1 to 20, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R9is hydrogen.

22. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1and X2are both N;A1is selected from the group consisting of N and CR10;A2is O;A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl; R1is selected from the group consisting of halogen and halo-C1-C6-alkyl;R2is selected from the group consisting of hydrogen and halogen;R3is selected from the group consisting of hydrogen and halogen;R4is selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; R5is selected from the group consisting of hydrogen and C1-C6-alkyl;R6is selected from the group consisting of hydrogen and halo- C1-C6-alkyl; and R7is hydrogen; orR6and R7, taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl;R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of Ci-Ce- alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; and wherein said 3- to 6- membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl;R8bis hydrogen;R9is hydrogen; andR10is hydrogen.

23. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1and X2are both N;A1is selected from the group consisting of N and CR10;A2is O;A is selected from the group consisting of phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo[l.l.l]pentane;R1is selected from the group consisting of fluoro, chloro, CHF2, and CF3;R2is selected from the group consisting of hydrogen and fluoro;R3is selected from the group consisting of hydrogen and fluoro;R4is selected from the group consisting of methyl and cyclopropyl;R5is selected from the group consisting of hydrogen and methyl;R6is selected from the group consisting of hydrogen and CF3; andR7is hydrogen; orR6and R7, taken together with the carbon atom to which they are attached, form a cyclopropyl;R8ais selected from the group consisting of IH-pyrazolyl, pyrazinyl, 1H- pyridazin-6-one, lH-pyrazin-2-one, and lH-pyridin-2-one, wherein said 1H-pyrazolyl, pyrazinyl, lH-pyridazin-6-one, lH-pyrazin-2-one, and IH-pyridin- 2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl;R8bis hydrogen;R9is hydrogen; andR10is hydrogen.

24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1and X2are both N;A1is selected from the group consisting of N and CR10;A2is O;A is C6-C10-aryl;R1is halogen;R2is selected from the group consisting of hydrogen and halogen;R3is hydrogen;R4is Ci-Ce-alkyl;R5is hydrogen;R6is hydrogen;R7is hydrogen;R8ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl;R8bis hydrogen;R9is hydrogen; andR10is hydrogen.

25. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1and X2are both N;A1is selected from the group consisting of N and CR10;A2is O;A is phenyl;R1is selected from the group consisting of fluoro and chloro;R2is selected from the group consisting of hydrogen and fluoro;R3is hydrogen;R4is methyl;R5is hydrogen;R6is hydrogen;R7is hydrogen;R8ais selected from the group consisting of IH-pyrazolyl and lH-pyridin-2-one, wherein said IH-pyrazolyl and lH-pyridin-2-one are substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl; R8bis hydrogen;R9is hydrogen; andR10is hydrogen.

26. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from:( 1 aRS, 7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [(2 S)-2-( 1 -methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[(2S)-2-(l-methylpyrazol- 4-yl)morpholino] - 1 a, 7b-dihy dro- 1 H-cy clopropafc] [2, 6]naphthyri din-3 -one;( 1 aRS, 7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [(2R)-2-( 1 -methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2S*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2S*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[(2R*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2S*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[(2R*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2S*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[(2R*)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin-3-one; rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2S*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin- 3 -one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-la,2-dimethyl-5-[(2R*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-l,7b-dihydrocyclopropa[c][2,6]naphthyridin- 3 -one;( 1 RS, 1 aSR, 7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [(2 SR)-2-( 1 - methylpyrazol-4-yl)morpholin-4-yl]-l -(trifluoromethyl)- la, 7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;( 1 aSR, 7bRS)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5 - [(2 SR)-2-( 1 -methylpyrazol- 4-yl)morpholin-4-yl]spiro[ 1 a,7b-dihydrocyclopropa[c] [2,6]naphthyridine- 1,1'- cy clopropane] -3 -one;rel-(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one;rel-(2S*,4S*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2S*)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one;rel-(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l- methylpyrazol-4-yl)morpholin-4-yl]-5, 8,10-tri azatri cyclo[5.4.0.02, 4]undeca- 1(1 l),7,9-trien-6-one;rel-(2S*,4S*)-l l-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[(2R*)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6- one;rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2S*,4S*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2R*,4R*)-ll-(4-chloro-2-fluoro-phenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien-6-one; rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien- 6-one;rel-(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2S*,4R*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10- trien-6-one;rel-(2S*,4S*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10-trien- 6-one;rel-(2R*,4R*)-ll-(4-chlorophenyl)-5-methyl-9-[rel-(2R*,4S*)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-l(7),8,10- trien-6-one;rel-(2R*,4R*)-5-methyl-9-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-11-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-1(7),8,10-trien-6-one;rel-(2S*,4S*)-5-methyl-9-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-11-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-5,8,10-triazatricyclo[5.4.0.02,4]undeca-1(7),8,10-trien-6-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2R*,4S*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-5-[rel-(2S*,4R*)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -7-(2-fluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -7-(2-fluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(4,4-difluorocyclohexyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(2R*,4R*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(2,4-difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2S*,4S*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(2,4-difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2R*,4R*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(2,4-difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2S*,4S*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(2,4-difluorophenyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2R*,4R*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(4,4-difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2S*,4S*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(4,4-difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2R*,4R*)-9-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(4,4-difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2S*,4S*)-9-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 l-(4,4-difluorocyclohexyl)-5-methyl-5,8,10-triazatricyclo[5.4.0.02,4]undeca- 1(1 l),7,9-trien-6-one;rel-(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-9-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2R*,4R*)-l l-(4-chloro-2-fluoro-phenyl)-9-[rel-(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2S*,4S*)-l l-(4-chloro-2-fluoro-phenyl)-9-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(2S*,4S*)-l l-(4-chloro-2-fluoro-phenyl)-9-[rel-(2S*,4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-methyl-5,8,10- triazatricyclo[5.4.0.02,4]undeca-l(l l),7,9-trien-6-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro- lH-cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro- lH-cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro- lH-cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro- lH-cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l -methyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aR*,7bR*)-7-(4,4-difluorocy cl ohexyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l -methyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aS*, 7bS*)-7-(4,4-difluorocyclohexyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l -methyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;7-(4-chloro-2-fluoro-phenyl)-5-[2-(5-methoxypyrazin-2-yl)tetrahydropyran-4-yl]-2- methyl- 1 a,7b-dihydro- lH-cyclopropa[c] [2,6]naphthyridin-3 -one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-5-[rel-(2S*,4R*)-2-(5-keto-4-methyl- pyrazin-2-yl)tetrahy dropyran-4-yl] -2-methyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-5-[rel-(2R*,4S*)-2-(5-keto-4-methyl- pyrazin-2-yl)tetrahy dropyran-4-yl] -2-methyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chloro-2-fluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxopyridazin-4-yl)oxan-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxopyridazin-4-yl)oxan-4-yl]-la,7b-dihydro-lH-cyclopropa[c][2,6]naphthyridin- 3 -one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l-methyl-6- oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l-methyl-6- oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- y 1 ] -7-(4-fluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -7-(4-fluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -7-(4-fluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- y 1 ] -7-(4-fluorophenyl)-2-m ethyl- 1 a, 7b-dihy dro- 1 H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*, 4S*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*, 4R*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aS*, 7bS*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l- methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2R*,4S*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-( 1 aR*, 7bR*)-7-(2,4-difluorophenyl)-5 - [rel-(2R*,4 S *)-2-(5 -methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-( 1 aR*, 7bR*)-7-(2,4-difluorophenyl)-5 - [rel - (2 S *,4R*)-2-(5 -methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-5-[rel-(2R*,4S*)-2-(5-methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-5-[rel-(2S*,4R*)-2-(5-methoxypyrazin-2- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(4-methyl-5- oxo-pyrazin-2-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(4-methyl-5- oxo-pyrazin-2-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2R*,4S*)-2- (l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2S*,4R*)-2- (l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2R*,4S*)-2- (l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-5-[rel-(2S*,4R*)-2- (l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chlorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(4-chlorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-[2-fluoro-4-(trifluoromethyl)phenyl]-5-[rel-(2R*,4S*)-2-(6-keto-l- methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-[2-fluoro-4-(trifluoromethyl)phenyl]-5-[rel-(2S*,4R*)-2-(6-keto-l- methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-keto- pyridazin-4-yl)tetrahydropyran-4-yl]-2-methyl- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-keto- pyridazin-4-yl)tetrahydropyran-4-yl]-2-methyl- 1 a,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2S*,4R*)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-(4-chlorophenyl)-5-[rel-(2R*,4S*)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;;9uo-£-uipuXipqdpu[9‘ ][o]pdojdopX9'HI -ojpXqip-q£‘p i -[Aqi9ui-£-([Au9qdojonpip-p‘£)- _-[[A-p-ui3jAdojpAqi3Ji9i([A-17-uizppuXd-oj9 [-9-iXdojdopXo-i)- -(sitsi7‘*'as)-F.i] -(* ‘*'aBl);guo-£-uipuXqjqdpu[9‘ ][9]pdojdopX9 os -HI-°-ip^q!p-QZ,‘Bi-[iX-p-upjXdojpXqpj j-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-l)-Z-('a9‘*St7‘*HZ)]-S-I^ ra-Z-(^u9qdojon9-p)-^-(*sqZ.‘*S^l)-P-i;guo-£-uipuXqjqdpu[9‘ ][9]pdojdopX9-HI-°-ip^q!p-QZ,‘Bi-[iX-p-upjXdojpXqpj j-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-i)-z;-(S9‘*'ai7‘*sz;)] -i^9ui-z;-(^u9qdojoHo- -£-(sit'Hq£‘sit'aBi)-pj sz;9uo-£-uipuXqjqdpu[9‘ ][9]pdojdopXo-HI-°-ip^ ip-qz,‘Bi-[iX-p-upjXdojpXqpj j-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-i)-z-(S9‘*'at7‘*sz)]-s-i q tu-z-(i u9qdojon9-p)-^-(*sqz.‘*s^i)-p-i;9uo-£-uipuXqjqdpu[9‘ ][9]pdojdopXo-HI-°-ip^ ip-qz,‘Bi-[iX-p-upjXdojpXqpj j-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9 oz -l)-Z-('a9‘*St7‘*HZ)]-S-I^ ui-Z-(^u9 dojon9-p)-^-(^q^‘*'aPi)-pj;9uo-£-uipuXqjqdpu[9‘ ][9]pdojdopXo-HI-°-ip^ ip-qz,‘Bi-[iX-p-upjXdojpXqpj j-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-i)-z-('a9‘*'at7‘*sz)]-s-i tu-z-(i u9 dojon9-p)-^-(*sqz.‘*s^i)-p-i;9uo-£-uipuXqjqdpu[9‘ ][9]pdojdopXo ST -HI-°-ip^!p-qz,‘Bi-[iX-p-upjXdojpXqpj T-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-l)-Z-(S9‘*St7‘*HZ)]-S-I^ ui-Z-(^u9 dojon9-p)-^-(*sqZ.‘*S^l)-P-i;guo-£-uipuXqjqdpu[9‘ ][9]pdojdopX9-HI-°-ip^!p-qz,‘Bi-[iX-p-upjXdojpXqpj T-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-i)-z-('a9‘*'at7‘*sz)]-s-i tu-z-(i u9 dojon9-p)-^-(^q^‘*'aPi)-pj ox;guo-£-uipuXqjqdpu[9‘ ][9]pdojdopX9-HI-°-ip^!p-qz,‘Bi-[iX-p-upjXdojpXqpj T-|Xq ui-9-(|X-p-pzpjXd|XdojdopX9-l)-Z-(S9‘*St7‘*HZ)]-S-I^ ui-Z-(^u9 dojon9-p)-^-(^q^‘*'aPi)-pj;guo-£-uipuXqjqdpu[9‘ ][9]pdojdopX9-HI-°-ip^!p-qz,‘Bi-iX ui- -[|X-p-upjXdojpX pj j(|XpuXd s -E-lXq ui-i-o 5[-9)- -(^p‘*sz)-P-i]-S-(^u9 dojon9-p)-^-(*'aq^‘*'aPi);guo-£-uipuXqjqdpu[9‘ ][9]pdojdopX9-HI-°-ip^!p-qz,‘Bi-iX ui- -[|X-p-upjXdojpX pj j(|XpuXd-E-lXq ui-i-o 5[-9)- -(*st7‘*HZ)-P-i]-S-(^u9 dojon9-p)-^-(*'aq^‘*'aPi)- 6EZ -(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-keto-pyridazin-4- yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-5-[rel-(2R*,4S*)-2-(l-cyclopropyl-6-keto-pyridazin-3- yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-5-[rel-(2S*,4R*)-2-(l-cyclopropyl-6-keto-pyridazin-3- yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l,5-dimethyl- 6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro- 1H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laS*,7bS*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l,5-dimethyl- 6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro- 1H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(l,5-dimethyl- 6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro- 1H- cyclopropa[c][2,6]naphthyridin-3-one;rel-(laR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(l,5-dimethyl- 6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 1 a,7b-dihydro- 1H- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-(2,4-difluorophenyl)-5-[rel-(2R*,4S*)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;(laR*,7bR*)-7-(2,4-difluorophenyl)-5-[rel-(2S*,4R*)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2-methyl-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2R*, 4S*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(l aR*,7bR*)-7-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-5-[rel-(2S*, 4R*)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-la,7b-dihydro-lH- cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aR*,7bR*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2R*,4S*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-(4-chloro-2,6-difluoro-phenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aR*,7bR*)-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-5-[rel-(2R*,4S*)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aR*,7bR*)-7-(2,4-difluorophenyl)-2-methyl-5-[rel-(2S*,4R*)-2-(4-methyl-5-oxo-pyrazin-2-yl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-5-[rel-(2R*,4S*)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aS*,7bS*)-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-5-[rel-(2S*,4R*)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aR*,7bR*)-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-5-[rac-rel-(2R*,4S*)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;rel-(1aR*,7bR*)-7-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2-methyl-5-[rac-rel-(2S*,4R*)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;(1aR*,7bR*)-5-[rel-(2R*,4S*)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-7-[4-(trifluoromethyl)phenyl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one;(1aR*,7bR*)-5-[rel-(2S*,4R*)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-7-[4-(trifluoromethyl)phenyl]-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one; and(1aR*,7bR*)-7-[4-(difluoromethyl)-2-fluoro-phenyl]-5-[rel-(2S*,4R*)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one and (1aR*,7bR*)-7-[4-(difluoromethyl)-2-fluoro-phenyl]-5-[rel-(2R*,4S*)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2-methyl-1a,7b-dihydro-1H-cyclopropa[c][2,6]naphthyridin-3-one.

27. The compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a therapeutically active substance.

28. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a therapeutically inert carrier.

29. A method of treating or preventing a condition associated with a loss of function of human TREM2 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 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, or the pharmaceutical composition according to claim 28.

30. The method according to claim 29, wherein said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

31. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition according to claim 28, for use in a method according to claim 29 or 30.

32. Use of a compound according to any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 28, in a method according to claim 29 or 30.

33. Use of a compound according to any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to claim 29 or 30.

34. The invention as described hereinbefore.

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