NZ794798A - New isoxazolyl ether derivatives as gaba a alpha5 pam - Google Patents

Abstract

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, X, Y and Z are as described herein, compositions including the compounds and methods of using the compounds.

Description

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, X, Y and Z are as bed herein, compositions including the compounds and methods of using the compounds.

NZ 794798 NEW ISOXAZOLYL ETHER DERIVATIVES AS GABA A ALPHA5 PAM This application is a divisional of New Zealand patent application 751837, which is the al phase entry in New Zealand of PCT ational application , filed 7 December 2017 and published as applications is incorporated herein by reference.

The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to GABAA α5 receptor positive allosteric modulators (PAMs) for the ent or prophylaxis of GABAA α5 receptor related diseases and diseases or conditions which can be treated by the modulation of GABAA α5 receptor activity, such Alzheimer’s disease, mild cognitive impairment (MCI), lated cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, raumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), e-X er.

The present invention provides novel compounds of formula (I) wherein X is ed from i) N, and ii) CH; Y is selected from i) N, and ii) CR10; Z is selected from i) N, and ii) CR11; R1 is selected from i) C1alkyl, ii) halo-C1alkyl, iii) C1alkoxy, iv) halo-C1alkoxy, v) y-C1alkyl, vi) C3cycloalkyl, vii) halogen, and viii) amino substituted on the nitrogen atom by one or two substituents independently selected from a. H, b. C1alkyl, and c. C3cycloalkyl; R2 is selected from i) H, and ii) n; R3 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl, iv) hydroxy-C1alkyl, and v) halo-C1alkyl; R4 is selected from i) H, ii) lkyl, iii) C1alkoxy, iv) C3cycloalkyl, and v) halogen; R5 is H; R6 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl tuted with R7, R8 and R9, iv) C3cycloalkyl-C1alkyl substituted with R7, R8 and R9, v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, vii) hydroxy-C1alkyl, viii) dihydroxy-C1alkyl, ix) halo-C1alkyl, x) heterocycloalkyl substituted with R7, R8 and R9, and xi) heterocycloalkyl-C1alkyl substituted with R7, R8 and R9; R7, R8 and R9 are independently selected from i) H, ii) C1alkyl, iii) C1alkoxy, iv) C1alkoxyalkyl, v) C1alkoxycarbonyl, vi) cyano, vii) C3cycloalkoxy, viii) C3cycloalkyl, ix) halo-C1alkoxy, x) halo-C1alkyl, xi) halogen, xii) hydroxy, xiii) hydroxy-C1alkyl, and xiv) oxo; R10 is selected from i) H, ii) C1alkyl, iii) C1alkoxy, iv) ycloalkyl, and v) halogen; R11 is selected from i) H, ii) C1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, and v) halogen; or R5 and R10 together form -(CH2)n-; or R5 and R11 together form -(CH2)n-; or R5 and R6 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R7, R8 and R9; n is selected from 1 and 2; or pharmaceutically acceptable salts.

Receptors for the major tory neurotransmitter, gamma-aminobutyric acid (GABA), are d into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily and (2) GABAB receptors, which are members of the G-protein linked receptor family. The GABAA or complex which is a membrane-bound heteropentameric protein r is composed principally of α, β and γ subunits. GABAA receptors are ligandgated chloride channels and the principal mediators of inhibitory neurotransmission in the human brain.

There are 19 genes encoding for GABAA receptor ts that assemble as pentamers with the most common stoichiometry being two α, two β and one γ subunit. GABAA subunit ations give rise to functional, circuit, and behavioral specificity (Sieghart, 2006; Vithlani et al., 2011). GABAA ors containing the α5 subunit (GABAA α5) are of particular interest due to their cted pattern of expression and unique physiological and pharmacological properties (Sur et al., 1999; Mohler, 2011). The GABAA α5 subunit-containing receptors are preferentially localized in the hippocampus, prefrontal cortex, nucleus accumbens and amygdala, which are key regions believed to be involved in the neuropathology and pathophysiology of a variety of CNS disorders.

Hippocampal hyperactivity as result of reduced GABAA α5 expression or GABAergic t or other conditions, is the common hallmark of a variety of CNS disorders terized by cognitive decline (memory and executive functions). In such a disease state, a GABAA α5 positive allosteric modulator (PAM) and not a negative allosteric modulator (NAM) may be an effective treatment for the cognitive ment associated with such es.

Multiple lines of evidence t that an imbalance between excitatory/inhibitory neurotransmission arising from dysfunction of GABAergic signaling system, the main inhibitory neurotransmitter system in the brain, to be at the core of the pathogenesis a variety of CNS disorders. Given the distribution of GABAA α5 receptors, they are very attractive targets for restoring levels of intracortical inhibition and consequently the (E/I) circuit balance in these conditions. Therefore compounds described herein and their pharmaceutically able salts and esters can be used, alone or in combination with other drugs, as disease-modifying or as symptomatic agents for the treatment or prevention of acute neurological disorders, chronic ogical disorders, cognitive disorders, Alzheimer’s disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Angelman syndrome, Prader-Willi syndrome, Rett me, Down syndrome, neurofibromatosis type I, sleep ers, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), fragile-X disorder, dementia caused by AIDS, age-associated memory impairment, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, post-traumatic stress disorder (PTSD), drug ions, movement disorders, Parkinson’s disease, restless leg syndrome, mild cognitive impairment (MCI), cognition deficiency disorders, age-related cognitive decline, multi-infarct dementia, mood ers, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, epilepsy, stroke and attentional disorders.

The most preferred indication in accordance with the present invention is autism spectrum disorder (ASD). ASD is a complex, heterogeneous neurodevelopmental disorder characterized by impairments in three core symptoms: social interactions, repetitive behaviors and cognitive deficits. The ted prevalence of ASD in the United States is 1 in 68 children (CDC, 2014), and it is ted that 1% of the world’s population have ASD (WHO, 2013).

No ed pharmacological treatment exists for the core social communication and repetitive ts of ASD Autism Spectrum Disorder, and this disorder continues to be an area of high unmet medical need. Current approved treatments for associated ms of ASD are limited to the antipsychotics (Risperidone and razole) indicated for the ent of irritability associated with ASD ms. Emerging evidence suggests that the GABAergic system, the main tory neurotransmitter system in the brain, plays a key role in the pathophysiology of ASD (Dhossche et al., 2002; Pizzarelli and Cherubini, 2011; Robertson et al., 2016).

Both genetic and imaging studies using positron emission tomography study (PET) and ic resonance oscopy (MRS) suggest alterations in GABAergic signaling in ASD.

GABAA receptor binding has been reported to be dramatically reduced in the superior and medial frontal cortex of patients with ASD using [123I]-iomazenil PET (Mori et al., 2012). Also, a pilot [11C]-RO154513 PET study found reduced binding of this tracer suggesting lower levels of GABAA α5 receptor in ASD (Mendez et al., 2012). MRS studies found altered GABA levels in ASD (Gaetz et al., 2014; Rojas et al., 2014) and in particular some recent studies showed reduced GABA and altered somatosensory function in children with ASD and (Puts et al., 2016; son et al., 2016). In line with these ations, postmortem reduced expression of GABAA receptor subunits including GABRB3 (DeLorey, 2005; Abrahams and Geschwind, 2008) and the GABA sizing enzymes, glutamic acid decarboxylase (GAD) 65 and 67 were found in parietal and cerebellar cortices of patients with autism (Fatemi et al., 2002). antly, a reduction of GABAergic inhibitory activity has been proposed to result in hyperexcitability observed in ASD, including the high incidence of seizures and auditory-tactile hypersensitivity (Rubenstein and Merzenich, 2003; Frye et al., 2016). The altered GABAergic function may reduce the threshold for developing seizures as demonstrated by the high comorbidity of epilepsy in ASD, occurring in up to one-third of affected people. Finally, enhancement of GABAA or activity by non-selective BZDs have been shown to ameliorate behavioral deficits in mouse models of ASD, however very narrow therapeutic margins were observed due to sedation mediated by the GABAA α1 subtype (Han et al., 2012, 2014; Soto et al. 2013). These findings support the notion that rebalancing of GABAergic transmission via GABAA α5 receptors can improve symptoms in ASD without the side effects of non-selective benzodiazepines.

Objects of the present invention are compounds of formula (I) and their pharmaceutically acceptable salts and esters, the preparation of the above ned compounds, ments containing them and their manufacture as well as the use of the above mentioned compounds in the treatment or prevention of diseases related to GABAA α5 receptor related diseases and diseases or ions which can be treated by the modulation of GABAA α5 receptor activity, such as Alzheimer’s disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism um disorder (ASD), Angelman me, Rett syndrome, -Willi me, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-X disorder.

Compounds of the present ion are selective GABAA α5 receptor positive allosteric modulators (PAMs) as they enhance the function of α5-containing GABAA receptors by sing GABAergic currents (influx of de) at a given EC20 concentration of gamma amino butyric acid (GABA). Most preferred are compounds with a Ki (nM) < 35 towards α5 subunit. In a preferred embodiment the compounds of the invention are binding selective for the α5 subunit relative to the α1, α2 and α3 subunits. Compatible with the α5-subtype brain distribution, ive GABAA α5 PAMs will restore GABAergic signaling in key brain s (e.g. hippocampus, amygdala, nucleus accumbens and preftrontal cortex) without the side-effects of non-selective GABAA modulators (e.g. benzodiazepines).

The term “C1alkoxy” denotes a group of the formula -O-R’, wherein R’ is an C1alkyl group. Examples of C1alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy , isobutoxy and tert-butoxy. Particular examples are methoxy and . In the case of R1, particular example is methoxy.

The term “C1alkoxy-C1alkyl” denotes an C1alkyl group n one of the hydrogen atoms of the C1alkyl group has been replaced by an C1alkoxy group. es of C1 alkoxy-C1alkyl groups include e methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl. Particular alkoxyalkyl group is methoxyethyl.

The term “C1alkoxycarbonyl” denotes a group of the formula -C(O)-R’, wherein R’ is a C1alkoxy group. Examples of lkoxycarbonyl groups include groups wherein R’ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or utoxy Particular example of C1alkoxycarbonyl is a group wherein R’ is ethoxy.

The term “C1alkyl” denotes a monovalent linear or ed saturated hydrocarbon group of 1 to 6 carbon atoms. Examples of C1alkyl include methyl, ethyl, propyl, isopropyl, nbutyl , iso-butyl, sec-butyl, tert-butyl and pentyl. Particular C1alkyl groups are methyl, ethyl, isopropyl and tert-butyl. In the case of R1, more particular example is methyl. In the case of R3, more particular examples are methyl and ethyl. In the case of R3, further more particular example is methyl.

The term “C1alkylsulfonyl” denotes a group of the formula -S(O)2-R’, n R’ is a C1alkyl group. Examples of C1alkylsulfonyl e groups wherein R’ is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tyl, tert-butyl or pentyl.

The term “C1alkylsulfonyl-C1alkyl” denotes a C1alkyl group n one of the hydrogen atoms of the C1alkyl group has been replaced by a C1alkylsulfonyl group.

Particular C1alkylsulfonyl-C1alky is methylsulfonyl(methyl)butanyl.

The term “amino” denotes a -NH2 group.

The term “bicyclic ring system” denotes two rings which are fused to each other via a common single or double bond (annelated ic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic. ic ring systems can comprise heteroatoms selected from N, O and S.

The term “carbonyl” denotes a -C(O)- group.

The term “cyano” s a -C≡N group.

The term “cyano-C1alkyl”denotes an -C1alkyl group wherein one of the hydrogen atoms of the lkyl group has been replaced by cyano group. Examples of cyano-C1alkyl include cyanomethyl, cyanoethyl, ropyl and cyanobutyl. Particular es are cyanoethyl and cyanobutyl.

The term “cyano-C1alkoxy”denotes an alkoxy group wherein one of the hydrogen atoms of the C1alkoxy group has been replaced by cyano group.

The term “C3cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic arbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having on or two carbon atoms in common. Examples of monocyclic C3 cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Particular monocyclic lkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl. Example of bicyclic C3cycloalkyl is spiro[3.3]heptanyl. In the case of R1 and R3, particular example of C3cycloalkyl is cyclopropyl.

The term “C3cycloalkyl-C1alkyl” denotes an -C1alkyl group wherein one of the hydrogen atoms of the C1alkyl group has been replaced by an C3cycloalkyl group. Examples of C3cycloalkyl-C1alkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, opropylbutyl, cyclopentylbutyl, exylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl and bicyclo[2.2.2]octanylethyl. Particular example of C3cycloalkyl-C1alkyl is cyclopropylmethyl.

The term “dihydroxy-C1alkyl”denotes an C1alkyl group wherein two of the hydrogen atoms of the lkyl group have been ed by an hydroxy group. es of dihydroxy- C1alkyl include dihydroxyethyl, dihydroxypropyl, dihydroxy(methyl)propyl and dihydroxybutyl. Particular example is dihydroxy(methyl)propyl.

The term C1alkoxy” denotes an C1alkoxy group wherein at least one of the hydrogen atoms of the C1alkoxy group has been replaced by same or different halogen atoms.

The term “perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.

Particular haloalkoxy groups are difluoromethoxy and difluoroethoxy.

The term “halo-C1alkyl” denotes an C1alkyl group wherein at least one of the hydrogen atoms of the C1alkyl group has been replaced by the same or different halogen atoms.

The term “perhalo-C1alkyl alkyl” denotes 6-alkyl alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. es of kyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular halo-C1alkyl l group is methyl, difluoromethyl are trifluoromethyl. More halo-C1alkyl l group trifluoromethyl.

The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo or iodo. Particular halogen is fluoro. In the case of R1, particular halogen is chloro.

The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated monoor ic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common. Examples for monocyclic saturated heterocycloalkyl are hydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, ydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl.

Examples for bicyclic saturated heterocycloalkyl are oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxaaza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxaaza-bicyclo[3.3.1]nonyl, or 3-thiaaza-bicyclo[3.3.1]nonyl.

Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, o- oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular heterocycloalkyl are oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, oxabicyclo[2.2.1]heptanyl, ro[3.3]heptanyl, azetidinyl, ydrothiophenyl and tetrahydrothiopyranyl. More particular heterocycloalkyl is tetrahydropyranyl.

In the case of the cycloalkyl formed by R5 and R6 together with the nitrogen atom to which they are attached, particular examples of heterocycloalkyl are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxaazabicyclo[3.1.1]heptanyl, oxaazabicyclo[2.2.1]heptanyl, azaspiro[3.3]heptanyl, oxaazaspiro[3.3]heptanyl and thiaazaspiro[3.3]heptanyl.

The term “heterocycloalkyl-C1alkyl” denotes an C1alkyl group wherein one of the hydrogen atoms of the C1alkyl group has been replaced by a heterocycloalkyl group. Particular heterocycloalkyl-C1alkyl is oxetanymethyl.

The term xy” denotes a -OH group.

The term “hydroxy-C1alkyl alkyl” denotes an C1alkyl alkyl group wherein at least one of the hydrogen atoms of the lkyl alkyl group has been replaced by a y group.

Examples of hydroxy-C1alkyl include hydroxymethyl, yethyl, hydroxypropyl, hydroxymethylpropyl, hydroxybutyl and hydroxypentyl. Particular example is hydroxypentyl.

The term “oxo” denotes a =O group.

The term “sulfonyl” s a -S(O)2- group.

The term "pharmaceutically acceptable salts" refers to those salts which retain the biological iveness 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 nic base include, but are not limited to, the sodium, potassium, lithium, um, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, ary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as pylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.

"Pharmaceutically acceptable " means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. es of such compounds include logically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable lents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) s a group which ively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. ary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.

Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further particular ting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular ting group is the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol µM.

The abbreviation uL means microliter and is equivalent to the symbol µL.

The abbreviation ug means microgram and is equivalent to the symbol µg.

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 reoisomers, mixtures of reoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration.

Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically able salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.

A particular embodiment of the present invention provides compounds ing to a (I) as described herein, wherein X is CH.

A particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein Y is N.

A particular embodiment of the present invention provides nds according to formula (I) as bed herein, wherein Z is CR11.

A particular embodiment of the present ion provides compounds according to a (I) as described herein, wherein R1 is selected from i) C1alkyl, ii) halo-C1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, v) halogen, and vi) amino substituted on the nitrogen atom by one or two substituents selected a. H, b. C1alkyl, and c. C3cycloalkyl.

A further particular embodiment of the present invention provides nds according to formula (I) as described herein, wherein R1 is selected from i) C1alkyl, ii) 1alkyl, iii) lkoxy, iv) C3cycloalkyl, v) halogen, and vi) amino substituted on the nitrogen atom by two independently selected C1 alkyl.

A more particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R1 is C1alkyl.

A further more particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R1 is methyl.

A particular embodiment of the present invention provides compounds according to formula (I) as bed herein, wherein R2 is H.

A particular embodiment of the present invention provides compounds according to formula (I) as bed herein, wherein R3 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl, and iv) halo-C1alkyl.

A further particular embodiment of the present invention provides compounds according to formula (I) as bed herein, wherein R3 is selected from i) H, ii) C1alkyl, and iii) C3cycloalkyl.

A more particular embodiment of the present invention provides compounds according to a (I) as described herein, wherein R3 is C1alkyl.

A further more particular embodiment of the present invention provides compounds according to formula (I) as described herein, n R3 is methyl.

A particular embodiment of the t invention es compounds according to formula (I) as bed herein, wherein R4 is selected from i) H, and ii) C1alkyl.

A particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R4 is H.

A ular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R6 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. lkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and l. hydroxy-C1alkyl; iv) C3cycloalkyl-C1alkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. lkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. n, k. hydroxy, and l. hydroxy-C1alkyl; v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, vii) hydroxy-C1alkyl, viii) dihydroxy-C1alkyl, ix) halo-C1alkyl, x) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. hydroxy, and d. oxo; and wherein the heterocycloalkyl is ed from a. oxetanyl, b. tetrahydrofuranyl, c. ydropyranyl, d. oxepanyl, e. oxabicyclo[2.2.1]heptanyl, f. oxaspiro[3.3]heptanyl, g. azetidinyl, h. tetrahydrothiophenyl, and i. tetrahydrothiopyranyl; and xi) oxetanyl-C1alkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, and b. hydroxy.

A further particular embodiment of the present invention provides compounds according to formula (I) as described herein, n R6 is ed from i) C1alkyl, ii) C3cycloalkyl tuted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxyalkyl, d. halo-C1alkyl; iii) hydroxy-C1alkyl, iv) halo-C1alkyl, v) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, and b. C1alkyl, and wherein the heterocycloalkyl is selected from a. oxetanyl, b. tetrahydrofuranyl, c. tetrahydropyranyl, and d. oxaspiro[3.3]heptanyl.

A particular ment of the present invention provides compounds according to formula (I) as described herein, wherein R7, R8 and R9 are independently selected from i) H, ii) C1alkyl, iii) lkoxy, iv) C1alkoxyalkyl, v) C1alkoxycarbonyl, vi) cyano, vii) C3cycloalkoxy, viii) 1alkoxy, ix) halo-C1alkyl, x) halogen, xi) hydroxy, xii) hydroxy-C1alkyl, and xiii) oxo.

A further particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R7 is selected from i) H, ii) C1alkyl, iii) C1alkoxy, iv) C1alkoxyalkyl, v) C1alkoxycarbonyl, vi) cyano, vii) C3cycloalkoxy, viii) halo-C1alkoxy, ix) halo-C1alkyl, x) halogen, xi) hydroxy, xii) hydroxy-C1alkyl, and xiii) oxo.

A more ular ment of the present invention es compounds according to formula (I) as described herein, wherein R7 is ed from i) H, ii) C1alkyl, iii) C1alkoxyalkyl, and iv) halo-C1alkyl.

A further particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R8 is selected from i) H, ii) C1alkyl, iii) halo-C1alkyl, iv) halogen, and v) oxo.

A more particular embodiment of the present invention provides nds according to formula (I) as described herein, wherein R8 is H.

A further ular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R9 is selected from i) H, and ii) halogen.

A more particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R9 is H.

A particular embodiment of the t invention provides compounds according to formula (I) as described herein, wherein R10 is ed from i) H, and ii) n.

A further particular ment of the present invention provides nds ing to formula (I) as described herein, wherein R10 is H.

A particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein R11 is selected from i) H, ii) lkyl, and iii) C1alkoxy.

A further particular embodiment of the present invention es compounds according to formula (I) as described herein, wherein R11 is H.

A particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein n is 1.

A further particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein X is selected from i) N, and ii) CH; Y is selected from i) N, and ii) CR10; Z is ed from i) N, and ii) CR11; R1 is selected from i) C1alkyl, ii) halo-C1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, v) halogen, and vi) amino substituted on the nitrogen atom by two independently selected C1 alkyl; R2 is selected from i) H, ii) halogen; R3 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl, and iv) halo-C1alkyl; R4 is selected from i) H, and ii) C1alkyl; R5 is H; R6 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl tuted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and l. hydroxy-C1alkyl; iv) ycloalkyl-C1alkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxy, d. lkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and l. hydroxy-C1alkyl; v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, vii) dihydroxy-C1alkyl, viii) halo-C1alkyl, ix) cycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. hydroxy, and d. oxo; and wherein the heterocycloalkyl is selected from a. oxetanyl, b. tetrahydrofuranyl, c. tetrahydropyranyl, d. oxepanyl, e. oxabicyclo[2.2.1]heptanyl, f. oxaspiro[3.3]heptanyl, g. azetidinyl, h. tetrahydrothiophenyl, and i. tetrahydrothiopyranyl; and x) yl-C1alkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. hydroxy; R10 is selected from i) H, and ii) halogen; R11 is selected from i) H, ii) C1alkyl, and iii) C1alkoxy; or R5 and R10 together form -(CH2)n-; or R5 and R11 together form -(CH2)n-; or R5 and R6 together with the nitrogen atom to which they are attached form a heterocycloalkyl tuted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. lkyl, c. C1alkoxy, d. cyano, e. halogen, f. hydroxy, and g. oxo; and wherein the heterocycloalkyl is selected from a. azetidinyl, b. pyrrolidinyl, c. piperidinyl, d. morpholinyl, e. thiomorpholinyl, f. oxaazabicyclo[3.1.1]heptanyl, g. oxaazabicyclo[2.2.1]heptanyl, h. azaspiro[3.3]heptanyl, i. oxaazaspiro[3.3]heptanyl, j. thiaazaspiro[3.3]heptanyl; n is 1; or pharmaceutically acceptable salts.

A particular embodiment of the present ion provides nds according to formula (I) as described herein, wherein X is selected from i) N, and ii) CH; Y is selected from i) N, and ii) CR10; Z is selected from i) N, and ii) CR11; R1 is selected from i) C1alkyl, ii) 1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, v) halogen, and vi) amino substituted on the nitrogen atom by two independently selected C1 alkyl; R2 is selected from i) H, ii) halogen; R3 is selected from i) H, ii) C1alkyl, iii) ycloalkyl, and iv) halo-C1alkyl; R4 is selected from i) H, and ii) C1alkyl; R5 is H; R6 is selected from i) H, ii) C1alkyl, iii) C3cycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. 1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and l. hydroxy-C1alkyl; iv) C3cycloalkyl-C1alkyl substituted with R7, R8 and R9, n R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and l. y-C1alkyl; v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, vii) dihydroxy-C1alkyl, viii) halo-C1alkyl, ix) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. hydroxy, and d. oxo; and wherein the heterocycloalkyl is selected from a. oxetanyl, b. tetrahydrofuranyl, c. tetrahydropyranyl, d. oxepanyl, e. oxabicyclo[2.2.1]heptanyl, f. oxaspiro[3.3]heptanyl, g. azetidinyl, h. ydrothiophenyl, and i. tetrahydrothiopyranyl; and x) oxetanyl-C1alkyl tuted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. hydroxy; R10 is selected from i) H, and ii) halogen; R11 is selected from i) H, ii) C1alkyl, and iii) C1alkoxy; or pharmaceutically acceptable salts.

A particular embodiment of the present ion provides compounds according to formula (I) as described , wherein X is selected from i) N, and ii) CH; Y is selected from i) N, and ii) CR10; Z is CR11; R1 is C1alkyl; R2 is selected from i) H, ii) halogen; R3 is selected from i) C1alkyl, ii) C3cycloalkyl, and iii) halo-C1alkyl; R4 is selected from i) H, and ii) C1alkyl; R5 is H; R6 is selected from i) lkyl, ii) C3cycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxyalkyl, and d. halo-C1alkyl; iii) hydroxy-C1alkyl, iv) 1alkyl, v) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, and b. C1alkyl; and wherein the heterocycloalkyl is selected from a. oxetanyl, b. tetrahydrofuranyl, c. tetrahydropyranyl, d. oxepanyl, and e. oxaspiro[3.3]heptanyl; R10 is H; R11 is H; or pharmaceutically acceptable salts.

A particular embodiment of the present invention es compounds according to formula (I) as bed herein, wherein X is CH; Y is N; Z is CR11; R1 is C1alkyl; R2 is H; R3 is C1alkyl; R4 is H; R5 is H; R6 is heterocycloalkyl substituted with R7, R8 and R9; R7, R8 and R9 are H; R11 is H; or pharmaceutically acceptable salts.

A particular embodiment of the present invention provides compounds according to formula (I) as described herein, wherein X is CH; Y is N; Z is CR11; R1 is lkyl; R2 is H; R3 is C1alkyl; R4 is H; R5 is H; R6 is tetrahydropyranyl substituted with R7, R8 and R9; R7, R8 and R9 are H; R11 is H; or pharmaceutically acceptable salts.

Particular examples of compounds of formula (I) as described herein are selected from 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide N-(cyclopropylmethyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; N-ethyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxamide; N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide (S)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran idazinecarboxamide; utyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one; 2-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one; utyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)nicotinamide; 2-(2-hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H- pyrrolo[3,4-c]pyridin-3(2H)-one; (S)(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; (S)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyrazinecarboxamide; -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyrazinecarboxamide; N-(1,1-dioxothiolanyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; methyl(6-methylpyridinyl)isoxazolyl)methoxy)nicotinamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxamide; N-((3S)-1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide; N-((3R)-1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide; N-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-pyran yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; N-((1S,2R)Hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1S,2S)Hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1R,2R)Hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-cyclopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-((1R,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((3S,4R)hydroxytetrahydropyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; ydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridazinecarboxamide; N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(2-cyanoethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1- trifluoropropanyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxetanyl)pyridazine- 3-carboxamide; (RS)-N-(1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridazinecarboxamide; N-ethyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-isopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2,2,2- trifluoroethyl)pyridazinecarboxamide; N-tert-butyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-(3,3-difluorocyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((3-(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridine carboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; N-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; (3,3-difluoroazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3,3-difluoropyrrolidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinyl)methanone; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((3-methyloxetan hyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(oxetan ylmethyl)pyridazinecarboxamide; N-((3-hydroxyoxetanyl)methyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((3R,4R) methyltetrahydropyranyl)pyridazinecarboxamide; (4,4-difluoropiperidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinyl)methanone; N-(1-(methoxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; (3-methoxyazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3-hydroxymethylazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinyl)methanone; azetidinyl(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazin yl)methanone; (RS)-N-(2,2-dimethyltetrahydropyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide; (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazin yl)(morpholino)methanone; (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinyl)(2-oxa azaspiro[3.3]heptanyl)methanone; 4-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide; (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinyl)(6-oxa azaspiro[3.3]heptanyl)methanone; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1-trifluoro methylpropanyl)pyridazinecarboxamide; (3-fluoroazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3-hydroxyazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3-fluoromethylazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; ethyl 1-(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine amido)cyclopropanecarboxylate; N-(1-cyanocyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; -methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; 5-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide; N-(1,1-dioxothianyl)((5-methyl(6-methylpyridyl)isoxazol hoxy)pyrazinecarboxamide; N-(2-hydroxy-1,1-dimethyl-ethyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide; N-cyclopropyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyrazine carboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclopropyl)pyridazinecarboxamide; -((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(oxetanyl)pyrazine carboxamide; -((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(2,2,2- trifluoroethyl)pyrazinecarboxamide; N-(4-hydroxymethylbutanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-methyl lsulfonyl)butanyl)pyridazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- tetrahydrofuranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; 1-(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carbonyl)azetidinecarbonitrile; N-(1-(hydroxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; (S)-N-(1-cyanobutanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; (R)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyrazinecarboxamide; N-(2-Hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyrazinecarboxamide; 2-(1,1-Dioxothianyl)[[5-methyl(6-methylpyridinyl)-1,2-oxazolyl]methoxy]- 1#H!-pyrrolo[3,4-c]pyridinone; (S)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyrazinecarboxamide; 2-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy]tetrahydropyranyl-7H- pyrrolo[3,4-b]pyridinone; N-(1,1-Dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyrazinecarboxamide; N-(Cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyrazinecarboxamide; 2-(4,4-Difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one; Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydro-2H- pyranyl)pyridazinecarboxamide; (R)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyrazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide; -((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan- 6-yl)pyrazinecarboxamide; 5-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((cis) (trifluoromethyl)cyclohexyl)pyrazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; N-((cis)Hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyrazinecarboxamide; N-((trans)Hydroxymethylcyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyrazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydro-2H- 4-yl)nicotinamide; 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-thiopyran- 4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridazinyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4- methyltetrahydrothiopyranyl)pyridazinecarboxamide; N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyranyl)((5-methyl(6-methylpyridin- 3-yl)isoxazolyl)methoxy)pyridazinecarboxamide; (2,2-dioxidothiaazaspiro[3.3]heptanyl)(6-((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinyl)methanone; (2,2-Dioxidothiaazaspiro[3.3]heptanyl)(5-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyrazinyl)methanone; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclopentyl)pyridazinecarboxamide; 5-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4,4,4- trifluorobutyl)pyrazinecarboxamide; N-(1-isopropylazetidinyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)(2-oxaspiro[3.3]heptan yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclobutyl)pyridazinecarboxamide; Ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)nicotinamide; N-(1,1-Dioxidotetrahydro-2H-thiopyranyl)((5-ethyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; N-cyclopropyl((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; (R)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)nicotinamide; 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyran- 4-yl-pyridinecarboxamide; N-((3R,4S)hydroxytetrahydropyranyl)((5-methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxamide; 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide (6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-(1,1-dioxothian yl)pyridinecarboxamide; N-((1R,2S)-3,3-difluorohydroxycyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; N-((1R,2R)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide; N-((1S,2R)-3,3-difluorohydroxycyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; N-((3S,4R)hydroxytetrahydro-2H-pyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; N-((1S,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide; 2-fluoro-N-methyl((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide; (6-methoxypyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydro-2H-pyran- 4-yl)nicotinamide; N-isopropyl((3-(6-methoxypyridinyl)methylisoxazolyl)methoxy)nicotinamide; (S)-N-(1-hydroxypentanyl)((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)nicotinamide; (1,1-dioxidothiomorpholino)(6-((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)pyridinyl)methanone; (S)((3-(6-(dimethylamino)pyridinyl)methylisoxazolyl)methoxy)-N-(1- hydroxypentanyl)nicotinamide; 4-methoxy((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro- 2H-pyranyl)nicotinamide; 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyran- 4-yl-pyridinecarboxamide; 6((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-isopropylpyridinecarboxamide 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; N-((1r,4r)hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; N-(1,3-dihydroxymethylpropanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1s,4s)hydroxymethylcyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; N-((1R,3S)hydroxy(trifluoromethyl)cyclopentyl)((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxamide; N-((1S,3R)hydroxy(trifluoromethyl)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; (1S,4S)oxaazabicyclo[2.2.1]heptanyl(6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinyl)methanone; N-((1RS,3RS)hydroxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxamide; trans-N-(4-hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; trans-N-(4-methoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; (6,6-difluoroazaspiro[3.3]heptanyl)(6-((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinyl)methanone; N-(3-hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-azabicyclo[3.1.1]heptanyl(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; cis-N-(4-methoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyridazinecarboxamide; (S)((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide; trans-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide; cis-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; trans-N-((1RS,3RS)methoxycyclopentyl)((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxamide; N-(6,6-difluorospiro[3.3]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran- 4-yl)pyridazinecarboxamide; cis-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; trans-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; cis-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; trans-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; cis-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; trans-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; trans-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; cis-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(2- oxaspiro[3.3]heptanyl)pyridazinecarboxamide; (S)((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(tetrahydrofuran- 3-yl)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2- oxaspiro[3.3]heptanyl)pyridazinecarboxamide; (S)((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydrofuranyl)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide; 6-((5-methyl(6-(trifluoromethyl)pyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide; N-((2S)oxabicyclo[2.2.1]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxepan yl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1R,3S,4R) oxabicyclo[2.2.1]heptanyl)pyridazinecarboxamide; )oxabicyclo[2.2.1]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1R,3R)ethoxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1R,3R)(2,2-difluoroethoxy)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran- 4-yl)pyridazinecarboxamide; 2,2-difluoroethoxy)cyclohexyl][[5-methyl(6-methylpyridinyl)-1,2-oxazol yl]methoxy]pyridazinecarboxamide; N-(4-ethoxycyclohexyl)[[5-methyl(6-methylpyridinyl)-1,2-oxazol yl]methoxy]pyridazinecarboxamide; or pharmaceutically acceptable salts f.

Further particular examples of compounds of formula (I) as described herein are selected from N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyridazinecarboxamide; N-cyclopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1- oropropanyl)pyridazinecarboxamide; N-isopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-tert-butyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-(1-(methoxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- uoromethyl)cyclopropyl)pyridazinecarboxamide; -methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclopropyl)pyridazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydro-2H- pyranyl)pyridazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclobutyl)pyridazinecarboxamide; 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran- 4-yl)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxepan yl)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran- 4-yl)pyridazinecarboxamide; or pharmaceutically acceptable salts thereof.

Further ular examples of compounds of formula (I) as described herein are ed from methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyridazinecarboxamide or pharmaceutically acceptable salts thereof.

Processes for the cture of compounds of formula (I) as described herein are also an object of the invention.

The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic . Syntheses of the invention are shown in the following general schemes. The skills ed for ng out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.

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. The reaction sequence is not limited to the one displayed in schemes 1 - 7, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.

Starting materials are either commercially available or can be prepared by s analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

The present compounds of formula (I) and their pharmaceutically acceptable salts can be prepared by a process described below (Scheme 1) amide ng HNR5R6 (II) (I) hydrolysis H2NR6 AlMe3, 1,4-dioxane DBU, toluene (III) Scheme 1: wherein Y is CH or N; Z is CH or N; with the proviso that not more than one of Y and Z is N; all other definitions are as described above and in the claims According to Scheme 1, a compound of formula (I) can be prepared by standard amide coupling reaction between a primary (R5 = H) or a secondary amine HNR5R6 and a carboxylic acid of formula (II). Carboxylic acids (II) can be conveniently prepared by hydrolysis of the corresponding methyl esters (III) under standard conditions. In ative, a compound of formula (I) can be prepared in one step from methyl esters (III) and a primary amine ) by treatment with Me3Al in 1,4-dioxane or DBU in e.

Alternatively, according to Scheme 2, compounds of formula (I) can be prepared by nucleophilic aromatic substitution reaction between a y alcohol (IV) and an aryl chloride (V) in presence of base (Cs2CO3).

Cs2CO3, DMA (IV ) (V) (I) Scheme 2: wherein Y is CH or N; Z is CH or N; with the proviso that not more than one of Y and Z is N; all other definitions are as described above and in the claims In certain embodiments of the invention, Rz or Ry and R5 are joined together to form -CH2- thereby forming a 5-membered heterocycloalkyl together with the interconnecting atoms. In such a case, compounds of formula (I-a) can be prepared by a process described in Scheme 3.

Pd(OAc)2, TrixiePhos H2NR6 NaBH(OAc)3 Cs2CO3 toluene (I-a) (1) (2) (IV ) Scheme 3: wherein all definitions are as bed above and in the claims ediate γ-lactams (2) can be prepared in a one-pot two-step procedure involving a reductive ion between commercially available 6-chloroformylnicotinic acid and a primary amine (H2NR6) ed by intramolecular lactam ion. Etherification reaction n γ-lactams (5) and alcohols (IV) can be accomplished by a palladium-mediated process in presence of a base (Cs2CO3) to form compounds of formula (I-a).

Conversely, regioisomeric compounds of formula (I-b) can be prepared by a process described in Scheme 4.

Pd(OAc)2 TrixiePhos Cs2CO3 AIBN H2NR6 toluene NBS THF (I-b) (3) (4) (5) (IV ) Scheme 4: wherein all definitions are as described above and in the claims Intermediate γ-lactams (5) can be prepared in two steps from commercially available ethyl 6-chloromethylnicotinate by a radical bromination reaction to form bromide (4). Its subsequent on with a primary amine (H2NR6) followed by intramolecular lactam formation afforded γ-lactams (5). Final etherification between γ-lactams (5) and alcohols (IV) can be accomplished again by a palladium-mediated process in presence of a base (Cs2CO3) to form compounds of formula (I-b).

NaH, THF N O 3 or N O 3 2 R 2 R R , MeCN R 1 X OH 1 X O R N R N [Cl,F] (IV) (III) N Y (6) O Scheme 5: wherein Y is CH or N; Z is CH or N; with the proviso that not more than one of Y and Z is N; all other tions are as described above and in the claims As illustrated in Scheme 5, methyl esters of formula (III) can be conveniently prepared by nucleophilic aromatic tution reaction between a commercially available heteroaryl chloride or fluoride and an alcohol of formula (IV) in presence of a base (NaH or Cs2CO3).

Pd(OAc)2 Na2CO3 NaH, THF CO(g), EtOH (IV) (VI) (III) Scheme 6: wherein all definitions are as described above and in the claims In alternative, according to Scheme 6, pyridazine esters of formula (III) can be obtained in a two-step procedure. First, an l of formula (IV) is d with commercially available 3,6-dichloropyridazines (7) in presence of a base (NaH). Finally, the resulting aryl chloride of formula (VI) undergo a palladium-mediated carbonylation reaction (CO(g) in EtOH) to e ethyl esters (III).

Synthesis of building blocks (A-P) of formula (IV) is highlighted in Scheme 7.

NH2OH NCS (8) (9) (10) LiAlH4 or (11) (12) DIBAL-H (IV) (VII) hydrolysis LiOH Cl C(O)OEt Et3N, NaBH4 (VIII) Scheme 7: synthesis of building blocks (A-P); wherein all definitions are as described above and in the claims Commercially available aldehydes (8) are converted into corresponding oximes (9) by treatment with ylamine hydrochloride in presence of a base (NaOH). Following electrophilic chlorination with N-chlorosuccinimide, the intermediate -oximes (10), in presence of a base (Et3N), undergo a 1,3-dipolar cycloaddition reaction with readily available enamines (11) or enols (12) to afford isoxazoles of formula (VII). Their final ion with LiAlH4 or DIBAL-H at controlled temperature provides the desired alcohols (IV). In alternative ls of formula (IV) can be obtained in a two-step synthetic route from ethyl esters (VII).

Saponification reaction (LiOH, water) of ethyl esters (VII) to the corresponding carboxylates (VIII), followed by their reduction by treatment with ethyl chloroformate in presence of a base (Et3N) and NaBH4, provide building blocks (A-P) of formula (IV).

Also an embodiment of the present invention is a process to prepare a compound of formula (I) as d above sing i) the reaction of a compound of a (II) with a compound of formula (III) ii) the reaction of a compound of formula (IV) with a compound of formula (V) wherein R1, R2, R3, R4, R5, R6, X, Y and Z are as defined herein and Ra is C1alkyl and Rb is bromo, chloro or iodo.

Also an object of the t invention is a compound according to formula (I) as described herein for use as a therapeutically active nce.

Likewise an object of the present invention is a ceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

A particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis, more particularly the treatment, of Alzheimer’s disease, mild cognitive impairment (MCI), age-related ive decline, negative and/or cognitive symptoms ated with schizophrenia, bipolar disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, aumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-X disorder, more particularly autism spectrum er (ASD), Angelman syndrome, Alzheimer’s disease, negative and/or ive ms associated with schizophrenia and post-traumatic stress disorder (PTSD).

The present invention also relates to the use of a compound ing to formula (I) as described herein for the preparation of a medicament for the ent or prophylaxis, more particularly the treatment, of Alzheimer’s disease, mild cognitive ment (MCI), age-related cognitive decline, negative and/or cognitive symptoms ated with phrenia, bipolar disorders, autism spectrum disorder (ASD), an syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-X disorder, more particularly autism spectrum disorder (ASD), Angelman syndrome, Alzheimer’s disease, negative and/or cognitive symptoms ated with schizophrenia and post-traumatic stress disorder (PTSD).

Also an object of the invention is a method for the treatment or prophylaxis, more ularly the treatment, of Alzheimer’s disease, mild cognitive ment (MCI), age-related cognitive decline, negative and/or ive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi me, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-X disorder, more particularly autism spectrum er (ASD), Angelman syndrome, Alzheimer’s disease, negative and/or cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD), which method comprises administering an effective amount of a compound according to formula (I) as described .

Also an embodiment of the present invention are compounds of formula (I) as described herein, when manufactured according to any one of the described processes.

Assay procedures Membrane preparation and binding assay The affinity of compounds at GABAA receptor subtypes was measured by competition for [3H]flumazenil (85 Ci/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) ors of composition α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2.

Cell pellets were suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized by polytron for ca. 20 sec on ice and centrifuged for 60 min at 4 °C (50000 g; Sorvall, rotor: SM24 = 20000 rpm). The cell pellets were resuspended in Krebs-tris buffer and homogenized by polytron for ca. sec on ice. Protein was measured (Bradford method, Bio-Rad) and aliquots of 1 mL were prepared and stored at –80 °C.

Radioligand binding assays were carried out in a volume of 200 mL (96-well plates) which contained 100 mL of cell membranes, [3H]-Flumazenil at a concentration of 1 nM for α1, α2, α3 subunits and 0.5 nM for α5 subunits and the test compound in the range of 103 x 10-6 M.

Nonspecific binding was defined by 10-5 M diazepam and typically represented less than 5% of the total binding. Assays were incubated to equilibrium for 1 hour at 4 °C and harvested onto GF/C uni-filters (Packard) by filtration using a Packard ter and washing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, filter-retained radioactivity was detected by liquid scintillation counting. Ki values were calculated using Excel-Fit (Microsoft) and are the means of two determinations.

The compounds of the accompanying es were tested in the above described assay, and the preferred compounds were found to possess a Ki value for displacement of [3H]- Flumazenil from α5 subunits of the human GABAA or of 100 nM or less. Most preferred are compounds with a Ki (nM) < 35. In a preferred embodiment the nds of the invention are binding selective for the α5 subunit relative to the α1, α2 and α3 t. Representative test results, obtained by the above described assay measuring binding affinity to HEK293 cells expressing human (h) receptors, are shown in the Table below.

Functional expression of GABAA receptors: Xenopus oocytes ation Xenopus laevis oocytes at tion stages V-VI were used for the expression of cloned mRNA ng GABAA or subunits. Oocytes ready for RNA micro-injection were bought from Ecocyte, Castrop-Rauxel, y and stored in modified Barth’s medium (composition in mM: NaCl 88, KCl 1, NaHCO3 2.4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) at 20°C until the experiment. s oocytes microinjection Oocytes were plated in 96-well plates to be used in an automated instrument (Robo-ocyte, MultiChannelSystems, Reutlingen, Germany) for microinjection and ophysiological recordings. Approximately 50 nl of an aqueous solution containing the RNA transcripts for the subunits of the desired GABAA receptor was injected into each oocyte. RNA concentrations ranged between 0.3 and 16 ng/µl/subunit and were adjusted in pilot experiments to obtain GABA responses of a suitable size and a maximal effect of the nce modulator, CM (β- CCM), a betacarboline negative allosteric modulator (NAM) at the GABAA receptor benzodiazepine (BZD) binding site or lam, a benzodiazepine positive allosteric modulator (PAM) at the GABAA receptor benzodiazepine (BZD) binding site. The concentration of the γ2 subunit encoding RNA usually was 5-to d higher than the RNAs encoding the other subunits. Oocytes were kept in modified Barth’s medium (composition in mM: NaCl 88, KCl 1, NaHCO3 4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) at 20°C until the experiment.

Electrophysiology ophysiological experiments were performed on days 3 to 5 after the injection of mRNA. During the experiment the oocytes were constantly superfused by a on containing (in mM) NaCl 90, KCl 1, HEPES 5, MgCl2 1, CaCl2 1 (pH 7.4). Oocytes were impaled by two glass microelectrodes (resistance: 0.4 MΩ) which were filled with a solution containing KCl 1M + K-acetate 1.5 M and voltage-clamped to -80 mV. The recordings were performed at room temperature using the Roboocyte two-electrode voltage clamp system (Multichannelsystem). After an initial equilibration period of 1.5 min GABA was added for 1.5 min at a concentration evoking approximately 20% of a maximal current response (EC20). After another rest interval of 2.5 min GABA was again added evoking a response of similar amplitude and shape. 0.5 min after the onset of this second GABA application the test compound, at a concentration corresponding to approximatively 30 fold its Ki, was added while GABA was still present. Current traces were ed at a digitization rate of 10 Hz during and shortly before and after the GABA application.

Each compound and concentration was tested on at least 3 oocytes. Different oocytes were used for different nd concentrations. β-CCM, a negative allosteric modulator, or Midazolam, a positive eric modulators, were tested on a few (3-6) oocytes on each 96-well plate for a positive control at a maximally effective. β-CCM inhibited the GABA-evoked current by approximatively 50% (Fold increase ~ 0.5), while Midazolam potentiated the nduced current by imatively 150% (Fold increase ~ 2.5).

Data analysis For the analysis, the digitized current traces of the first and second GABA response were mposed and, if necessary, rescaled to equal maximal amplitudes. The ratio between the two responses during the time interval of test compound application was calculated point by point. The extremum of the ing “ratio trace” was taken as the efficacy (“Fold increase”) of the compound expressed as "% modulation of GABA EC20" (100* (Fold increase-1)). The results are shown in Table 1.

Table 1 Ki Fold se h-GABA-A h-GABA-A Efficacy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 1 0.0048 1.42 42 2 0.0083 1.63 63 3 0.0014 1.41 41 4 0.0073 2.5 150 0.0586 3.45 245 6 0.0541 2.67 167 7 0.0256 2.02 102 8 0.0087 1.97 97 9 0.0137 1.62 62 0.0189 1.8 80 11 0.0112 1.55 55 12 0.0163 1.74 74 13 0.0144 2.58 158 14 0.0745 2.6 160 0.0198 1.55 55 16 0.0192 1.85 85 17 0.0098 1.6 60 18 0.0102 1.59 59 19 0.0052 1.77 77 Ki Fold increase h-GABA-A h-GABA-A Efficacy α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 0.0118 1.95 95 21 0.0054 2.19 119 22 0.0108 1.44 44 23 0.0204 1.89 89 24 0.0416 1.63 63 0.0094 1.59 59 26 0.0052 1.8 80 27 0.0123 1.54 54 28 0.008 1.52 52 29 0.008 1.81 81 0.0124 1.94 94 31 0.0142 2.02 102 32 0.0085 1.79 79 33 0.0116 1.76 76 34 0.0132 1.84 84 0.0044 1.82 82 36 0.0058 1.65 65 37 0.0076 1.73 73 38 0.0075 1.84 84 39 0.0146 1.89 89 40 0.0106 1.91 91 41 0.0194 2.04 104 42 0.0089 1.81 81 43 0.0164 1.82 82 Ki Fold increase h-GABA-A -A Efficacy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 44 0.0761 1.54 54 45 0.0066 1.84 84 46 0.0035 1.63 63 47 0.013 1.68 68 48 0.0316 1.74 74 49 0.0136 1.7 70 50 0.0076 1.72 72 51 0.0108 1.57 57 52 0.0289 1.67 67 53 0.0958 1.8 80 54 0.0199 1.86 86 55 0.0086 1.57 57 56 0.0079 1.64 64 57 0.0072 1.64 64 58 0.0161 1.71 71 59 0.0104 1.93 93 60 0.0934 1.99 99 61 0.0071 1.58 58 62 0.0208 1.42 42 63 0.0046 1.79 79 64 0.0176 1.86 86 65 0.0072 1.62 62 66 0.0058 1.69 69 67 0.0118 1.59 59 Ki Fold increase h-GABA-A -A Efficacy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 68 0.0562 1.72 72 69 0.0077 1.86 86 70 0.0012 1.54 54 71 0.0024 1.61 61 72 0.0114 2.3 130 73 0.0528 1.45 45 74 0.0092 1.28 28 75 0.0174 1.89 89 76 0.009 1.92 92 77 0.0052 1.11 11 78 0.0243 1.42 42 79 0.0113 1.96 96 80 0.0132 2.08 108 81 0.0104 1.8 80 82 0.0124 2.01 101 83 0.005 1.96 96 84 0.019 1.54 54 85 0.0063 1.76 76 86 0.017 2.2 120 87 0.0081 1.8 80 88 0.0409 1.68 68 89 0.0131 1.31 31 90 0.0167 1.37 37 91 0.0055 2.4 140 Ki Fold increase h-GABA-A -A Efficacy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 92 0.0132 1.67 67 93 0.0062 1.35 35 94 0.01 1.92 92 95 0.0134 1.67 67 96 0.0072 1.88 88 97 0.0136 1.71 71 98 0.0622 1.76 76 99 0.0068 1.73 73 100 0.0085 1.7 70 101 0.0506 1.82 82 102 0.0207 1.21 21 103 0.079 1.81 81 104 0.0663 1.43 43 105 0.0227 2.01 101 106 0.0603 1.64 64 107 0.0096 1.69 69 108 0.0004 1.2 20 109 0.0008 1.42 42 110 0.0155 1.65 65 111 0.0046 1.89 89 112 0.0065 1.43 43 113 0.0338 1.28 28 114 0.0281 1.74 74 115 0.0516 2.39 139 Ki Fold increase h-GABA-A h-GABA-A cy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 116 0.0049 1.59 59 117 0.0156 1.99 99 118 0.0123 1.88 88 119 0.031 2.02 102 120 0.0521 2.6 160 121 0.0403 2.09 109 122 0.0264 2.26 126 123 0.0221 2.06 106 124 0.0366 1.47 47 125 0.059 2.42 142 126 0.0498 1.49 49 127 0.0228 1.5 50 128 0.0061 2.07 107 129 0.0256 2.56 156 130 0.0304 2.28 128 131 0.026 1.51 51 132 0.0377 1.64 64 133 0.0431 1.95 95 134 0.0208 1.66 66 135 0.0304 1.92 92 136 0.0148 1.54 54 137 0.0254 1.55 55 138 0.0938 1.46 46 139 0.0194 2.52 152 Ki Fold increase h-GABA-A h-GABA-A cy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 140 0.056 1.13 13 141 0.0495 3.43 243 142 0.0047 1.44 44 143 0.0145 1.2 20 144 0.0136 1.15 15 145 0.029 2.44 144 146 0.01 1.78 78 147 0.0096 1.48 48 148 0.0138 1.77 77 149 0.005 1.37 37 150 0.0167 1.69 69 151 0.0458 1.68 68 152 0.0053 1.85 85 153 0.0055 1.84 84 154 0.01 1.97 97 155 0.0154 1.46 46 156 0.0078 1.98 98 157 0.006 1.76 76 158 0.0182 1.79 79 159 0.0237 1.55 55 160 0.0093 1.42 42 161 0.008 1.6 60 162 0.0112 1.37 37 163 0.0086 1.98 98 Ki Fold increase h-GABA-A h-GABA-A Efficacy α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 164 0.0115 1.95 95 165 0.0026 2.74 174 166 0.0076 1.7 70 167 0.0191 1.64 64 168 0.0324 2.02 102 169 0.0189 1.66 66 170 0.0088 1.6 60 171 0.0181 1.72 72 172 0.0088 1.65 65 173 0.0156 1.68 68 174 0.0088 1.55 55 175 0.0101 1.82 82 176 0.0127 1.64 64 177 0.0397 2.09 109 178 0.0429 1.73 73 179 0.043 1.82 82 180 0.0326 2.73 173 181 0.068 2.47 147 182 0.0596 2.41 141 183 0.0567 3.13 213 184 0.0512 1.96 96 185 0.0707 2.24 124 186 0.0166 1.72 72 187 0.0148 1.88 88 Ki Fold increase h-GABA-A h-GABA-A Efficacy Example α5β3γ2 α5β3γ2 (GABA)% (µM) oocyte 188 0.0207 1.71 71 189 0.0188 1.86 86 190 0.0127 1.63 63 191 0.0112 1.6 60 192 0.003 1.56 56 193 0.001 1.64 64 194 0.0133 1.84 84 195 0.0173 1.78 78 WO2009/071476 discloses reference compounds RO-159 as example 159, RO-251 as e 251, RO-272 as example 272 and RO-301 as example 301.

WO2009/071477 discloses reference nd RO-094 as example 94.

Reference examples RE-A and RE-B have been prepared as described herein.

RO-159 RO-251 RO-301 RO-094 RE-A RO-272 The reference compounds were also tested for their affinity towards the GABAA receptor α5β3γ2 subtypes as well as for their efficacy in GABAA α5β3γ2 overexpressing oocytes. The results are shown in Table 2.

Table 2 Fold increase Efficacy Ki an Example h-GABA-A α5β3γ2 (GABA) % oocyte Fold increase Efficacy Ki α5-human Example -A α5β3γ2 (GABA) % oocyte RO-159 0.028 0.88 - 12% RO-251 0.001 0.82 - 18% RO-272 0.001 0.68 - 32% RO-301 0.0002 0.82 - 18% RO-094 0.0029 0.82 - 18% RE-A 0.065 0.97 - 3% RE-B 0.0004 1.03 + 3% The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topical ocularly (e.g. in the form of solutions, ointments, gels or water soluble polymeric inserts). However, the administration can also be effected parenterally, such as intramuscularly, intravenously, or intraocularly (e.g. in the form of sterile ion solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées,hard gelatin capsules, injection solutions or topical formulations e, corn starch or derivatives f, talc, c acid or its salts etc. can be used, for example, as such adjuvants for s, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, olid substances and liquid polyols, etc.

Suitable nts for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable nts for injection solutions are, for example, water, alcohols, polyols, ol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for e, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, g agents, emulsifiers, ners, nts, flavorants, salts for g the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 dual doses, which can consist, for example, of the same amounts, should it be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg in can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.

Preparation of pharmaceutical compositions comprising compounds of the invention: Tablets of the following composition are manufactured in the usual manner: Ingredient mg/tablet 25 100 500 Compound of formula I 5 25 100 500 Lactose ous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 Magnesium te 1 1 1 1 Total 167 167 167 831 Manufacturing Procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with ed water. 2. Dry the granules at 50°C. 3. Pass the granules through le milling equipment. 4. Add ingredient 5 and mix for three minutes; compress on a suitable press. es of the following composition are manufactured: ingredient mg/capsule 25 100 500 Compound of formula I 5 25 100 500 Hydrous Lactose 159 123 148 - Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.

A compound of formula I lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is ed to the mixer; the talc is added thereto and mixed thoapproximatively. The mixture is filled by e into suitable capsules, e.g. hard gelatin es.

Injection solutions of the following composition are manufactured: ingredient mg/injection solution.

Compound of formula I 3 Polyethylene Glycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml The ion is illustrated hereinafter by Examples, which have no limiting character.

In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be obtained by s described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.

Examples Building block A (5-methyl(6-methylpyridinyl)isoxazolyl)methanol a) (3E)methylpyridinecarbaldehyde oxime To a on of 6-methylnicotinaldehyde (9.86 g, 77.3 mmol) in methanol (35 mL) was added under nitrogen hydroxylamine (50 wt.% in water, 5.93 mL, 101 mmol). The resulting sion was stirred for 3 hours at 40 °C and for 20 hours at room temperature. Concentration by rotary evaporation under reduced pressure afforded the title compound (10.89 g, 98%) as an off-white solid. MS (ESI): 137.0 ([M+H]+). b) ethyl 5-methyl(6-methylpyridinyl)isoxazolecarboxylate To a solution of (E)methylnicotinaldehyde oxime (10.89 g, 80.0 mmol) in DMF (95 mL) at 6 °C was added N-chlorosuccinimide (11.7 g, 88.0 mmol). Upon addition, the color of the reaction mixture changed from yellow to orange and the reaction was allowed to warm to room temperature. After 1 hour, the mixture was heated to 50 °C for 2 hours. The resulting brown suspension was led to 6 °C then (E)-ethyl 3-(pyrrolidinyl)butenoate (17.6 g, 96.0 mmol) was added and the reaction mixture was stirred at 50 °C ght. After g to room temperature, water (95 mL) was added dropwise and the resulting brown suspension was filtered through a sintered funnel. The residue was washed with water then dried at high vacuum to afford the title compound (11.80 g, 60%) as a brown solid. MS (ESI): 247.1 ([M+H]+). c) (5-methyl(6-methylpyridinyl)isoxazolyl)methanol To a solution of ethyl 5-methyl(6-methylpyridinyl)isoxazolecarboxylate (11.8 g, 47.9 mmol) in THF (160 mL) at 2 °C was added under nitrogen over a period of 20 min LiAlH4 (2.55 g, 67.1 mmol). After stirring at 4 °C for 1.5 hours, water (2.61 mL) was carefully added and the mixture was d for further 50 min before being quenched by addition of aqueous NaOH (15 wt.%, 2.61 mL). The reaction mixture was d for 30 min at room temperature before addition of water (7.8 mL). After stirring for 1 hour, the resulting suspension was filtered through a sintered funnel and the residue was washed with THF (20 mL) to afford the title nd (9.08 g, 93%) as an orange solid. MS (ESI): 205.1 ([M+H]+).

Building block B (5-ethyl(6-methylpyridinyl)isoxazolyl)methanol a) ethyl 5-ethyl(6-methylpyridinyl)isoxazolecarboxylate In analogy to experiment of building block A b, (E)methylnicotinaldehyde oxime, using ethyl rolidinyl)pentenoate instead of (E)-ethyl 3-(pyrrolidinyl)butenoate, was converted into the title compound (1.81 g, 63%) which was obtained as a yellow oil. MS (ESI): 261.3 ([M+H]+). b) (5-ethyl(6-methylpyridinyl)isoxazolyl)methanol In analogy to experiment of building block A c, ethyl 5-ethyl(6-methylpyridinyl)isoxazole- 4-carboxylate instead of ethyl 5-methyl(6-methylpyridinyl)isoxazolecarboxylate was converted into the title compound (1.44 g, 95%) which was obtained as an orange solid. MS (ESI): 219.2 ([M+H]+).

Building block C (5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methanol a) ethyl 4-fluorooxo-butanoate To a stirred solution of ethyl acetate (9.59 g, 10.7 mL, 109 mmol) in ous Et2O (100 mL) under argon at -78 °C (CO2-acetone bath) was added over 30 min LDA (2.0 m solution in cyclohexane/ethylbenzene/THF, 59 mL, 118 mmol). The on mixture was stirred for 2 hours at -78 °C then ethyl 2-fluoroacetate (10.5 g, 9.62 mL, 99 mmol) was added over 15 min. The CO2-Acetone bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was slowly poured into cold aqueous HCl (10 wt.%, 100 mL) and extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered and evaporated at 35 °C by rotary evaporation under reduced pressure (650 mbar-200 mbar). The resulting colourless liquid was purified by distillation at reduced pressure using a 30 cm Vigreux column. Fractions collected at 13 mbar at 71°C (vapor temperature) afforded the title compound (12.67 g, 86.4 %) as a colourless liquid. MS (ESI): 149.1 ([M+H]+). b) ethyl oromethyl)(6-methylpyridinyl)isoxazolecarboxylate To a stirred solution of (E)methylnicotinaldehyde oxime (1.00 g, 7.34 mmol) in anhydrous THF (6.7 mL) at 6 °C was added rosuccinimide (1.10 g, 8.08 mmol). After 30 min, the mixture was heated to 50 °C for 1 hour then all the solvent was removed under reduced pressure.

The resulting residue o-oxime) was dissolved in EtOH (6.7 mL) and stirred at room temperature for 30 min. In a te flask, Et3N (2.05 mL, 14.7 mmol) was added to a solution of ethyl 4-fluorooxobutanoate (1.65 g, 7.34 mmol) in THF (6.6 mL) and the resulting suspension was stirred at room temperature. After 30 min, the suspension was cooled to 0 °C and the previously prepared suspension of chloro-oxime in EtOH was slowly added via cannula. The resulting yellow suspension was stirred for 3 hours at room temperature. The reaction was diluted with EtOAc (100 mL) and the organic phase washed with water and brine, dried 4) and concentrated in vacuo. cation by flash tography (silica, gradient: 0% to 50% EtOAc in heptane) afforded the title compound (1.1 g, 57%) as a white solid. MS (ESI): 265.2 ([M+H]+). c) (5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methanol To a stirred suspension of ethyl 5-(fluoromethyl)(6-methylpyridinyl)isoxazole carboxylate (404 mg, 1.53 mmol) in anhydrous toluene (4 mL) at -78 °C was added dropwise DIBAL-H (1.0 m in toluene, 1.84 mL, 1.84 mmol). The reaction was stirred at -78 °C for 30 min before being quenched by the addition of EtOAc (0.5 mL). After 15 min, the reaction was allowed to warm to 0 °C and saturated aqueous NaHCO3 (5 mL) was added. The mixture was stirred usly for 20 min then diluted with EtOAc (30 mL) and the organic phase washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) afforded the title nd (193 mg, 57%) as a white solid. MS (ESI): 223.2 ([M+H]+).

Building block D (5-cyclopropyl(6-methylpyridyl)isoxazolyl)methanol a) ethyl 5-cyclopropyl(6-methylpyridinyl)isoxazolecarboxylate In analogy to experiment of building block A b, (E)methylnicotinaldehyde oxime, using (Z)- ethyl 3-cyclopropyl(pyrrolidinyl)acrylate instead of (E)-ethyl 3-(pyrrolidinyl)but enoate, was converted into the title compound (0.215 g, 43%) which was obtained as a yellow oil.

MS (ESI): 273.2 ([M+H]+). b) (5-cyclopropyl(6-methylpyridyl)isoxazolyl)methanol In analogy to experiment of building block A c, ethyl 5-cyclopropyl(6-methylpyridin yl)isoxazolecarboxylate instead of ethyl 5-methyl(6-methylpyridinyl)isoxazole carboxylate was converted into the title compound (0.52 g, 83%) which was obtained as a yellow solid. MS (ESI): 231.2 ([M+H]+).

Building block E (5-methyl(6-(trifluoromethyl)pyridyl)isoxazolyl)methanol a) (3E)(trifluoromethyl)pyridinecarbaldehyde oxime In analogy to ment of building block A a, 6-(trifluoromethyl)pyridinecarboxaldehyde instead of 6-methylnicotinaldehyde was converted into the title compound (10.94 g, 96%) which was ed as a light yellow solid. MS (ESI): 191.1 ([M+H]+). b) ethyl 5-methyl(6-(trifluoromethyl)pyridyl)isoxazolecarboxylate In analogy to experiment of building block A b, (E)-ethyl 3-(pyrrolidinyl)butenoate, using (3E)(trifluoromethyl)pyridinecarbaldehyde oxime instead of (E)methylnicotinaldehyde oxime, was converted into the title compound (7.95 g, 96%) which was obtained as a yellow solid. MS (ESI): 301.1 ([M+H]+). c) 5-methyl(6-(trifluoromethyl)pyridyl)isoxazolecarboxylic acid To a stirred on of ethyl 5-methyl(6-(trifluoromethyl)pyridinyl)isoxazole ylate (5.91 g, 19.7 mmol) in a mixture of THF (21 mL), MeOH (21 mL) and water (21 mL) at 0 °C was added LiOH·H2O monohydrate (2.03 g, 48.4 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was led to 0 °C then acidified with aqueous citric acid (5 wt.%) to pH~5 (a precipitate was formed). The organic solvents were removed by rotary evaporation under d pressure. The resulting aqueous suspension was cooled to 0 °C then filtered on a sintered funnel. The collected solid was rinsed with ice cold water (50 mL) and dried under high vacuum to afford the title compound (4.88 g, 91 % yield) as a light yellow solid. MS (ESI): 273.1 ([M+H]+). d) (5-methyl(6-(trifluoromethyl)pyridyl)isoxazolyl)methanol In analogy to experiment of building block H c, yl(6-(trifluoromethyl) pyridyl)isoxazolecarboxylic acid instead of 3-(6-methylpyridyl)isoxazolecarboxylic acid was converted into the title compound (3.87 g, 84%) which was obtained as a light yellow solid.

MS (ESI): 259.1 ([M+H]+).

Building block F (3-(6-chloropyridyl)methyl-isoxazolyl)methanol a) (E)chloronicotinaldehyde oxime To a solution of 6-chloronicotinaldehyde (100 mg, 0.706 mmol) in acetonitrile (1 mL) were added hydroxylamine hydrochloride (73.6 mg, 1.06 mmol) and ium ate tribasic (75 mg, 0.353 mmol). The mixture was stirred at room temperature for 30 min before on of water (0.2 mL). After 1 hour, the resulting suspension was diluted with water (5 mL) and the solid was collected through filtration on a sintered funnel then dried in vacuo to afford the title compound (57 mg, 51%) as a white solid. MS (ESI): 157.0 ([M+H]+). b) ethyl 3-(6-chloropyridinyl)methylisoxazolecarboxylate In analogy to experiment of building block A b, (E)-ethyl 3-(pyrrolidinyl)butenoate, using (E)chloronicotinaldehyde oxime instead of (E)methylnicotinaldehyde oxime, was converted into the title compound (92 mg, 78%) which was obtained as a white solid. MS (ESI): 267.1 ([M+H]+). c) (3-(6-chloropyridinyl)methylisoxazolyl)methanol To a stirred solution of ethyl 3-(6-chloropyridinyl)methylisoxazolecarboxylate (77 mg, 0.289 mmol) in anhydrous THF (2 mL) at 0 °C was added dropwise DIBAL-H (1.0 m in hexane, 0.924 mL, 0.924 mmol). The resulting light yellow solution was allowed to warm to room temperature and stirred for 4.5 hours before being re-cooled to 0 °C (ice bath) and quenched by addition of aqueous Na/K tartrate (10 wt.%, 7 mL). The mixture was vigorously stirred at room temperature (ice bath removed) for 30 min then diluted with EtOAc (10 mL). Upon addition of aqueous NH4Cl (20 wt.%, 3 mL) and aqueous HCl (1.0 m, 1 mL) the s layer was separated and ted with EtOAc (2 x 15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) ed the title compound (48 mg, 74%) as a white solid. MS (ESI): 225.0 ([M+H]+).

Building block G (3-(6-chloropyridyl)cyclopropyl-isoxazolyl)methanol a) ethyl 3-(6-chloropyridinyl)cyclopropylisoxazolecarboxylate In analogy to experiment of building block A b, (E)chloronicotinaldehyde oxime, using (Z)- ethyl opropyl(pyrrolidinyl)acrylate instead of (E)-ethyl 3-(pyrrolidinyl)but , was converted into the title nd (317 mg, 85%) which was obtained as a light yellow solid. MS (ESI): 293.1 ([M+H]+). b) (3-(6-chloropyridyl)cyclopropyl-isoxazolyl)methanol In analogy to experiment of building block F c, ethyl hloropyridinyl) cyclopropylisoxazolecarboxylate instead of ethyl 3-(6-chloropyridinyl)methylisoxazole- 4-carboxylate was converted into the title compound (177 mg, 82%) which was obtained as a light yellow solid. MS (ESI): 251.1 ([M+H]+).

Building block H (3-(6-methylpyridyl)isoxazolyl)methanol a) ethyl 3-(6-methylpyridyl)isoxazolecarboxylate In analogy to experiment of building block A b, (E)methylnicotinaldehyde oxime, using ethyl (dimethylamino)propenoate instead of (E)-ethyl 3-(pyrrolidinyl)butenoate, was converted into the title compound (2.45 g, 57%) which was obtained as a light brown oil. MS (ESI): 233.1 ([M+H]+). b) 3-(6-methylpyridyl)isoxazolecarboxylic acid In analogy to experiment of building block E c, ethyl 3-(6-methylpyridyl)isoxazole carboxylate instead of ethyl 5-methyl(6-(trifluoromethyl)pyridinyl)isoxazolecarboxylate was converted into the title nd (1.48 g, 70%) which was obtained as an off white solid.

MS (ESI): 205.0 +). c) (3-(6-methylpyridyl)isoxazolyl)methanol To a stirred suspension of 3-(6-methylpyridyl)isoxazolecarboxylic acid (1.48 g, 7.25 mmol) in anhydrous THF (24 mL) was added triethylamine (1.1 mL, 7.9 mmol). The resulting solution was cooled to -15 °C (NaCl/ice bath) before a solution of ethyl chloroformate (0.73 mL, 7.6 mmol) in THF (4 mL) was added dropwise. After 2 hours, the resulting white precipitate was filtered through a sintered funnel and the ted solid rinsed with a minimal amount of THF.

The filtrate was re-cooled to -15 °C (NaCl/ice bath) and a solution of NaBH4 (686 mg, 18.1 mmol) in water (16 mL) was added dropwise. Upon addition, the reaction mixture was allowed to warm to room ature and stirred for 3 hours. A further amount of NaBH4 (137 mg, 3.62 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the on of aqueous NaOH (2.0 m, 30 mL) then extracted with EtOAc (2 x 160 mL). The combined organic ts were dried (Na2SO4) and trated in vacuo.

Purification by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) afforded the title compound (606 mg, 44%) as an off-white solid. MS (ESI): 191.1 ([M+H]+).

Building block I (5-methyl(6-methylpyridazinyl)isoxazolyl)methanol a) (E)methylpyridazinecarbaldehyde oxime To a stirred solution of 6-methylpyridazinecarbaldehyde (880 mg, 7.21 mmol) in EtOH (1.25 mL) were added hydroxylamine hydrochloride (551 mg, 7.93 mmol) followed by aqueous NaOH (2.0 m, 9.2 mL, 18.4 mmol). The reaction e was stirred at room temperature for 3 hours then treated with acetic acid to pH~ 5. The resulting precipitate was collected by filtration and dried at high vacuum to afford the title compound (943 mg, 95%) as an off-white solid. MS (ESI):138.1 +). b) ethyl yl(6-methylpyridazinyl)isoxazolecarboxylate In analogy to experiment of building block A b, (E)methylpyridazinecarbaldehyde oxime instead of (E)methylnicotinaldehyde oxime was converted into the title compound (1.15 g, 67%) which was obtained as a brown oil. MS (ESI): 248.1 ([M+H]+). c) (5-methyl(6-methylpyridazinyl)isoxazolyl)methanol To a stirred suspension of calcium de (1.8 g, 16.2 mmol) in a mixture of anhydrous THF (50 mL) and EtOH (33 mL) at 0 °C were added ethyl 5-methyl(6-methylpyridazin yl)isoxazolecarboxylate (1.0 g, 4.04 mmol) ed by NaBH4 (1.22 g, 32.4 mmol, portionwise addition). The mixture was stirred at 0 °C for 30 min then allowed to warm to room temperature and stirred for further 1 hour. The reaction mixture was re-cooled to 0 °C and quenched by addition of saturated aqueous NH4Cl. The organic solvents were removed by rotary evaporation under reduced pressure and the ing s layer was extracted with CH2Cl2 (2 x 50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 20% to 100% EtOAc in heptane) afforded the title compound (407 mg, 49%) as a yellow solid. MS (ESI): 206.1 ([M+H]+).

Building block J (5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methanol a) (Z)-4,4-difluoropyrrolidinyl-butenoate To a stirred solution of ethyl 4,4-difluorooxobutanoate (1.6 mL, 15.5 mmol) in cyclohexane (11 mL) was added pyrrolidine (1.4 mL, 16.9 mmol). The reaction was heated to 110 °C overnight using a Dean-Stark trap before being cooled to room temperature. The reaction mixture was filtered ly through a pad of Na2SO4 and the filtrate concentrated in vacuo to afford the title compound (2.49 g, 62%) as a brown oil. MS (ESI): 220.2 ([M+H]+). b) ethyl 5-(difluoromethyl)(6-methylpyridyl)isoxazolecarboxylate In analogy to experiment of building block A b, (3E)methylpyridinecarbaldehyde oxime, using ethyl (Z)-4,4-difluoropyrrolidinyl-butenoate instead of (E)-ethyl 3-(pyrrolidin yl)butenoate, was converted into the title compound (362 mg, 58%) which was obtained as an orange oil. MS (ESI): 283.2 ([M+H]+). c) (5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methanol To a stirred solution of ethyl 5-(difluoromethyl)(6-methylpyridinyl)isoxazole carboxylate (0.490 g, 1.56 mmol) in anhydrous toluene (16 mL) at -78 °C was added dropwise DIBAL-H (1.0 m in toluene, 3.2 mL, 3.2 mmol). The reaction was stirred at -78 °C for 3.5 hours before the addition of a further amount of DIBAL-H (1.0 m in toluene, 0.78 mL, 0.78 mmol).

After 1.5 hours, the on mixture was carefully quenched by the addition of aqueous Na/K tartrate (10 wt.%, 10 mL). The biphasic mixture was allowed to warm to room temperature and stirred vigorously for 1 hour before being extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried 4) and concentrated in vacuo. Purification by flash chromatography (silica, nt: 0% to 70% EtOAc in heptane) ed the title compound (165 mg, 44%) as a light yellow solid. MS (ESI): 241.1 Building block K (3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methanol a) (Z)-N-((6-bromopyridinyl)methylidene)hydroxylamine To a stirred solution of ylamine hydrochloride (11.0 g, 161 mmol) in EtOH (300mL) was added triethylamine (33.0 mL, 242 mmol) and the reaction was stirred at room temperature for min before on of 6-bromo-pyridinecarbaldehyde (15.0 g, 80.6 mmol). The reaction mixture was heated at reflux for 1 hour then all the volatiles were removed by rotary evaporation under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate (2 x 200 mL). The combined organic ts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc in hexane) afforded the title compound (12.5 g, 77%) as a white solid. MS (ESI): 201.3 ([M+H]+). b) ethyl 3-(6-bromopyridyl)methyl-isoxazolecarboxylate In analogy to experiment of building block A b, (Z)-N-((6-bromopyridin yl)methylidene)hydroxylamine instead of methylnicotinaldehyde oxime, was converted into the title compound (16 g, 86%) which was ed as a brown oil. MS (ESI): 311.0 ([M+H]+). c) ethyl yclopropylpyridyl)methyl-isoxazolecarboxylate A round-bottomed flask was charged with ethyl 3-(6-bromopyridyl)methyl-isoxazole carboxylate (8.00 g, 25.7 mmol), cyclopropyl boronic acid (8.80 g, 102 mmol), K3PO4 (19.0 g, 90 mmol), tricyclohexylphosphine (2.89 g, 10.2 mmol) and Pd(OAc)2 (1.16 g, 5.14 mmol). The flask was degassed by alternative evacuation and back filling with argon. A previously degassed :1 solution of toluene/ water (264 mL) was added and the resulting mixture was flushed with argon for 15 min. The reaction mixture was stirred at 100 °C for 3 hours before being cooled to room ature and filtered directly through a plug of celite. The filter cake was rinsed with EtOAc and the filtrate concentrated in vacuo. Purification by flash tography (silica, 10% EtOAc in hexanes) ed the title nd (5.5 g, 78%) as a yellow solid. MS (ESI): 272.7 ([M+H]+). d) (3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methanol To a stirred solution of ethyl 3-(6-cyclopropylpyridyl)methyl-isoxazolecarboxylate (2.7 g, 11.4 mmol) in anhydrous THF (20 mL) at -10 °C was added dropwise LiAlH4 (1.0 m in THF, 13.7 mL, 13.7 mmol). After 30 min, the reaction mixture was allowed to warm to 0 °C before being quenched by the addition of sodium sulfate decahydrate. The reaction was filtered directly through a plug of celite. The filter cake was rinsed with EtOAc and the filtrate concentrated in vacuo to afford the title compound (1.8 g, 81%) as an off white solid. MS (ESI): 236.1 ([M+H]+).

Building block L (5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methanol ethyl 5-cyclopropyl(6-methylpyridazinyl)isoxazolecarboxylate In analogy to ment of building block A b, 6-methylpyridazinecarbaldehyde oxime, using ethyl 3-cyclopropyl(pyrrolidinyl)acrylate instead of (E)-ethyl 3-(pyrrolidinyl)but- 2-enoate, was converted into the title compound (352 mg, 42%) which was obtained as an orange oil. MS (ESI): 274.1 ([M+H]+). -cyclopropyl(6-methylpyridazinyl)isoxazolecarboxylic acid In analogy to experiment of ng block E c, ethyl 5-cyclopropyl(6-methylpyridazin yl)isoxazolecarboxylate instead of ethyl 5-methyl(6-(trifluoromethyl)pyridin yl)isoxazolecarboxylate was converted into the title compound (260 mg, 95%) which was obtained as an orange solid. MS (ESI): 246.1 ([M+H]+). (5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methanol In y to experiment of building block H c, opropyl(6-methylpyridazin yl)isoxazolecarboxylic acid d of 3-(6-methylpyridyl)isoxazolecarboxylic acid was converted into the title compound (85 mg, 47%) which was obtained as an orange solid. MS (ESI): 232.1 ([M+H]+).

Building block M (3-(6-methoxypyridyl)methyl-isoxazolyl)methanol a) (3E)methoxypyridinecarbaldehyde oxime To a stirred suspension of 6-methoxypyridinecarbaldehyde (1.50 g, 10.9 mmol) in ethanol (2 mL) was added under argon ice-cold water (11 mL) and hydroxylamine hydrochloride (836 mg, 12 mmol). After 10 min, aqueous NaOH (2.0 m, 13.9 mL, 27.9 mmol) was added dropwise and the reaction mixture was d at room temperature for 3 hours. The ing colourless solution was treated with acetic acid to pH~5 (a white precipitate was formed). The resulting precipitate was collected by filtration and dried at high vacuum to afford the title compound (1.47 g, 88%) as a white solid. MS (ESI):153.1 ([M+H]+). b) ethyl 3-(6-methoxypyridyl)methyl-isoxazolecarboxylate To a stirred solution of (3E)methoxypyridinecarbaldehyde oxime (1.45 g, 9.53 mmol) in DMF (20 mL) at room temperature was added N-chlorosuccinimide (1.4 g, 10.5 mmol). The reaction was stirred at room temperature for 3.5 hours before addition of (E)-ethyl 3-(pyrrolidin- 1-yl)butenoate (2.1 g, 11.4 mmol). The mixture was heated to 50 °C overnight to obtain a clear brown solution then cooled to room temperature. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (75 mL) and brine (75 mL), dried (MgSO4) and concentrated in vacuo. cation by flash chromatography (silica, gradient: 0% to 30% EtOAc in heptane) afforded the title nd (2.31 g, 92%) as a light brown solid. MS (ESI): 263.1 ([M+H]+). c) (3-(6-methoxypyridyl)methyl-isoxazolyl)methanol To a stirred on of ethyl 3-(6-methoxypyridyl)methyl-isoxazolecarboxylate (2.3 g, 8.77 mmol) in anhydrous THF (30 mL) at 0 °C was added under argon and portionwise LiAlH4 (466 mg, 12.3 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours before being led to 0 °C and carefully quenched by addition of water (0.5 mL). After gas evolution had ceased, aqueous NaOH (4.0 m, 0.5 mL) was added followed by water (1.5 mL) and the mixture was stirred at 0 °C for 1 hours. The resulting light yellow suspension was filtered on a sintered funnel and the residue was washed with THF. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, gradient: 0% to 5% MeOH in CH2Cl2) to afford the title compound (1.44 g, 75%) as a yellow solid. MS (ESI): 221.2 ([M+H]+). ng block N (3-(6-(dimethylamino)pyridyl)methyl-isoxazolyl)methanol a) (3E)(dimethylamino)pyridinecarbaldehyde oxime To a stirred suspension of 6-(dimethylamino)pyridinecarbaldehyde (1.71 g, 11.4 mmol) in l (2 mL) was added under argon ice-cold water (11 mL) and hydroxylamine hloride (871 mg, 12.5 mmol). After 10 min, aqueous NaOH (2.0 m, 14.5 mL, 29.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The resulting colourless solution was treated with acetic acid to pH~5 (a white precipitate was formed) then diluted with water (15 mL). After stirring for 15 min, the precipitate was collected by filtration on a sintered , washed with water and dried at high . The resulting solid was triturated in a 1:1 mixture of CH2Cl2 and heptane (30 mL) then filtered and dried to obtain the title compound (1.54 g, 82%) as an off-white solid. MS (ESI):166.2 +). b) ethyl 3-(6-(dimethylamino)pyridyl)methyl-isoxazolecarboxylate To a stirred solution of (3E)(dimethylamino)pyridinecarbaldehyde oxime (1.09 g, 6.58 mmol) in DMF (15 mL) at room ature was added N-chlorosuccinimide (0.967 g, 7.24 mmol). The reaction was heated to 50 °C for 3 hours before being re-cooled to room temperature and (E)-ethyl 3-(pyrrolidinyl)butenoate (1.45 g, 7.9 mmol) was added in one portion. The mixture was heated again to 50 °C overnight to obtain a clear brown solution. After cooling to room temperature, the reaction was d with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 50% EtOAc in heptane) afforded the title nd (0.632 g, 33%) as a yellow solid. MS (ESI): 276.2 ([M+H]+). c) (3-(6-(dimethylamino)pyridyl)methyl-isoxazolyl)methanol To a stirred solution of ethyl 3-(6-(dimethylamino)pyridyl)methyl-isoxazolecarboxylate (220 mg, 0.799 mmol) in anhydrous THF (5 mL) at 0 °C was carefully added under argon LiAlH4 (42.5 mg, 1.12 mmol). The reaction mixture was d for 2 hours before being quenched carefully by addition of water (0.05 mL). After gas evolution had ceased, aqueous NaOH (4.0 m, 0.05 mL) was added followed by water (0.150 mL) and the mixture was allowed to warm to room temperature and stirred for 1 hour. The resulting light yellow slurry was filtered off and the cake was rinsed with THF. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2Cl2) to afford the title compound (140 mg, 75%) as an off-white solid. MS (ESI): 234.2 ([M+H]+).

Building block O (3-(5-fluoromethylpyridinyl)methyl-1,2-oxazolyl)methanol a) (3E)fluoromethyl-pyridinecarbaldehyde oxime To a stirred suspension of 5-fluoromethyl-pyridinecarbaldehyde (450 mg, 3.23 mmol) in ethanol (0.7 mL) was added under argon ice-cold water (4.3 mL) and hydroxylamine hydrochloride (247 mg, 3.56 mmol). After 10 min, aqueous NaOH (2.0 m, 4.12 mL, 8.25 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The resulting colourless solution was treated with acetic acid to pH~5 (a white precipitate was formed). After stirring for 15 min, the itate was collected by filtration on a sintered funnel, washed with water and dried at high vacuum to afford the title compound (383 mg, 77%) as a white solid. MS (ESI):155.1 ([M+H]+). b) ethyl 3-(5-fluoromethylpyridyl)methyl-isoxazolecarboxylate To a stirred solution of (3E)fluoromethyl-pyridinecarbaldehyde oxime (380 mg, 2.47 mmol) in DMF (5 mL) at room temperature was added rosuccinimide (329 mg, 2.47 mmol). The reaction was stirred at room temperature for 3.5 hours before addition of hyl 3- (pyrrolidinyl)butenoate (452 mg, 2.47 mmol). The mixture was heated to 50 °C overnight to obtain a clear brown solution. After cooling to room temperature, the reaction was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 30% EtOAc in heptane) afforded the title compound (475 mg, 73%) as a light brown solid. MS (ESI): 265.2 ([M+H]+). c) (3-(5-fluoromethylpyridinyl)methyl-1,2-oxazolyl)methanol To a stirred solution of ethyl 3-(5-fluoromethylpyridyl)methyl-isoxazolecarboxylate (470 mg, 1.78 mmol) in ous THF (10 mL) at 0 °C was carefully added under argon LiAlH4 (94.5 mg, 2.49 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours before being re-cooled to 0 °C and carefully ed by addition of water (0.1 mL).

After gas evolution had ceased, s NaOH (4.0 m, 0.1 mL) was added followed by water (0.35 mL) and the mixture was stirred at 0 °C for 30 min. The resulting light yellow suspension was filtered off and the cake was rinsed with THF. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, nt: 0% to 5% MeOH in CH2Cl2) to afford the title compound (221 mg, 56%) as a yellow solid. MS (ESI): 223.2 ([M+H]+).

Building block P (5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methanol a) ethyl (E)fluoropyrrolidinyl-butenoate To a stirred solution of ethyl rooxo-butanoate (1.0 g, 6.75 mmol) in exane (10 mL) was added dropwise on exothermic) pyrrolidine (0.60 mL, 7.22 mmol) followed by a catalytic amount of p-toluenesulfonic acid drate (64.2 mg, 0.338 mmol). The mixture was stirred at room temperature for 30 min then the bottom flask was equipped with a Dean- Stark trap and heated at reflux overnight.

The reaction e was cooled to room temperature then all the volatiles were removed by rotary evaporation under reduced pressure. The resulting crude residue (orange oil) was used directly in the following step without further purification. b) ethyl 5-(fluoromethyl)(6-methylpyridazinyl)isoxazolecarboxylate To a stirred suspension of (E)methylpyridazinecarbaldehyde oxime (350 mg, 2.55 mmol) in DMF (5 mL) at 6 °C was added N-chlorosuccinimide (375 mg, 2.81 mmol). Upon addition, the color of the reaction mixture changed from yellow to orange and the reaction was allowed to warm to room temperature. After 1 hour, the mixture was heated to 50 °C for 2 hours. The ing brown suspension was re-cooled to 6 °C then a solution of ethyl (E)fluoro pyrrolidinyl-butenoate (685 mg, 3.06 mmol, purity 90%) in DMF (1.0 mL) was added dropwise and the reaction mixture was stirred at 50 °C overnight. After cooling to room temperature, the reaction was diluted with water (20 mL) and ted with EtOAc (3 x 40 mL).

The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 50% EtOAc in heptane) afforded the title compound (498 mg, 74%) as an orange oil. MS (ESI): 266.1 ([M+H]+). c) (5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methanol To a stirred suspension of ethyl oromethyl)(6-methylpyridazinyl)isoxazole carboxylate (498 mg, 1.88 mmol) in anhydrous toluene (16 mL) at -78 °C was added dropwise DIBAL-H (1.0 m in toluene, 5.63 mL, 5.63 mmol). The reaction was stirred at -78 °C for 1 hour then allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C then ed by addition of aqueous NaOH (1.0 m, 15 mL) ed by EtOAc (20 mL). The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 40 mL).

The combined organic extracts were washed with brine, dried (Na2SO4) and trated in vacuo. Purification by flash chromatography a, gradient: 0% to 100% EtOAc in heptane) afforded the title compound (105 mg, 25%) as a light yellow powder. MS (ESI): 224.2 ([M+H]+).

Example 1 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl- necarboxamide a) methyl 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylate To a d solution of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A, 1.39 g, 6.81 mmol) in anhydrous THF (30 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 286 mg, 7.15 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 min before being re-cooled to 0 °C. Methyl 6-chloronicotinate (1.28 g, 7.49 mmol) was added over a period of 5 min and the reaction mixture was stirred for 5 hours. The reaction was poured into a mixture of aqueous citric acid (5 wt.%, 30 mL) and ice then extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica, nt: % to 100% EtOAc in e) afforded the title compound (2.07 g, 90%) as a light yellow solid. MS (ESI): 340.2 ([M+H]+). b) 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridine- 3-carboxamide To a stirred solution of tetrahydropyranamine (119 mg, 1.18 mmol) in anhydrous 1,4-dioxane (10 mL) at room temperature was added dropwise trimethylaluminium (2.0 m solution in e, 0.60 mL, 1.2 mmol). After 1 hour, a solution of methyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate (100 mg, 0.295 mmol) in anhydrous 1,4- dioxane (5 mL) was added dropwise. The reaction mixture was heated to 90 °C four 2 hours before being cooled to room temperature and poured into a mixture of ice and aqueous Na/K tartrate (10 wt.%, 20 mL). After 20 min vigorous stirring, the mixture was extracted with dichloromethane (2 x 30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 3% MeOH in ) afforded the title compound (89 mg, 74%) as a white solid MS (ESI): 409.4 ([M+H]+).

Example 2 N-(cyclopropylmethyl)((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine- 3-carboxamide In analogy to experiment of example 1b, methyl 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylate, using cyclopropylmethanamine instead of ydropyran- 4-amine, was converted into the title nd (60 mg, 54%) which was obtained as a white solid. MS (ESI): 379.4 ([M+H]+).

Example 3 N-ethyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxamide In y to experiment of e 1b, methyl 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylate, using ethylamine instead of tetrahydropyranamine, was converted into the title compound (62 mg, 60%) which was obtained as a white solid. MS (ESI): 353.3 ([M+H]+).

Example 4 (S)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide a) 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid To a stirred solution of methyl 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylate (1.43 g, 3.49 mmol, purity 83%) in a mixture of THF (10 mL), MeOH (10 mL) and water (10 mL) was added LiOH (335 mg, 14.0 mmol). The reaction was stirred at room temperature for 2 hours before being quenched by the addition of aqueous citric acid (5 wt.%, 20 mL). The mixture was diluted with water (20 mL) and stirred at 0 °C for 1 hour. The resulting suspension was filtered on a sintered funnel and the collected solid was rinsed with ice cold water (2 x 10 mL) and dried under high vacuum to afford the title nd (1.08 g, 95%) as a white solid. MS (ESI): 326.1 +). b) (1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide To a stirred solution of 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxylic acid (92 mg, 0.284 mmol) and (S)aminopentanol (44 mg, 0.426 mmol) in anhydrous DMF (3 mL) was added N,N-diisopropylethylamine (0.248 mL, 1.42 mmol) followed by TBTU (109 mg, 0.341 mmol). The resulting light yellow solution was stirred overnight at room temperature then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude e was purified by flash chromatography (silica, gradient: 95% to 100% EtOAc in e then 5% MeOH in EtOAc) to afford the title compound (67 mg, 57%) as an off-white solid. MS (ESI): 411.3 ([M+H]+).

Example 5 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide a) methyl cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine ylate In analogy to experiment of example 1a, (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol ing block D) instead of (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A) was converted into the title compound (632 mg, 71%) which was obtained as a light yellow oil. MS (ESI): 366.2 +). b) 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 4a, methyl 6-((5-cyclopropyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((5-methyl(6- methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (632 mg, 71%) which was obtained as a white solid. MS (ESI): 352.2 ([M+H]+). c) 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-cyclopropyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid was converted into the title compound (96 mg, 96%) which was obtained as a white solid. MS (ESI): 437.2 ([M+H]+).

Example 6 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide In analogy to experiment of e 4b, 6-((5-cyclopropyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid d of 6-((5-methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid, using tetrahydropyranamine d of (S) aminopentanol, was converted into the title compound (64 mg, 63%) which was obtained as a white solid. MS (ESI): 435.3 ([M+H]+).

Example 7 (S)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) methyl methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylate To a solution of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A, 170 mg, 0.832 mmol) in anhydrous THF (6 mL) at 0 °C was added NaH (55% in mineral oil, 40.0 mg, 0.999 mmol). The reaction mixture was warmed to room temperature and stirred for 4 hours. After cooling to 0 °C, methyl 6-chloropyridazinecarboxylate (187 mg, 1.08 mmol) was added and the reaction was maintained at 0 °C overnight using a thawing ice bath. Upon addition of a further amount of methyl 6-chloropyridazinecarboxylate (187 mg, 1.08 mmol) and NaH (55% in mineral oil, 40.0 mg, 0.999 mmol), the reaction mixture was heated to 80 °C overnight.

The reaction mixture was led to room temperature then poured into water and ice and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude e was purified by flash chromatography (silica, gradient: 5% to 100% EtOAc in heptane then 5% MeOH in EtOAc) to afford the title compound (132 mg, 47%) as an off-white solid. MS (ESI): 341.1 ([M+H]+). b) (S)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide To a stirred solution of methyl 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylate (70 mg, 0.206 mmol) in toluene (0.5 mL) was added under argon (S)aminopentanol (25.5 mg, 0.247 mmol) and 1,5,7-triazabicyclo[4.4.0]decene (17.2 mg, 0.123 mmol). The reaction mixture was stirred at room temperature for 6 hours before the addition of a further amount of (S)aminopentanol (25.5 mg, 0.247 mmol). After 16 hours, the resulting solution was concentrated in vacuo to provide a brown oil which was purified by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2Cl2) to afford the title compound (45 mg, 43%) as an off-white solid. MS (ESI): 412.3 ([M+H]+).

Example 8 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to experiment of example 4b, methyl 6-((5-methyl(6-methylpyridinyl)isoxazol- ethoxy)pyridazinecarboxylate instead of 6-((5-methyl(6-methylpyridyl)isoxazol- ethoxy)pyridinecarboxylic acid, using tetrahydropyranamine d of (S) aminopentanol, was converted into the title compound (6 mg, 8%) which was obtained as an ite solid. MS (ESI): 410.3 ([M+H]+).

Example 9 utyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one a) 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone To a suspension of 6-chloroformylnicotinic acid (520 mg, 2.8 mmol) in acetic acid (1.12 mL, 19.6 mmol) was added under en isobutylamine (0.323 mL, 3.22 mmol), hydrochloric acid (4.0 m solution in 1,4-dioxane, 0.771 mL, 3.08 mmol) and sodium triacetoxyborohydride (891 mg, 4.2 mmol). The on mixture was stirred at room temperature for 18 hours then heated to 60 °C for 5 hours. After this time, a second portion of isobutylamine (0.225 mL, 2.24 mmol) and sodium triacetoxyborohydride (475 mg, 2.24 mmol) were added and the reaction mixture was stirred at room temperature for further 18 hours. The mixture was diluted with EtOAc (30 mL) and the organic layer was washed with aqueous Na2CO3 (1.0 m on, 30 mL), water (30 mL) and brine (30 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (438 mg, 70%). MS (ESI): 410.3 ([M+H]+). b) 2-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one A round-bottomed flask was charged with (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A, 107 mg, 0.524 mmol), 6-chloroisobutyl-1H-pyrrolo[3,4- c]pyridin-3(2H)-one (177 mg, 0.786 mmol), Cs2CO3 (333 mg, 1.02 mmol), rac(di-tertbutylphosphino )-1,1'-binaphthyl (20.9 mg, 52.4 µmol) and Pd(OAc)2 (9.41 mg, 41.9 µmol). The flask was degassed by alternative evacuation and back filling with argon before on of anhydrous toluene (2.0 mL). The mixture was flushed with argon for 15 min then stirred at 90 °C for 18 hours before being concentrated in vacuo. The resulting brown oil crude residue was purified by flash chromatography (silica, gradient: 30% to 100% EtOAc in heptane) to afford the title compound (166 mg, 81%) as a white solid. MS (ESI): 393.2 ([M+H]+).

Example 10 yl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- din-3(2H)-one a) 6-chloromethyl-1H-pyrrolo[3,4-c]pyridinone In analogy to experiment of example 9a, 6-chloroformylnicotinic acid, using amine instead of isobutylamine, was converted into the title compound (408 mg, 69%) which was obtained as a light yellow solid. MS (ESI): 183.0 ([M+H]+). b) 2-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one In y to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol, using 6-chloromethyl-1H-pyrrolo[3,4-c]pyridinone instead of 6-chloro isobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (89 mg, 78%) which was obtained as a white foam. MS (ESI): 351.2 ([M+H]+).

Example 11 N-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)nicotinamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using isobutylamine instead of (S)aminopentanol, was converted into the title compound (67 mg, 74%) which was obtained as a white solid. MS (ESI): 381.2 ([M+H]+). 2-(2-hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H- pyrrolo[3,4-c]pyridin-3(2H)-one a) 6-chloro(2-hydroxyethyl)-1H-pyrrolo[3,4-c]pyridinone In analogy to experiment of example 9a, 6-chloroformylnicotinic acid, using oethanol instead of isobutylamine, was converted into the title compound (466 mg, 81%) which was ed as a white solid. MS (ESI): 213.1 ([M+H]+). b) 2-(6-chlorooxo-1H-pyrrolo[3,4-c]pyridinyl)ethyl acetate To a stirred solution of 6-chloro(2-hydroxyethyl)-1H-pyrrolo[3,4-c]pyridinone (270 mg, 1.28 mmol) in THF (5 mL) at room temperature was added acetic anhydride (0.360 mL, 3.81 mmol). The reaction mixture was heated to 60 °C for 2 hours before being concentrated in vacuo to afford the title compound (369 mg, 100%, purity 87%) as a white solid. MS (ESI): 255.0 +). c) 2-(2-hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H- pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 2-(6-chlorooxo-1H-pyrrolo[3,4-c]pyridinyl)ethyl acetate instead of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (12 mg, 12%) which was obtained as a white solid. MS (ESI): 381.2 ([M+H]+).

Example 13 (S)(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one a) 6-chloro((1S)(hydroxymethyl)butyl)-1H-pyrrolo[3,4-c]pyridinone In analogy to experiment of e 9a, 6-chloroformylnicotinic acid, using (S) entanol instead of isobutylamine, was converted into the title compound (693 mg, 100%, purity 50%) which was obtained as a light brown foam. MS (ESI): 253.1 ([M+H]+). b) ((2S)(6-chlorooxo-1H-pyrrolo[3,4-c]pyridinyl)pentyl) acetate In analogy to experiment of example 12b, 6-chloro((1S)(hydroxymethyl)butyl)-1H- pyrrolo[3,4-c]pyridinone instead of 6-chloro(2-hydroxyethyl)-1H-pyrrolo[3,4-c]pyridin one was converted into the title compound (560 mg, 70%) which was obtained as a white solid.

MS (ESI): 297.1 ([M+H]+). c) (S)(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 2-(6-chlorooxo-1H-pyrrolo[3,4-c]pyridin yl)pentyl) acetate instead of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (140 mg, 73%) which was obtained as a white foam. MS (ESI): 423.2 ([M+H]+).

N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide a) methyl 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyrazinecarboxylate To a d solution of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A, 154 mg, 0.754 mmol) in acetonitrile (3 mL) was added Cs2CO3 (491 mg, 1.51 mmol) followed by methyl 5-chloropyrazinecarboxylate (195 mg, 1.13 mmol). The reaction mixture was stirred at room temperature overnight before being diluted with EtOAc (15 mL) and washed with aqueous Na2CO3 (1.0 m, 15 mL), water (15 mL) and brine (15 mL). The aqueous layers were extracted with EtOAc 15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica gel, 30% to 100% EtOAc in heptane) afforded the title compound (199 mg, 78%) as a white solid MS (ESI): 341.2 ([M+H]+) b) 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy]pyrazinecarboxylic acid To a stirred solution of methyl 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylate (2.09 g, 6.14 mmol) in a mixture of THF (17 mL), MeOH (17 mL) and water (17 mL) at 0 °C was added LiOH monohydrate (773 mg, 18.4 mmol). The reaction was allowed to warm to room temperature and stirred for 30 min before being quenched by the addition of aqueous citric acid (5 wt.%, 20 mL). The mixture was diluted with water (20 mL) and stirred at 0 °C for 1 hour. The resulting suspension was filtered on a sintered funnel and the ted solid was rinsed with ice cold water (2 x 10 mL) and dried under high vacuum to afford the title compound (1.47 g, 74%) as a white solid. MS (ESI): 327.1 +). c) N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide To a stirred solution of 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyrazine ylic acid (51 mg, 0.16 mmol) and (S)aminopentanol (24 mg, 0.23 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (136 µL, 0.78 mmol) followed by TBTU (60 mg, 0.19 mmol). The resulting light yellow solution was stirred overnight at room ature then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined c extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, gradient: 80% to 100% EtOAc in heptane then 5% MeOH in EtOAc) to afford the title compound (60 mg, 93%) as a white solid. MS (ESI): 412.2 ([M+H]+).

Example 15 -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid, using ydropyranamine instead of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (52 mg, 92%) which was obtained as a white solid. MS (ESI): 410.3 ([M+H]+).

Example 16 -dioxothiolanyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using 1,1-dioxothiolanamine instead of (S) aminopentanol, was converted into the title compound (66 mg, 80%) which was obtained as a white solid. MS (ESI): 443.2 +).

Example 17 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)nicotinamide To a stirred solution of 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxylic acid (86.8 mg, 0.267 mmol) in anhydrous DMF (2 mL) at room temperature was added 1,1′-carbonyldiimidazole (56.2 mg, 0.347 mmol). The reaction mixture was heated to 60 °C for 1 hour before being re-cooled to room temperature. After 15 min, ammonium hydroxide (25 wt.%, 0.416 mL, 2.67 mmol) was added and the on was stirred at room temperature.

After 1 hour, isolute® was added and the ng solid-suspension was dried in vacuo then purified directly by flash chromatography a, gradient: 0% to 10% MeOH) to afford the title compound (70 mg, 81%) as a white solid. MS (ESI): 325.1 ([M+H]+). 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxamide To a suspension of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A, 54 mg, 0.226 mmol) and 6-chloropyridazinecarbonitrile (44.3 mg, 0.317 mmol) in THF (2 mL) was added under nitrogen at room temperature NaH (60% in mineral oil, 12.7 mg, 0.317 mmol).

After 1 hour, DMF (1 mL) was added and the reaction mixture was stirred for further 2 hours.

Aqueous NaOH (1.0 m, 0.529 mL, 0.529 mmol) was added and the reaction mixture was heated to 50 °C for 18 hours. The reaction was quenched by addition of s citric acid (5 wt.%, 2 mL) followed by addition of 1.0 m aqueous NaHCO3 to adjust the pH to ~7. The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash tography (silica, gradient: 0% to 5% MeOH in EtOAc) afforded the title compound (17 mg, 20%) as an off-white solid. MS (ESI): 326.1 ([M+H]+).

N-((3S)-1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using 1,1-dioxothiolanamine instead of (S) aminopentanol, was converted into the racemic title compound (66 mg, 80%) which was obtained as a white solid. MS (ESI): 443.2 ([M+H]+). tion of the enantiomers by chiral HPLC (column: Chiralcel OD) afforded the (+)-title compound (16 mg) which was obtained as a white solid. MS (ESI): 443.2 ([M+H]+).

Example 20 N-((3R)-1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 19, tion of the enantiomers by chiral HPLC (column: Chiralcel OD) afforded the (–)-title compound (16 mg) which was obtained as a white solid. MS (ESI): 443.2 ([M+H]+).

Example 21 N-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide a) methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydrothiopyranylpyridinecarboxamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using tetrahydrothiopyranamine d of (S) aminopentanol, was converted into the title compound (136 mg, 91%) which was obtained as an off-white solid. MS (ESI): 425.2 ([M+H]+). b) -dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide To a stirred suspension of 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N- tetrahydrothiopyranyl-pyridinecarboxamide (122 mg, 0.287 mmol) in a mixture of MeOH (3 mL) and water (3 mL) at room ature was added oxone® (353 mg, 0.575 mmol). After 3 hours, the suspension was basified by addition of aqueous Na2CO3 (0.5 m, 4 mL) and the mixture was stirred at room temperature for 1 hour. The suspension was filtered through a sintered funnel and the collected solid was washed with water (5 mL) and TBME (2 mL) then dried at high vacuum to afford the title compound (118 mg, 90%) as a white solid. MS (ESI): 457.2 ([M+H]+).

Example 22 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-pyranyl)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one a) 6-chlorotetrahydropyranyl-1H-pyrrolo[3,4-c]pyridinone In analogy to experiment of example 9a, 6-chloroformylnicotinic acid, using ydropyran- 4-amine instead of isobutylamine, was converted into the title nd (544 mg, 75%) which was obtained as a white solid. MS (ESI): 253.1 ([M+H]+). b) 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-pyranyl)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 6-chlorotetrahydropyranyl-1H-pyrrolo[3,4- c]pyridinone instead of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title nd (99 mg, 83%) which was obtained as a white solid. MS (ESI): 421.2 ([M+H]+).

Example 23 N-((1S,2R)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) 4-((6-chloropyridazinyloxy)methyl)methyl(6-methylpyridinyl)isoxazole To a solution of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol ing block A, 15.9 g, 77.8 mmol) in anhydrous THF (500 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 4.05 g, 101 mmol). The resulting solution was warmed to room temperature and stirred for 30 min before being cooled to 0 °C. 3,6-dichloropyridazine (13.9 g, 93.4 mmol) was added over a period of 5 min and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into water and ice and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. cation by flash chromatography (silica, gradient: 10% to 20% EtOAc in heptane) afforded the title compound (18.7 g, 76 % yield) as a yellow solid. MS (ESI): 317.1 ([M+H]+). b) ethyl 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylate To a solution of chloropyridazinyloxy)methyl)methyl(6-methylpyridin yl)isoxazole (18.7 g, 56.0 mmol) in EtOH (280 mL) was added Na2CO3 (6.25 g, 59.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene (3.27 g, 5.9 mmol) and Pd(OAc)2 (1.33 g, 5.94 mmol). The resulting black suspension was purged by evacuation and then back filled with a stream of CO(g) (balloon, 1.3 L) for three time before being heated to 50 °C overnight under a CO(g) atmosphere.

The reaction mixture was ed directly h a plug of dicalite and the filter cake was rinsed with with EtOH (200 mL) then EtOAc (200 mL). The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica, gradient: 0% to 20% EtOAc in heptane) to afford the title compound (14.8 g, 75%) as a light yellow solid. MS (ESI): 355.2 ([M+H]+). c) 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylic acid To a stirred solution of ethyl 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylate (2.20 g, 6.21 mmol) in a mixture of THF (7 mL) and MeOH (7 mL) and water (7 mL) was added LiOH·H2O (782 mg, 18.6 mmol). The on mixture was stirred at room temperature overnight. The pH was adjusted to ~5 by addition of aqueous citric acid (5 wt.%) then the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined c extracts were washed with water (~20 mL) and brine (~20 mL) and the resulting solid precipitated during the work-up was collected through filtration on a sintered funnel. The solid was combined with the c layers and trated in vacuo. The e was triturated with EtOAc then filtered and dried under high vacuum to afford the title compound (1.51 g, 75%) as an off-white solid. MS (ESI): 327.1 ([M+H]+). d) N-((1S,2R)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide To a stirred suspension of 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid (35 mg, 0.107 mmol) and (1R,2S) aminocyclohexanol hydrochloride (30 mg, 0.198 mmol) in DMF (0.6 mL) was added N,N- diisopropylethylamine (95 µL, 0.544 mmol) followed by TBTU (38 mg, 0.118 mmol). The resulting light yellow solution was stirred overnight at room temperature then poured into water (3 mL) and extracted with TBME (3 x 10 mL). The combined organic extracts were washed with water (3 x 3 mL), brine (~3 mL), dried (Na2SO4) and concentrated in vacuo. The resulting precipitate was triturated with TBME and EtOAc then filtered and dried under high vacuum to afford the title compound (39 mg, 86%) as an off-white solid. MS (ESI): 424.3 ([M+H]+).

Example 24 N-((1S,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxamide In analogy to experiment of example 23d, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (1S,2S)aminocyclohexanol hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (29 mg, 64%) which was obtained as an off-white solid. MS (ESI): 424.2 ([M+H]+).

Example 25 ,2R)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of e 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (1R,2R)aminocyclohexanol hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title nd (37 mg, 82%) which was obtained as an off-white solid. MS (ESI): 424.3 ([M+H]+).

Example 26 N-cyclopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to ment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cyclopropylamine instead of (1R,2S) aminocyclohexanol hydrochloride was ted into the title nd (51 mg, 80%) which was obtained as a white solid. MS (ESI): 366.2 ([M+H]+).

Example 27 N-((1R,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (1S,2R)aminocyclohexanol hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (31 mg, 68%) which was obtained as a light-brown solid. MS (ESI): 424.3 ([M+H]+).

Example 28 N-((3S,4R)hydroxytetrahydropyranyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (3S,4R)aminotetrahydro-2H-pyranol hydrochloride d of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (19 mg, 42%) which was ed as an off-white foam. MS (ESI): 426.2 ([M+H]+).

Example 29 N-(2-hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide To a stirred suspension of 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid (35 mg, 0.107 mmol) in DMF (0.75 mL) was added 1,1′-carbonyldiimidazole (23 mg, 0.142 mmol) and the on mixture was heated to 60 °C for 1 hour. After cooling to room ature, ethanolamine (65 µL, 0.107 mmol) was added and the mixture was stirred for further 2 hours. The reaction mixture was poured into water (~3 mL) and extracted with TBME (2 x 10 mL). The combined organic extracts were washed with water (3 x 3 mL), brine (3 x 3 mL), dried (Na2SO4) and concentrated in vacuo. The aqueous layers were ted with CH2Cl2 (2 x 20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification of the combined residues by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2Cl2) afforded the title compound (25 mg, 63%) as a white solid. MS (ESI): 370.2 ([M+H]+).

Example 30 N-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridazinecarboxamide To a stirred sion of 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid (40 mg, 0.123 mmol) and (1,1-dioxidotetrahydro-2H- thiopyranyl)amine hydrochloride (37 mg, 0.199 mmol) in EtOAc (2.2 mL) was added triethylamine (100 µL, 0.717 mmol) followed by a solution of 1-propylphosphonic acid cyclic anhydride in EtOAc (50 wt.%, 160 mg, 150 µL, 0.252 mmol). The reaction e was heated to 50 °C overnight before being cooled to room temperature, diluted with EtOAc (~50 mL) and washed with ted aqueous NaHCO3 (2 x 10 mL). The aqueous layers were extracted with EtOAc (~50 mL). The combined organic ts were washed with water (~5 mL) and brine (~5 mL), dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2Cl2) afforded the title compound (40 mg, 68%) as an off- white solid. MS (ESI): 458.2 ([M+H]+).

Example 31 N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (aminomethyl)-cyclopropane instead of ethanolamine, was converted into the title compound (39 mg, 80%) which was obtained as an off-white solid. MS (ESI): 380.2 ([M+H]+).

Example 32 N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 29, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 2-aminomethylpropanol instead of ethanolamine, was converted into the title nd (35 mg, 82%) which was obtained as a white foam. MS (ESI): 398.2 ([M+H]+).

Example 33 N-(2-cyanoethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-aminopropionitrile d of ethanolamine, was converted into the title compound (34 mg, 84%) which was obtained as an off-white solid.

MS (ESI): 379.2 ([M+H]+).

Example 34 (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1- trifluoropropanyl)pyridazinecarboxamide In analogy to experiment of example 23d, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (RS)-1,1,1-trifluoropropanamine hydrochloride instead of )aminocyclohexanol hydrochloride, was converted into the title compound (19 mg, 42%) which was obtained as an off-white solid. MS (ESI): 422.2 ([M+H]+).

Example 35 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxetanyl)pyridazine carboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using oxetanamine hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title nd (36 mg, 57%) which was obtained as an off-white solid. MS (ESI): 382.2 ([M+H]+).

Example 36 (RS)-N-(1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 30, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using ,1-dioxothiolanamine instead of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (89 mg, 82%) which was obtained as an off-white solid. MS (ESI): 444.2 ([M+H]+).

Example 37 N-ethyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using ethylamine (2.0 m in THF) d of ethanolamine, was converted into the title compound (42 mg, 86%) which was obtained as an off-white solid. MS (ESI): 354.2 +).

N-isopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using isopropylamine instead of ethanolamine, was converted into the title compound (44 mg, 87%) which was obtained as an off-white solid. MS (ESI): 368.2 ([M+H]+).

Example 39 N-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of example 29, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using isobutylamine d of ethanolamine, was converted into the title compound (46 mg, 83%) which was obtained as an off-white solid. MS (ESI): 382.2 ([M+H]+).

Example 40 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2,2,2- trifluoroethyl)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 2,2,2-trifluoroethanamine hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (34 mg, 61%) which was obtained as an off-white solid. MS (ESI): 408.2 +).

Example 41 N-tert-butyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using tert-butylamine instead of ethanolamine, was converted into the title nd (46 mg, 83%) which was obtained as an off-white solid. MS (ESI): 382.2 ([M+H]+).

Example 42 N-(3,3-difluorocyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using 3,3-difluorocyclobutanamine hloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (36 mg, 63%) which was obtained as an off-white solid. MS (ESI): 416.2 ([M+H]+).

Example 43 N-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of e 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 4,4-difluorocyclohexanamine hloride instead of (1R,2S)aminocyclohexanol hloride, was converted into the title compound (51 mg, 79%) which was obtained as an off-white solid. MS (ESI): 444.2 ([M+H]+).

Example 44 6-((3-(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridine carboxamide a) methyl 6-((3-(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylate In analogy to experiment of example 1a, (3-(6-methylpyridyl)isoxazolyl)methanol (building block H) d of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A) was converted into the title compound (821 mg, 48%) which was obtained as a white solid. MS (ESI): 326.1 ([M+H]+). b) 6-((3-(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 4a, methyl 6-((3-(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylate instead of methyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate was co nverted into the title compound (837 mg, 88%) which was obtained as a white solid. MS (ESI): 312.1 ([M+H]+). c) 6-((3-(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridine carboxamide In analogy to experiment of example 4b, (6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid, using tetrahydropyranamine instead of (S) aminopentanol, was converted into the title compound (65 mg, 80%) which was obtained as a white solid. MS (ESI): 395.2 ([M+H]+).

Example 45 (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide In analogy to experiment of example 23d, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (RS)-tetrahydrofuranamine hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title nd (33 mg, 58%) which was obtained as an off-white solid. MS (ESI): 396.3 ([M+H]+).

Example 46 N-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of e 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using amine (2.0 m on in THF) instead of ethanolamine, was converted into the title compound (38 mg, 73%) which was obtained as an off-white solid. MS (ESI): 340.2 ([M+H]+).

Example 47 (3,3-difluoroazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3,3-difluoroazetidine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hloride, was converted into the title compound (53 mg, 82%) which was obtained as an off-white solid. MS (ESI): 402.2 ([M+H]+).

Example 48 (3,3-difluoropyrrolidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In y to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3,3-difluoropyrrolidine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (46 mg, 80%) which was obtained as an off-white solid. MS (ESI): 416.2 ([M+H]+). 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((3-methyloxetan yl)methyl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (3-methyloxetanyl)methanamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (40 mg, 71%) which was obtained as an off-white solid. MS (ESI): 410.2 ([M+H]+).

Example 50 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(oxetan yl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-aminomethyloxetane instead of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hloride, was converted into the title compound (33 mg, 58%) which was obtained as an off-white solid. MS (ESI): 396.2 ([M+H]+).

Example 51 N-((3-hydroxyoxetanyl)methyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to ment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-(aminomethyl)oxetanol instead of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (44 mg, 74%) which was obtained as an off-white foam. MS (ESI): 412.2 ([M+H]+).

Example 52 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((3R,4R) methyltetrahydropyranyl)pyridazinecarboxamide In analogy to experiment of e 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (3R,4R)methyltetrahydro-2H-pyranamine hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (44 mg, 75%) which was obtained as an ite foam. MS (ESI): 424.3 ([M+H]+).

Example 53 (4,4-difluoropiperidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 4,4-difluoropiperidine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (41 mg, 59%) which was obtained as a white solid. MS (ESI): 430.2 ([M+H]+).

Example 54 N-(1-(methoxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1-(methoxymethyl)cyclopropanamine hydrochloride d of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was ted into the title compound (41 mg, 59%) which was obtained as an off-white solid. MS (ESI): 410.3 ([M+H]+).

Example 55 (3-methoxyazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-methoxyazetidine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title nd (45 mg, 74%) which was obtained as an ite solid. MS (ESI): 396.2 ([M+H]+).

Example 56 roxymethylazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-methylazetidinol hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (27 mg, 45%) which was obtained as an off-white foam. MS (ESI): 396.2 ([M+H]+).

Example 57 azetidinyl(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazin yl)methanone In y to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using azetidine instead of ethanolamine, was converted into the title compound (26 mg, 44%) which was obtained as an off-white solid. MS (ESI): 366.2 ([M+H]+).

Example 58 (RS)-N-(2,2-dimethyltetrahydropyranyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide In analogy to ment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (RS)-2,2-dimethyltetrahydropyranamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (52 mg, 78%) which was obtained as a white foam. MS (ESI): 438.3 ([M+H]+). 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1-(trifluoromethyl)cyclopropanamine hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was ted into the title compound (46 mg, 69%) which was obtained as an off-white solid. MS (ESI): 434.2 ([M+H]+).

Example 60 (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazin rpholino)methanone In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using morpholine instead of ethanolamine was converted into the title nd (41 mg, 68%) which was obtained as an off-white solid. MS (ESI): 396.3 ([M+H]+).

Example 61 (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinyl)(2-oxa azaspiro[3.3]heptanyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 2-oxaazaspiro[3.3]heptane hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was ted into the title compound (20 mg, 30%) which was obtained as a white foam. MS (ESI): 408.2 Example 62 4-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide a) chloromethyl-pyridazinyl)oxymethyl)methyl(6-methylpyridyl)isoxazole In analogy to experiment of example 23a, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 3,6-dichloromethylpyridazine instead of 3,6- dichloropyridazine, was converted into a 1:1 mixture of the title compound and the isomeric 4- ((6-chloromethyl-pyridazinyl)oxymethyl)methyl(6-methylpyridyl)isoxazole (1.45 g, 89%) which was obtained as a light brown oil. MS (ESI): 331.1 ([M+H]+). b) ethyl 4-methyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridazine carboxylate In analogy to experiment of example 23b, 4-((6-chloromethyl-pyridazinyl)oxymethyl) methyl(6-methylpyridyl)isoxazole and 4-((6-chloromethyl-pyridazinyl)oxymethyl)- yl(6-methylpyridyl)isoxazole instead of 4-((6-chloropyridazinyloxy)methyl) methyl(6-methylpyridinyl)isoxazole was converted into the title compound (310 mg, 21%) as a light yellow oil, following separation of regioisomers by flash chromatography (silica, nt: 0% to 80% EtOAc in heptane). MS (ESI): 369.2 ([M+H]+). c) 4-methyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridazinecarboxylic In analogy to ment of example 23c, ethyl 4-methyl((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylate instead of ethyl 6-((5-methyl(6- methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylate was converted into the title compound (213 mg, 72%) which was obtained as a white solid. MS (ESI): 341.1 ([M+H]+). d) 4-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran- 4-yl)pyridazinecarboxamide In analogy to experiment of example 23d, 4-methyl((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6- methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using tetrahydropyran- 4-amine instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (49 mg, 89%) which was ed as a white solid. MS (ESI): 424.2 ([M+H]+).

Example 63 (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinyl)(6-oxa azaspiro[3.3]heptanyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 6-oxaazaspiro[3.3]heptane oxalate d of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (43 mg, 62%) which was obtained as an off-white foam. MS (ESI): 408.2 ([M+H]+).

Example 64 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1-trifluoro methylpropanyl)pyridazinecarboxamide In analogy to ment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1,1,1-trifluoromethylpropanamine instead of ioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (41 mg, 62%) which was obtained as an off-white solid. MS (ESI): 436.2 ([M+H]+).

Example 65 (3-fluoroazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-fluoroazetidine hydrochloride instead of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (52 mg, 89%) which was obtained as an off-white solid. MS (ESI): 384.2 ([M+H]+). (3-hydroxyazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-hydroxyazetidine hloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (19 mg, 31%) which was obtained as an off-white solid. MS (ESI): 382.2 ([M+H]+).

Example 67 oromethylazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-fluoromethylazetidine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (51 mg, 84%) which was ed as an off-white solid. MS (ESI): 398.2 ([M+H]+).

Example 68 ethyl 1-(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamido)cyclopropanecarboxylate In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using ethyl 1-aminocyclopropanecarboxylate hloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (99 mg, 92%) which was obtained as an off-white solid. MS (ESI): 438.3 ([M+H]+).

Example 69 N-(1-cyanocyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1-aminocyclopropanecarbonitrile hydrochloride d of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (44 mg, 74%) which was obtained as a white solid. MS (ESI): 391.2 ([M+H]+).

Example 70 yl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide a) 4-((6-chloromethyl-pyridazinyl)oxymethyl)methyl(6-methylpyridyl)isoxazole In y to experiment of example 23a, (5-methyl(6-methylpyridinyl)isoxazol hanol (building block A), using 3,6-dichloromethylpyridazine instead of 3,6- dichloropyridazine, was converted into a 1:1 mixture of the title compound and the isomeric 4- ((6-chloromethyl-pyridazinyl)oxymethyl)methyl(6-methylpyridyl)isoxazole (1.45 g, 89%) which was obtained as a light brown oil. MS (ESI): 331.1 ([M+H]+). b) ethyl 5-methyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridazine carboxylate In analogy to experiment of example 23b, chloromethyl-pyridazinyl)oxymethyl) methyl(6-methylpyridyl)isoxazole and chloromethyl-pyridazinyl)oxymethyl)- -methyl(6-methylpyridyl)isoxazole instead of 4-((6-chloropyridazinyloxy)methyl) methyl(6-methylpyridinyl)isoxazole was converted into the title nd (271 mg, 18%) as a white solid, following separation of regioisomers by flash chromatography (silica, gradient: 0% to 80% EtOAc in heptane). MS (ESI): 369.2 ([M+H]+). c) 5-methyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridazinecarboxylic In analogy to experiment of example 23c, ethyl 5-methyl((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylate instead of ethyl 6-((5-methyl(6- methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylate was converted into the title compound (372 mg, 72%) which was obtained as a white solid. MS (ESI): 341.2 ([M+H]+). d) 5-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In analogy to experiment of example 29, 5-methyl((5-methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using um hydroxide solution (~25 wt.%) d of ethanolamine, was converted into the title compound (15 mg, 31%) which was obtained as a white solid. MS (ESI): 340.1 ([M+H]+).

Example 71 -methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide In analogy to experiment of example 23d, 5-methyl((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6- methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using tetrahydropyran- 4-amine instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (43 mg, 86%) which was obtained as a light-brown oil. MS (ESI): 424.3 ([M+H]+).

Example 72 -dioxothianyl)((5-methyl(6-methylpyridyl)isoxazol hoxy)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxylic acid was converted into the title compound (45 mg, 64%) which was obtained as a white solid. MS (ESI): 458.2 ([M+H]+).

Example 73 N-(2-hydroxy-1,1-dimethyl-ethyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide In analogy to ment of example 29, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 2-aminomethylpropanol instead of ethanolamine, was converted into the title compound (51 mg, 84%) which was obtained as a white foam. MS (ESI): 398.3 ([M+H]+).

Example 74 N-cyclopropyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyrazine carboxamide In analogy to experiment of example 30, methyl 6-((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxylate instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using cyclopropanamine d of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title nd (53 mg, 95%) which was obtained as a white solid. MS (ESI): 366.2 ([M+H]+).

Example 75 (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide In analogy to ment of e 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (RS)aminomethyloxolane instead of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride was converted into the title compound (50 mg, 76%) which was obtained as an off-white foam. MS (ESI): 410.3 ([M+H]+).

Example 76 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- cyclopropyl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1-methylcyclopropanamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride was converted into the title compound (54 mg, 93%) which was obtained as an off-white solid. MS (ESI): 380.2 ([M+H]+).

Example 77 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(oxetanyl)pyrazine carboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using oxetanamine hydrochloride d of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (50 mg, 86%) which was obtained as a white solid. MS (ESI): 382.2 ([M+H]+).

Example 78 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(2,2,2- trifluoroethyl)pyrazinecarboxamide In analogy to experiment of example 30, methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 2,2,2-trifluoroethanamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (54 mg, 87%) which was obtained as a white solid. MS (ESI): 408.2 +).

Example 79 N-(4-hydroxymethylbutanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-aminomethylbutanol instead of ethanolamine, was converted into the title nd (45 mg, 71%) which was ed as an off-white solid. MS (ESI): 412.2 ([M+H]+).

Example 80 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-methyl (methylsulfonyl)butanyl)pyridazinecarboxamide In analogy to ment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 2-methylmethylsulfonyl-butanamine instead of ethanolamine, was converted into the title compound (36 mg, 47%) which was obtained as an off-white foam. MS (ESI): 474.2 ([M+H]+).

Example 81 (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide or enantiomer Separation of the omers of (RS)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)-N-(3-methyltetrahydrofuranyl)pyridazinecarboxamide (example 75) by chiral HPLC n: Chiralpak AD, 35 mL/min, i-PrOH/heptane: 40/60; 18 bar; 220 nm) afforded the (+)-title compound (22 mg) which was obtained as an off-white solid. MS (ESI): 410.2 ([M+H]+).

Example 82 (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- tetrahydrofuranyl)pyridazinecarboxamide or enantiomer Separation of the enantiomers of (RS)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)-N-(3-methyltetrahydrofuranyl)pyridazinecarboxamide (example 75) by chiral HPLC (column: Chiralpak AD, 35 mL/min, i-PrOH/heptane: 40/60; 18 bar; 220 nm) afforded the (–)-title compound (20 mg) which was obtained as an off-white foam. MS (ESI): 410.2 ([M+H]+).

Example 83 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide In analogy to ment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-methyloxetanamine hydrochloride instead of )aminocyclohexanol hydrochloride, was converted into the title compound (61 mg, 84%) which was obtained as an off-white solid. MS (ESI): 396.2 ([M+H]+).

Example 84 1-(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carbonyl)azetidinecarbonitrile In analogy to experiment of e 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using azetidinecarbonitrile hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (42 mg, 70%) which was obtained as an off-white solid. MS (ESI): 391.2 ([M+H]+).

Example 85 N-(1-(hydroxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide To a stirred sion of 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid (78 mg, 0.191 mmol) in anhydrous THF (1.5 mL) was added triethylamine (30 µL, 0.215 mmol). The resulting solution was cooled to -16 °C (NaCl/ice bath) before a solution of ethyl chloroformate (22.6 mg, 20 µL, 0.208 mmol) in THF (0.2 mL) was added se. After 30 min, the resulting white precipitate was filtered through a ed funnel and the collected solid rinsed with a minimal amount of anhydrous THF. The filtrate was re-cooled to -16 °C (NaCl/ice bath) and a solution of NaBH4 (18 mg, 0.476 mmol) in water (0.8 mL) was added dropwise. Upon addition, the reaction was allowed to warm to 0 °C for 2 hours then to room temperature for 1 hour. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL), then diluted with water (5 mL) and extracted with EtOAc (2 x 15 mL).

The ed organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 5% MeOH in CH2Cl2) ed the title nd (21 mg, 27%) as an off-white solid. MS (ESI): 396.2 ([M+H]+).

Example 86 N-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 4,4-difluorocyclohexanamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title nd (41 mg, 88%) which was obtained as an off-white solid. MS (ESI): 444.3 +).

Example 87 (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (S)-tetrahydrofuranamine hloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (52 mg, 82%) which was obtained as a white foam. MS (ESI): 396.2 ([M+H]+).

Example 88 (S)-N-(1-cyanobutanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 29, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (S)aminopentanenitrile instead of ethanolamine, was converted into the title compound (61 mg, 93%) which was obtained as an ite foam. MS (ESI): 407.2 ([M+H]+).

Example 89 ((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using (R)-tetrahydrofuranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title nd (40 mg, 73%) which was obtained as an off-white solid. MS (ESI): 396.2 ([M+H]+).

Example 90 N-(2-Hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyrazine- 2-carboxamide In analogy to experiment of example 14c, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid, using ethanolamine instead of (S)aminopentanol, was converted into the title compound (39 mg, 77%) which was ed as a white solid. MS (ESI): 370.2 ([M+H]+).

Example 91 2-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazolyl)methoxy)-1H- pyrrolo[3,4-c]pyridinone a) 6-chloro(1,1-dioxothianyl)-1H-pyrrolo[3,4-c]pyridinone In analogy to experiment of example 9a, 6-chloroformylnicotinic acid, using (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride instead of isobutylamine, was ted into the title compound (137 mg, 42%) which was obtained as a light yellow solid. MS (ESI): 301.0 ([M+H]+). b) 2-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazolyl)methoxy)-1H- o[3,4-c]pyridinone In analogy to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 6-chloro(1,1-dioxothianyl)-1H-pyrrolo[3,4- c]pyridinone d of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (15 mg, 12%) which was obtained as a yellow solid. MS (ESI): 469.2 ([M+H]+).

Example 92 (S)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol hoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using (S)-tetrahydrofuranamine hydrochloride instead of ioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (37 mg, 76%) which was obtained as a white solid. MS (ESI): 396.2 ([M+H]+). 2-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy]tetrahydropyranyl-7H- pyrrolo[3,4-b]pyridinone a) ethyl 2-(bromomethyl)chloro-pyridinecarboxylate To a stirred solution of ethyl 6-chloromethylnicotinate (0.810 g, 4.06 mmol) in CCl4 (8 mL) at room temperature was added N-bromosuccinimide (1.00 g, 5.62 mmol) followed by AIBN (33 mg, 0.201 mmol). The reaction e was heated at reflux overnight before all the volatiles were removed by rotary evaporation under reduced pressure. The resulting crude residue was purified by flash chromatography (silica, gradient: 0% to 15% EtOAc in heptane) to afford the title compound (1.04 g, 55%, purity ca. 60%) as a light yellow oil. MS (ESI): 278.1 ([M+H]+). b) 2-chlorotetrahydropyranyl-7H-pyrrolo[3,4-b]pyridinone To a d solution of ethyl 2-(bromomethyl)chloro-pyridinecarboxylate (0.380 g, 0.819 mmol, purity ca. 60%) in anhydrous THF (3.4 mL) at room temperature was added tetrahydropyranamine (0.34 mL, 3.28 mmol). The reaction mixture was heated to 50 °C overnight before being re-cooled to room temperature. The mixture was diluted with EtOAc (40 mL) and the organic layer washed with a mixture of water (5 mL) and brine (5 mL). The aqueous layer was extracted with EtOAc (40 mL) and the combined organic extracts were dried (Na2SO4) and trated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2Cl2) afforded the title compound (192 mg, 93%) as a white solid. MS (ESI): 253.1 ([M+H]+). c) 2-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)tetrahydropyranyl-7H- pyrrolo[3,4-b]pyridinone In y to ment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 2-chlorotetrahydropyranyl-7H-pyrrolo[3,4- b]pyridinone instead of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (77 mg, 75%) which was obtained as a light yellow solid. MS (ESI): 421.3 ([M+H]+).

N-(1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxylic acid, using 3-aminotetrahydrothiophene 1,1- dioxide instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (40 mg, 65%) which was ed as a white solid. MS (ESI): 444.4 +).

Example 95 N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using cyclopropylmethanamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (50 mg, 86%) which was obtained as a white solid. MS (ESI): 380.2 ([M+H]+).

Example 96 2-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H- pyrrolo[3,4-c]pyridin-3(2H)-one a) 6-chloro(4,4-difluorocyclohexyl)-1H-pyrrolo[3,4-c]pyridinone In y to experiment of example 9a, 6-chloroformylnicotinic acid, using 4,4- difluorocyclohexanamine hydrochloride instead of ylamine, was converted into the title compound (211 mg, 45%) which was obtained as an off-white solid. MS (ESI): 287.1 ([M+H]+). b) 2-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H- pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 6-chloro(4,4-difluorocyclohexyl)-1H-pyrrolo[3,4- c]pyridinone d of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (90 mg, 81%) which was obtained as a light brown solid. MS (ESI): 455.3 ([M+H]+).

Example 97 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydropyran- 4-yl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 4-methyltetrahydropyranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was ted into the title compound (54 mg, 79%) which was obtained as an off-white foam. MS (ESI): 424.3 ([M+H]+).

Example 98 (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using (R)-tetrahydropyranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (49 mg, 87%) which was obtained as a white solid. MS (ESI): 410.3 ([M+H]+).

Example 99 (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to ment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (R)-tetrahydropyranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was ted into the title compound (51 mg, 90%) which was obtained as a white solid. MS (ESI): 410.3 ([M+H]+). e 100 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 2-oxaspiro[3.3]heptanamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (388 mg, 70%) which was obtained as an off-white solid. MS (ESI): 422.2 ([M+H]+).

Example 101 -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyrazinecarboxamide In analogy to ment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 2-oxaspiro[3.3]heptanamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hloride, was converted into the title compound (355 mg, 72%) which was obtained as a white solid. MS (ESI): 422.3 ([M+H]+).

Example 102 -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(cis (trifluoromethyl)cyclohexyl)pyrazinecarboxamide In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 4- (trifluoromethyl)cyclohexanamine hloride instead of (1,1-dioxidotetrahydro-2H- ranyl)amine hydrochloride, was converted into the title compound (45 mg, 34%) which was obtained as an off-white foam. MS (ESI): 476.2 ([M+H]+).

Example 103 (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using (S)-tetrahydropyranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (43 mg, 76%) which was obtained as a white foam. MS (ESI): 410.3 ([M+H]+).

Example 104 N-(cishydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyrazinecarboxamide In analogy to experiment of example 14c, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid, using cisaminomethylcyclohexanol 2,2,2- trifluoroacetate instead of aminopentanol, was converted into the title compound (18 mg, 13%) which was ed as an off-white solid. MS (ESI): 438.2 ([M+H]+).

Example 105 N-(transhydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyrazinecarboxamide In analogy to experiment of example 14c, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid, using transaminomethylcyclohexanol 2,2,2- trifluoroacetate instead of (S)aminopentanol, was converted into the title compound (50 mg, 37%) which was obtained as an off-white solid. MS (ESI): 438.2 ([M+H]+).

Example 106 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydropyran- 4-yl)nicotinamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 4-methyltetrahydropyranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (48 mg, 75%) which was obtained as a ess oil. MS (ESI): 423.3 ([M+H]+).

Example 107 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-thiopyran- 4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one a) 6-chlorotetrahydrothiopyranyl-1H-pyrrolo[3,4-c]pyridinone In analogy to experiment of example 9a, 6-chloroformylnicotinic acid, using ydrothiopyranamine instead of isobutylamine, was converted into the title compound (585 mg, 45%) which was ed as a light brown solid. MS (ESI): 269.1 ([M+H]+). b) 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-thiopyran yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to experiment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using 6-chlorotetrahydrothiopyranyl-1H-pyrrolo[3,4- c]pyridinone instead of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (379 mg, 59%) which was ed as a yellow solid. MS (ESI): 437.3 ([M+H]+).

Example 108 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide methyl 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)pyridinecarboxylate In analogy to experiment of example 1a, (5-methyl(6-methylpyridazinyl)isoxazol yl)methanol (building block I) instead of (5-methyl(6-methylpyridinyl)isoxazol yl)methanol ing block A) was ted into the title compound (751 mg, 60%) which was obtained as a light yellow oil. MS (ESI): 341.1 ([M+H]+). 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to ment of example 4a, methyl 6-((5-methyl(6-methylpyridazin yl)isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (400 mg, 83%) which was obtained as a white solid. MS (ESI): 327.0 ([M+H]+). 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridazinyl)isoxazol yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methylpyridyl)isoxazol- ethoxy)pyridinecarboxylic acid, using tetrahydropyranamine instead of (S) entanol, was converted into the title compound (85 mg, 67%) which was obtained as a white solid. MS (ESI): 410.1 ([M+H]+).

Example 109 N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridazinyl)isoxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridazinyl)isoxazol yl)methoxy)pyridinecarboxylic acid d of methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid was converted into the title compound (151 mg, 79%) which was obtained as a white solid. MS (ESI): 412.1 ([M+H]+).

Example 110 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4- methyltetrahydrothiopyranyl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 4-methyltetrahydrothiopyranamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (94 mg, 83%) which was obtained as an off-white foam. MS (ESI): 440.3 ([M+H]+).

Example 111 N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide To a stirred suspension of 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4- methyltetrahydro-2H-thiopyranyl)pyridazinecarboxamide (example 68, 60 mg, 0.130 mmol) in a mixture of MeOH (1.4 mL) and water (0.14 mL) was added oxone® (159 mg, 0.259 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The suspension was basified by addition of aqueous Na2CO3 (0.5 m, 3 mL) and stirred for r 2 hours. The reaction mixture was poured into water (5 mL) and extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. cation by flash chromatography (silica, gradient: 20% to 100% EtOAc in heptane) afforded the title compound (41 mg, 64%) as an off-white foam. MS (ESI): 472.3 +). e 112 (2,2-dioxidothiaazaspiro[3.3]heptanyl)(6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinyl)methanone In analogy to experiment of e 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 2-thiaazaspiro[3.3]heptane 2,2-dioxide 2,2,2- trifluoroacetate instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hloride, was converted into the title compound (53 mg, 90%) which was obtained as an off-white solid. MS (ESI): 456.3 ([M+H]+).

Example 113 (2,2-dioxidothiaazaspiro[3.3]heptanyl)(5-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyrazinyl)methanone In analogy to experiment of example 30, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 2-thiaazaspiro[3.3]heptane 2,2- e 2,2,2-trifluoroacetate instead of ioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (45 mg, 80%) which was obtained as an off-white solid. MS (ESI): 456.3 ([M+H]+).

Example 114 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclopentyl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using 1-methylcyclopentanamine hydrochloride instead of ioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (46 mg, 88%) which was obtained as an off-white foam. MS (ESI): 408.3 ([M+H]+).

Example 115 -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4,4,4- trifluorobutyl)pyrazinecarboxamide In analogy to experiment of example 14c, 5-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxylic acid, using 4,4,4-trifluorobutanamine instead of (S) aminopentanol, was converted into the title nd (50 mg, 94%) which was obtained as an off-white solid. MS (ESI): 436.2 ([M+H]+).

Example 116 N-(1-isopropylazetidinyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1-isopropylazetidinamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (25 mg, 41%) which was obtained as a white foam. MS (ESI): 423.3 ([M+H]+).

Example 117 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(2-oxaspiro[3.3]heptan yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one a) 6-chloro(2-oxaspiro[3.3]heptanyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to experiment of example 9a, 6-chloroformylnicotinic acid, using 2- oxaspiro[3.3]heptanamine hloride instead of isobutylamine, was converted into the title compound (96 mg, 37%) which was obtained as a light yellow solid. MS (ESI): 265.2 ([M+H]+). b) 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(2-oxaspiro[3.3]heptanyl)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one In analogy to ment of example 9b, (5-methyl(6-methylpyridinyl)isoxazol yl)methanol, using 6-chloro(2-oxaspiro[3.3]heptanyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one instead of 6-chloroisobutyl-1H-pyrrolo[3,4-c]pyridinone, was converted into the title compound (59 mg, 51%) which was ed as a light yellow solid. MS (ESI): 433.3 +).

Example 118 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclobutyl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 1-methylcyclobutanamine hloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (23 mg, 48%) which was obtained as a white foam. MS (ESI): 394.3 ([M+H]+).

Example 119 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide a) methyl 6-((5-ethyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylate In analogy to experiment of e 1a, (5-ethyl(6-methylpyridyl)isoxazolyl)methanol (building block B) instead of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A) was ted into the title compound (743 mg, 77%) which was obtained as a light yellow oil. MS (ESI): 354.3 +). b) 6-((5-ethyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 4a, methyl 6-((5-ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylate instead of methyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (591 mg, 87%) which was obtained as an off-white solid. MS (ESI): 340.2 ([M+H]+). c) 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridine- 3-carboxamide In analogy to experiment of example 30, ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using tetrahydropyranamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hloride, was converted into the title compound (56 mg, 90%) which was obtained as an off-white solid. MS (ESI): 423.3 ([M+H]+).

Example 120 N-(1,1-dioxidotetrahydro-2H-thiopyranyl)((5-ethyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridinecarboxamide In analogy to experiment of example 30, 6-((5-ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid was converted into the title compound (44 mg, 64%) which was ed as an off-white solid. MS (ESI): 471.3 ([M+H]+).

Example 121 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide a) 4-((6-chloropyridazinyl)oxymethyl)ethyl(6-methylpyridyl)isoxazole In analogy to experiment of example 23a, (5-ethyl(6-methylpyridyl)isoxazolyl)methanol (building block B) instead of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol ( building block A) was converted into the title compound (1.2 g, 91%) which was obtained as a yellow oil. MS (ESI): 331.2 ([M+H]+). b) ethyl ethyl(6-methylpyridyl)isoxazolyl)methoxy)pyridazinecarboxylate In analogy to experiment of e 23b, 4-((6-chloropyridazinyl)oxymethyl)ethyl(6- methylpyridyl)isoxazole instead of 4-((6-chloropyridazinyl)oxymethyl)methyl(63-pyridyl)isoxazole was converted into the title compound (272 mg, 21%) which was obtained as a light-brown oil. MS (ESI): 369.2 ([M+H]+). c) 6-((5-ethyl(6-methylpyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid In analogy to experiment of example 23c, ethyl 6-((5-ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxylate instead of ethyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylate was converted into the title compound (192 mg, 91%) which was obtained as an off-white solid. MS (ESI): 341.2 ([M+H]+). d) 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to experiment of e 23d, 6-((5-ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using tetrahydropyranamine in place of )aminocyclohexanol hydrochloride, was converted into the title compound (38 mg, 87%) which was obtained as an off-white solid. MS (ESI): 424.3 ([M+H]+).

Example 122 ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 3-methyloxetanamine hydrochloride in place of (1R,2S)aminocyclohexanol hloride, was converted into the title compound (46 mg, 96%) which was obtained as an off-white solid. MS (ESI): 410.3 ([M+H]+).

Example 123 N-cyclopropyl((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide In y to experiment of example 23d, 6-((5-ethyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using cyclopropanamine in place of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (37 mg, 95%) which was obtained as an off-white solid. MS (ESI): 380.2 ([M+H]+).

Example 124 (R)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using aminopentanol instead of (S) aminopentanol, was converted into the title compound (156 mg, 82%) which was obtained as a white solid. MS (ESI): 411.3 ([M+H]+).

Example 125 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide a) methyl 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxylate In analogy to experiment of example 1a, (5-(difluoromethyl)(6-methylpyridyl)isoxazol yl)methanol ing block J) instead of hyl(6-methylpyridinyl)isoxazol yl)methanol (building block A) was converted into the title compound (146 mg, 58%) which was obtained as a colorless oil. MS (ESI): 376.2 ([M+H]+). b) 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 4a, methyl 6-((5-(difluoromethyl)(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((5-methyl(6- methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (23 mg, 97%) which was obtained as an ite solid. MS (ESI): 362.2 ([M+H]+). c) 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid instead of methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid was converted into the title compound (13 mg, 50%) which was obtained as an off-white foam. MS (ESI): 447.3 ([M+H]+).

Example 126 (difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyran yl-pyridinecarboxamide In analogy to experiment of example 4b, 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid instead of 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid, using tetrahydropyranamine instead of (S)aminopentanol, was ted into the title compound (17 mg, 29%) which was obtained as an off-white solid. MS (ESI): 445.3 ([M+H]+).

Example 127 N-((3R,4S)hydroxytetrahydropyranyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide To a d solution of 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxylic acid (50 mg, 0.154 mmol) in anhydrous DMF (2 mL) were added at room temperature under an argon atmosphere (3R,4S)aminotetrahydro-2H-pyranol hydrochloride (28 mg, 0.184 mmol), HATU (70 mg, 0.184 mmol) and N-ethyldiisopropylamine (131 µL, 0.768 mmol). The reaction mixture was stirred for 17 hours at room temperature. The ing clear yellow solution was was poured into water (10 mL) then extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2Cl2) afforded the title compound (59 mg, 90%) as a white solid. MS (ESI): 425.3 ([M+H]+).

Example 128 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide a) methyl 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)pyridine carboxylate In analogy to ment of e 1a, (3-(6-cyclopropylpyridyl)methyl-isoxazol yl)methanol (building block K) instead of (5-methyl(6-methylpyridinyl)isoxazol yl)methanol (building block A), using methyl 6-fluoropyridinecarboxylate instead of methyl 6-chloronicotinate, was converted into the title compound (920 mg, 25%) which was obtained as colorless oil. MS (ESI): 365.8 ([M+H]+). b) 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 4a, methyl 6-((3-(6-cyclopropylpyridyl)methyl- isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (740 mg, 83%) which was obtained as a white solid. MS (ESI): 352.0 ([M+H]+). c) 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide In analogy to experiment of example 4b, 6-((3-(6-cyclopropylpyridyl)methyl-isoxazol yl)methoxy)pyridinecarboxylic acid instead of methyl(6-methylpyridyl)isoxazol- ethoxy)pyridinecarboxylic acid, using tetrahydropyranamine instead of (S) aminopentanol, was converted into the title compound (120 mg, 74%) which was obtained as a white solid. MS (ESI): 435.1 +).

Example 129 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide In analogy to experiment of example 4b, 6-((3-(6-cyclopropylpyridyl)methyl-isoxazol yl)methoxy)pyridinecarboxylic acid instead of methyl(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridinecarboxylic acid was converted into the title compound (140 mg, 59%) which was ed as yellow oil. MS (ESI): 437.1 ([M+H]+).

Example 130 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-(1,1-dioxothian yl)pyridinecarboxamide In analogy to experiment of example 4b, 6-((3-(6-cyclopropylpyridyl)methyl-isoxazol yl)methoxy)pyridinecarboxylic acid d of 6-((5-methyl(6-methylpyridyl)isoxazol- ethoxy)pyridinecarboxylic acid, using (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride instead of (S)aminopentanol, was converted into the title compound (110 mg, 87%) which was obtained as a white solid. MS (ESI): 483.1 ([M+H]+).

Example 131 N-((1R,2S)-3,3-difluorohydroxycyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridinecarboxamide In analogy to ment of example 127, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using (1S,6R)amino-2,2-difluorocyclohexanol instead of (3R,4S)aminotetrahydro-2H-pyranol hydrochloride, was converted into the title compound (50 mg, 70%) which was obtained as a white solid. MS (ESI): 459.5 ([M+H]+).

Example 132 N-((1R,2R)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 127, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using (1R,2R)aminocyclohexanol hloride instead of (3R,4S)aminotetrahydro-2H-pyranol hydrochloride, was converted into the title compound (39 mg, 60%) which was ed as a white solid. MS (ESI): 423.4 ([M+H]+).

Example 133 N-((1S,2R)-3,3-difluorohydroxycyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridinecarboxamide In analogy to ment of example 127, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using (1R,6S)amino-2,2-difluorocyclohexanol instead of (3R,4S)aminotetrahydro-2H-pyranol hydrochloride, was converted into the title compound (66 mg, 94%) which was obtained as a white solid. MS (ESI): 459.4 ([M+H]+).

Example 134 N-((3S,4R)hydroxytetrahydro-2H-pyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridinecarboxamide In analogy to experiment of example 127, 6-((5-methyl(6-methylpyridyl)isoxazol hoxy)pyridinecarboxylic acid, using (3S,4R)aminotetrahydro-2H-pyranol hydrochloride instead of (3R,4S)aminotetrahydro-2H-pyranol hydrochloride, was converted into the title nd (51 mg, 78%) which was obtained as a white solid. MS (ESI): 425.3 ([M+H]+).

Example 135 N-((1S,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridinecarboxamide In analogy to experiment of example 127, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using (1S,2S)aminocyclohexanol hydrochloride instead of (3R,4S)aminotetrahydro-2H-pyranol hydrochloride, was converted into the title compound (30 mg, 46%) which was obtained as a white solid. MS (ESI): 423.4 +).

Example 136 2-fluoro-N-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridine carboxamide a) methyl ro((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-pyridine ylate To a stirred solution of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (0.5 g, 2.45 mmol) in THF (12 ml) at 0 °C was added under argon methyl 2,6-difluoropyridinecarboxylate (551 mg, 3.18 mmol) followed by NaH (55% dispersion in mineral oil, 139 mg, 3.18 mmol). The mixture was stirred at room temperature for 3 hours before a second portion of NaH (55% sion in mineral oil, 139 mg, 3.18 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours before being poured into water (30 mL) then extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 40% EtOAc in heptane) afforded the title nd (323 mg, 37%, white solid) as a 2:5 mixture with its regioisomer methyl 6-fluoro((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylate. MS (ESI): 358.2 ([M+H]+). b) 2-fluoro((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic To a stirred solution of methyl 2-fluoro((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)-pyridinecarboxylate and methyl 6-fluoro((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate (418 mg, 1.17 mmol) in a e of MeOH (3 mL) and THF (3 mL) at room temperature were added water (0.9 mL) followed by aqueous NaOH (1.0 m, 1.64 mmol, 1.64 mL). The reaction mixture was d at room temperature for 1 hour, before being quenched by addition of aqueous HCl (1.0 m, 1.64 mL).

The mixture was ated to dryness by rotary evaporation under reduced pressure to provide the title compound (546 mg, quantitative, white solid) as a 2:5 mixture with its regioisomer 6- fluoro((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-pyridinecarboxylic acid.

MS (ESI): 344.1 ([M+H]+). c) 2-fluoro-N-methyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxamide In analogy to experiment of example 127, 6-((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxylic acid, using amine hydrochloride instead of (3R,4S) aminotetrahydro-2H-pyranol hloride, was converted into the title compound (35 mg, 7%) which was obtained as a white solid after preparative HPLC removal of the undesired regioisomer. MS (ESI): 357.1 ([M+H]+).

Example 137 6-((3-(6-methoxypyridinyl)methylisoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide a) methyl 6-((3-(6-methoxypyridyl)methyl-isoxazolyl)methoxy)pyridinecarboxylate To a stirred on of (3-(6-methoxypyridinyl)methylisoxazolyl)methanol (building block M, 1.44 g, 6.54 mmol) in ous THF (30 mL) at 0 °C were added under argon methyl 6-chloropyridinecarboxylate (1.18 g, 6.87 mmol) followed by NaH (55% dispersion in mineral oil, 300 mg, 6.87 mmol). The reaction mixture was stirred at room temperature for 18 hours before being poured into water (50 mL) then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water, dried (MgSO4) and concentrated in vacuo.

Purification by flash tography (silica, gradient: 0% to 30% EtOAc in heptane) afforded the title nd (1.51 g, 65%) as a white solid. MS (ESI): 356.1 ([M+H]+). b) 6-((3-(6-methoxypyridyl)methyl-isoxazolyl)methoxy)pyridinecarboxylic acid To a stirred solution of methyl 6-((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)pyridinecarboxylate (1.51 g, 4.25 mmol) in a mixture of MeOH (11 mL) and THF (11 mL) at room temperature were added water (3 mL) followed by aqueous NaOH (1.0 m, 8.5 ml, 8.5 mmol). The reaction mixture was stirred at room temperature for 1 hour then heated to 50 °C for 1.5 hours until a solution was formed. The mixture was cooled to room temperature then quenched by addition of aqueous HCl (1.0 m, 8.5 mL). The resulting suspension was d with water (10 mL) and filtered on a sintered funnel. The collected solid was rinsed with water (40 mL) and heptane (20 mL) then dried under high vacuum to provide the title compound (1.39 g, 96%) as white solid. MS (ESI): 342.1 ([M+H]+). c) 6-((3-(6-methoxypyridinyl)methylisoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide To a stirred solution of 6-((3-(6-methoxypyridyl)methyl-isoxazolyl)methoxy)pyridine- 3-carboxylic acid (200 mg, 586 µmol) in anhydrous DMF (3 mL) was added at room temperature under an argon atmosphere tetrahydropyranamine (72.8 µL, 0.703 mmol), N- ethyldiisopropylamine (512 µL, 2.93 mmol) and HATU (267 mg, 0.703 mmol). The ing yellow solution was d at room temperature overnight before being poured into water (20 mL) then extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. cation by flash tography (silica, gradient: 0% to 5% MeOH in CH2Cl2) afforded the title compound (230 mg, 92%) as white solid. MS (ESI): 425.2 ([M+H]+).

Example 138 N-isopropyl((3-(6-methoxypyridinyl)methylisoxazolyl)methoxy)pyridine carboxamide In analogy to experiment of example 137, 6-((3-(6-methoxypyridyl)methyl-isoxazol yl)methoxy)pyridinecarboxylic acid, using isopropylamine d of tetrahydropyran amine, was converted into the title compound (218 mg, 97%) which was obtained as a white solid. MS (ESI): 383.2 ([M+H]+).

Example 139 (S)-N-(1-hydroxypentanyl)((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)pyridinecarboxamide In analogy to ment of example 137, 6-((3-(6-methoxypyridyl)methyl-isoxazol yl)methoxy)pyridinecarboxylic acid, using aminopentanol instead of ydropyranamine, was converted into the title compound (131 mg, 52%) which was obtained as a white solid. MS (ESI): 427.3 ([M+H]+).

Example 140 (1,1-dioxidothiomorpholino)(6-((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)pyridinyl)methanone In analogy to experiment of example 137, 6-((3-(6-methoxypyridyl)methyl-isoxazol yl)methoxy)pyridinecarboxylic acid, using thiomorpholine 1,1-dioxide instead of tetrahydropyranamine, was converted into the title compound (244 mg, 91%) which was obtained as a white solid. MS (ESI): 459.2 ([M+H]+).

Example 141 (S)((3-(6-(dimethylamino)pyridinyl)methylisoxazolyl)methoxy)-N-(1- hydroxypentanyl)nicotinamide a) methyl 6-((3-(6-(dimethylamino)pyridyl)methyl-isoxazolyl)methoxy)pyridine carboxylate In y to experiment of example 137a, (3-(6-(dimethylamino)pyridinyl) methylisoxazolyl)methanol (building block N) instead of (3-(6-methoxypyridinyl) methylisoxazolyl)methanol (building block M) was converted into the title compound (843 mg, 70%) which was obtained as a light yellow solid. MS (ESI): 369.2 ([M+H]+). b) 6-((3-(6-(dimethylamino)pyridyl)methyl-isoxazolyl)methoxy)pyridinecarboxylic In y to experiment of example 137b, methyl 6-((3-(6-(dimethylamino)pyridyl) methyl-isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((3-(6- methoxypyridinyl)methylisoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (563 mg, 74%) which was obtained as a white solid. MS (ESI): 355.0 ([M+H]+). c) (S)((3-(6-(dimethylamino)pyridinyl)methylisoxazolyl)methoxy)-N-(1- hydroxypentanyl)nicotinamide In analogy to experiment of example 137c, 6-((3-(6-(dimethylamino)pyridyl)methylisoxazolyl )methoxy)pyridinecarboxylic acid d of 6-((3-(6-methoxypyridyl) methyl-isoxazolyl)methoxy)pyridinecarboxylic acid, using (S)aminopentanol instead of tetrahydropyranamine, was converted into the title compound (93 mg, 67%) which was obtained as a white solid. MS (ESI): 440.3 ([M+H]+).

Example 142 4-methoxy((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)nicotinamide a) methyl 4-methoxy((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxylate In analogy to experiment of example 137a, hyl(6-methylpyridinyl)isoxazol yl)methanol (building block A) instead of (3-(6-methoxypyridinyl)methylisoxazol yl)methanol (building block M), using methyl 6-chloromethoxy-pyridinecarboxylate d of methyl 6-chloropyridinecarboxylate, was converted into the title compound (67 mg, 27%) which was obtained as a light yellow solid. MS (ESI): 370.1 ([M+H]+). b) 4-methoxy((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 137b, methyl 4-methoxy((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((3-(6- methoxypyridinyl)methylisoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (70 mg, 99%) which was obtained as a light yellow solid. MS (ESI): 356.2 +). c) (S)((3-(6-(dimethylamino)pyridinyl)methylisoxazolyl)methoxy)-N-(1- ypentanyl)nicotinamide In analogy to experiment of example 137c, 4-methoxy((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylic acid instead of 6-((3-(6-methoxy pyridyl)methyl-isoxazolyl)methoxy)pyridinecarboxylic acid was converted into the title compound (29 mg, 46%) which was obtained as a white solid. MS (ESI): 439.2 ([M+H]+).

Example 143 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyran yl-pyridinecarboxamide a) methyl 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)pyridine carboxylate In analogy to experiment of example 137a, (3-(5-fluoromethylpyridinyl)methyl-1,2- oxazolyl)methanol (building block O) instead of (3-(6-methoxypyridinyl) isoxazolyl)methanol (building block M), using methyl 6-fluoropyridinecarboxylate instead of methyl 6-chloropyridinecarboxylate, was converted into the title compound (118 mg, 62%) which was obtained as a light yellow solid. MS (ESI): 358.2 ([M+H]+). b) 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)pyridinecarboxylic acid In analogy to experiment of example 137b, methyl 6-((3-(5-fluoromethylpyridyl) methyl-isoxazolyl)methoxy)pyridinecarboxylate instead of methyl 6-((3-(6- methoxypyridinyl)methylisoxazolyl)methoxy)pyridinecarboxylate was converted into the title compound (120 mg, 99%) which was obtained as a light yellow solid. MS (ESI): 344.1 ([M+H]+). c) 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyran yl-pyridinecarboxamide In analogy to experiment of e 137c, 6-((3-(5-fluoromethylpyridyl)methylisoxazolyl )methoxy)pyridinecarboxylic acid instead of 6-((3-(6-methoxypyridyl) methyl-isoxazolyl)methoxy)pyridinecarboxylic acid was converted into the title compound (28 mg, 38%) which was obtained as a white solid. MS (ESI): 427.3 ([M+H]+).

Example 144 -fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-isopropyl-pyridine- 3-carboxamide In analogy to experiment of example 137c, 6-((3-(5-fluoromethylpyridyl)methylisoxazolyl )methoxy)pyridinecarboxylic acid instead of (6-methoxypyridyl) -isoxazolyl)methoxy)pyridinecarboxylic acid, using isopropylamine instead of tetrahydropyranamine, was converted into the title compound (20 mg, 59%) which was obtained as a yellow solid. MS (ESI): 385.2 ([M+H]+).

Example 145 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide In analogy to experiment of example 137c, 6-((3-(5-fluoromethylpyridyl)methylisoxazolyl )methoxy)pyridinecarboxylic acid instead of 6-((3-(6-methoxypyridyl) methyl-isoxazolyl)methoxy)pyridinecarboxylic acid, using (S)aminopentanol instead of tetrahydropyranamine, was converted into the title compound (27 mg, 54%) which was obtained as an off-white solid. MS (ESI): 429.2 ([M+H]+).

Example 146 N-((1r,4r)hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using transaminomethylcyclohexanol instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (107 mg, 91%) which was obtained as an off-white foam. MS (ESI): 438.3 ([M+H]+).

Example 147 -dihydroxymethylpropanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide To a stirred suspension of 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyloxetanyl)pyridazinecarboxamide (example 83, 32.5 mg, 82.2 µmol) in water (100 mL) at room temperature was added aqueous HCl (1.0 m, 82.2 µL, 82.2 µmol). After 2 hours, a second portion of aqueous HCl (1.0 m, 411 µL, 411 µmol) was added and the mixture was stirred for another 2 hours. Finally, a third portion of aqueous HCl (1.0 m, 3.29 mL, 3.29 mmol) was added and the resulting solution was stirred at room temperature for 20 hours. The reaction was quenched by the addition of aqueous NaHCO3 (1.0 m, 9 mL), then diluted with EtOAc (10 mL). The layers were separated and the s phase was uently extracted with EtOAc (2 x 10 mL). The combined organic ts were dried (MgSO4) and concentrated in vacuo.

Purification by flash chromatography (silica, gradient: 50% EtOAc in heptane to 10% MeOH in EtOAc) afforded the title nd (9 mg, 27%) as a light-brown oil. MS (ESI): 414.3 ([M+H]+).

Example 148 N-((1s,4s)hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cisaminomethylcyclohexanol 2,2,2- oroacetate instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (64 mg, 64%) which was obtained as a white solid. MS (ESI): 438.3 ([M+H]+).

Example 149 N-((1R,3S)hydroxy(trifluoromethyl)cyclopentyl)((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxamide or enantiomer In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid using, cisamino(trifluoromethyl)cyclopentanol hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the racemic title compound (161 mg, 47%) which was obtained as a white solid.

MS (ESI): 478.2 +). tion of the enantiomers by chiral HPLC (column: Chiralpak AD) afforded the title nd (65 mg) which was obtained as a white solid. MS (ESI): 478.4 ([M+H]+).

Example 150 N-((1S,3R)hydroxy(trifluoromethyl)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide or enantiomer In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cisamino(trifluoromethyl)cyclopentanol hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the racemic title compound (161 mg, 47%) which was obtained as a white solid.

MS (ESI): 478.2 ([M+H]+).

Separation of the omers by chiral HPLC (column: Chiralpak AD) afforded the title compound (82 mg) which was obtained as a white solid. MS (ESI): 478.4 ([M+H]+).

Example 151 (1S,4S)oxaazabicyclo[2.2.1]heptanyl(6-((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (1S,4S)oxaazabicyclo[2.2.1]heptane hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title nd (26 mg, 69%) which was obtained as a light brown foam. MS (ESI): 408.2 ([M+H]+).

Example 152 N-((1RS,3RS)hydroxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using racemic trans-(1RS,3RS)aminocyclopentanol hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (21 mg, 56%) which was obtained as a light brown foam. MS (ESI): 410.2 ([M+H]+).

Example 153 trans-N-(4-hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using 4-aminocyclohexanol d of (1R,2S)- 2-aminocyclohexanol hydrochloride, was converted into the title compound (23 mg, 59%) which was obtained as a light brown solid. MS (ESI): 424.2 ([M+H]+).

Example 154 trans-N-(4-methoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to ment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using transmethoxycyclohexanamine hydrochloride instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (22 mg, 55%) which was obtained as a light brown foam. MS (ESI): 438.3 ([M+H]+).

Example 155 (6,6-difluoroazaspiro[3.3]heptanyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 6,6-difluoroazaspiro[3.3]heptane 2,2,2- trifluoroacetate instead of (1R,2S)aminocyclohexanol hloride, was converted into the title compound (12 mg, 30%) which was obtained as a white foam. MS (ESI): 442.2 ([M+H]+).

Example 156 N-(3-hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In y to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-aminocyclohexanol instead of (1R,2S) aminocyclohexanol hydrochloride, was converted into the title nd (16 mg, 41%) which was obtained as an off-white foam. MS (ESI): 424.2 ([M+H]+).

Example 157 3-oxaazabicyclo[3.1.1]heptanyl(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone In analogy to experiment of e 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 3-oxaazabicyclo[3.1.1]heptane 2,2,2- trifluoroacetate instead of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (21 mg, 56%) which was obtained as a off-white foam. MS (ESI): 408.2 ([M+H]+).

Example 158 cis-N-(4-methoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cismethoxycyclohexanamine d of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (18 mg, 45%) which was obtained as a off-white foam. MS (ESI): 438.3 ([M+H]+).

Example 159 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to ment of example 183, (3-(6-chloropyridyl)methyl-isoxazol yl)methanol (building block F) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D) was converted into the title nd (32 mg, 33%) which was obtained as a white solid. MS (ESI): 430.2 ([M+H]+).

Example 160 (S)((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide In analogy to experiment of e 183, (3-(6-chloropyridyl)methyl-isoxazol yl)methanol (building block F) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using (S)chloro-N-(tetrahydrofuranyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (18 mg, 32%) which was obtained as a white solid. MS (ESI): 438.1 +). e 161 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide In analogy to ment of example 183, (3-(6-chloropyridyl)methyl-isoxazol yl)methanol (building block F) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using 6-chloro-N-(3-methyloxetanyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (18 mg, 32%) which was obtained as a white solid. MS (ESI): 416.2 ([M+H]+).

Example 162 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide Cl N In y to experiment of example 183, (3-(6-chloropyridyl)methyl-isoxazol hanol (building block F) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol ing block D), using 6-chloro-N-(2-oxaspiro[3.3]heptanyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (17 mg, 29%) which was obtained as a white solid. MS (ESI): 442.2 ([M+H]+).

Example 163 trans-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide a) tert-butyl N-(3-methoxycyclobutyl)carbamate To a stirred solution of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate (100 mg, 0.534 mmol) in anhydrous THF (2.0 mL) at 0 °C was added NaH (60% in mineral oil, 32 mg, 0.801 mmol).

After 30 min, iodomethane (43.4 µL, 0.694 mmol) wad added and the reaction mixture was allowed to warm to room temperature for 2.5 hours. LC-MS analysis showed no starting material left but only mono-methylated and di-methylated products. The reaction was quenched by addition of saturated aqueous NaHCO3 (1 mL), diluted with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica, nt: 0% to 15% EtOAc in heptane) afforded the title compound (32 mg, 30%) as white crystals. MS (ESI): 146.1 ([M- C4H8+H]+). b) transmethoxycyclobutanamine 2,2,2-trifluoroacetate To a stirred solution of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate (42 mg, 0.209 mmol) in CH2Cl2 (2 mL) at 0 °C was added TFA (130 µl, 1.69 mmol) and the resulting yellow solution was allowed to warm to room temperature. After 2 hours, all volatiles were removed by rotary evaporation under reduced pressure to afford the title compound (60 mg, quantitative) as a light yellow oil. MS (ESI): 102.2 ([M+H]+). c) trans-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide To a stirred solution of 3-methoxycyclobutanamine 2,2,2-trifluoroacetate (45 mg, 0.209 mmol) in anhydrous DMF (0.8 mL) under argon was added 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid (45 mg, 0.138 mmol), N,N- ropylethylamine (200 µL, 1.15 mmol) and TBTU (66.4 mg, 0.207 mmol). The resulting yellow solution was stirred overnight at room temperature then purified directly by preparative HPLC (column: C-18, eluent: H2O and CH3CN with 0.05 % HCO2H) to afford the title compound (18.2 mg, 32.3 %) as an orange powder. MS (ESI): 410.2 ([M+H]+).

Example 164 cis-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol hoxy)pyridazinecarboxamide a) cis-tert-butyl N-(3-methoxycyclobutyl)carbamate In analogy to experiment of example 163a, cis-tert-butyl N-(3-hydroxycyclobutyl) carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate was converted into the title nd (59 mg, 55%) which was obtained as white crystals. MS (ESI): 146.1 ([M-C4H8+H]+). b) cismethoxycyclobutanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, cis-tert-butyl N-(3-methoxycyclobutyl) carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted into the title compound (62 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 102.2 ([M+H]+). c) (3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cismethoxycyclobutanamine 2,2,2- oroacetate instead of 3-methoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (10.7 mg, 17%) which was obtained as an orange powder. MS (ESI): 410.3 ([M+H]+).

Example 165 6-((5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide N O O In analogy to experiment of example 183, (5-cyclopropyl(6-methylpyridazinyl)isoxazol yl)methanol ing block L) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D) was converted into the title compound (10 mg, 19%) which was obtained as an off-white solid. MS (ESI): 437.3 +).

Example 166 trans-N-((1RS,3RS)methoxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using racemic trans-(1RS,3RS) methoxycyclopentanamine bis-2,2,2-trifluoroacetate instead of )aminocyclohexanol hydrochloride, was converted into the title compound (33 mg, 51%) which was obtained as a white solid. MS (ESI): 424.2 ([M+H]+). e 167 N-(6,6-difluorospiro[3.3]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 23d, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 6,6-difluorospiro[3.3]heptanamine in place of (1R,2S)aminocyclohexanol hydrochloride, was converted into the title compound (20 mg, 47%) which was obtained as a light brown amorphous. MS (ESI): 456.5 ([M+H]+).

Example 168 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran- 4-yl)pyridazinecarboxamide a) ethyl 6-((5-(fluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)pyridazine carboxylate In analogy to experiment of e 7a, (5-(fluoromethyl)(6-methylpyridinyl)isoxazol yl)methanol (building block C) instead of hyl(6-methylpyridinyl)isoxazol yl)methanol (building block A) was converted into the title compound (120 mg, 19%) which was obtained as an orange oil. MS (ESI): 359.2 ([M+H]+). b) 6-((5-(fluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)pyridazinecarboxylic In analogy to experiment of example 23c, ethyl (fluoromethyl)(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylate instead of ethyl methyl(6- methylpyridyl)isoxazolyl)methoxy)pyridazinecarboxylate was converted into the title nd (65 mg, 94%) which was obtained as an off-white solid. MS (ESI): 345.2 ([M+H]+). c) 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-(fluoromethyl)(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using tetrahydropyranamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the title compound (81 mg, 50%) which was obtained as an off-white solid. MS (ESI): 428.3 ([M+H]+).

Example 169 cis-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) cis-tert-butyl N-(3-(2,2-difluoroethoxy)cyclobutyl)carbamate In analogy to experiment of example 163a, rt-butyl N-(3-hydroxycyclobutyl) carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate d of iodomethane, was converted into the title compound (109 mg, 81%) which was obtained as white crystals. MS (ESI): 196.1 ([M-C4H8+H]+). b) cis(2,2-difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, cis-tert-butyl N-(3-(2,2- difluoroethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3- methoxycyclobutyl)carbamate was ted into the title compound (81 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 152.2 ([M+H]+). c) cis-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In y to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cis(2,2-difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (25 mg, 45%) which was obtained as a colorless amorphous.

MS (ESI): 460.3 +).

Example 170 trans-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) trans-tert-butyl N-(3-(2,2-difluoroethoxy)cyclobutyl)carbamate In analogy to experiment of example 163a, trans-tert-butyl N-(3-hydroxycyclobutyl) carbamate, using fluoroethyl trifluoromethanesulfonate instead of iodomethane, was converted into the title compound (95 mg, 71%) which was ed as white crystals. MS (ESI): 196.1 ([MC4H8 +H]+). b) trans(2,2-difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, trans-tert-butyl N-(3-(2,2- difluoroethoxy)cyclobutyl)carbamate d of tert-butyl N-(3- methoxycyclobutyl)carbamate was converted into the title compound (70 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 152.2 ([M+H]+). c) N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using trans(2,2-difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (34 mg, 60%) which was obtained as a white foam. MS (ESI): 460.2 ([M+H]+).

Example 171 cis-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) cis-tert-butyl N-(3-ethoxycyclobutyl)carbamate In analogy to experiment of example 163a, cis-tert-butyl N-(3-hydroxycyclobutyl) carbamate d of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate, using iodoethane instead of thane, was converted into the title compound (83 mg, 73%) which was obtained as a white solid. MS (ESI): 216.1 ([M+H]+), 160.1 ([M-C4H8+H]+). b) ethoxycyclobutanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, cis-tert-butyl N-(3-ethoxycyclobutyl)carbamate instead of trans-tert-butyl ethoxycyclobutyl)carbamate was converted into the title compound (90 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 116.1 ([M+H]+). c) cis-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cisethoxycyclobutanamine 2,2,2- oroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (54 mg, 61%) which was obtained as a white foam. MS (ESI): 424.3 ([M+H]+).

Example 172 trans-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) trans-tert-butyl N-(3-ethoxycyclobutyl)carbamate In analogy to experiment of example 163a, trans-tert-butyl ydroxycyclobutyl) carbamate, using iodoethane instead of thane, was converted into the title compound (72 mg, 63%) which was obtained as white solid. MS (ESI): 160.1 ([M-C4H8+H]+). b) transethoxycyclobutanamine 2,2,2-trifluoroacetate In y to experiment of example 163b, trans-tert-butyl N-(3-ethoxycyclobutyl)carbamate instead of trans-tert-butyl ethoxycyclobutyl)carbamate was converted into the title compound (88 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 116.1 ([M+H]+). c) trans-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using transethoxycyclobutanamine 2,2,2- trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (70 mg, 77%) which was obtained as a white foam. MS (ESI): 424.3 ([M+H]+).

Example 173 cis-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) cis-tert-butyl N-(3-(difluoromethoxy)cyclobutyl)carbamate To a stirred solution of cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate (100 mg, 0.534 mmol) in acetonitrile (2 mL) under argon was added CuI (20.3 mg, 0.107 mmol). The reaction mixture was stirred usly and heated to 45 °C for 30 min, before a solution of 2,2-difluoro (fluorosulfonyl)acetic acid (190 mg, 110 µL, 1.07 mmol) in itrile (2.0 mL) was added dropwise over a period of 40 min. The on mixture was d at 45 °C for 3 hours then cooled to room temperature, adsorbed on silica and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% EtOAc in heptane) afforded the title compound (82.5 mg, 65.1%) as a white solid. MS (ESI): 182.1 ([M-C4H8+H]+). b) (difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, cis-tert-butyl N-(3- (difluoromethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3- methoxycyclobutyl)carbamate was converted into the title compound (43 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 138.1 ([M+H]+). c) cis-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cis(difluoromethoxy)cyclobutanamine 2,2,2- trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (41 mg, 66%) which was obtained as a colorless amorphous.

MS (ESI): 446.3 ([M+H]+).

Example 174 trans-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) trans-tert-butyl N-(3-(difluoromethoxy)cyclobutyl)carbamate In analogy to experiment of example 173a, trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate was converted into the title compound (97 mg, 77%) which was obtained as a white solid. MS (ESI): 182.0 H8+H]+). b) trans(difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate In y to experiment of example 163b, trans-tert-butyl N-(3- (difluoromethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3- methoxycyclobutyl)carbamate was converted into the title compound (42 mg, quantitative) which was ed as a light yellow oil. MS (ESI): 138.1 ([M+H]+). c) trans-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using trans(difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (37 mg, 60%) which was ed as a white solid. MS (ESI): 446.3 ([M+H]+).

Example 175 trans-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) trans-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate A round-bottomed flask was charged with trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate (150 mg, 0.801 mmol), 4,7-diphenyl-1,10-phenanthroline (2.70 mg, 8.12 µmol), Pd(OAc)2 (3 mg, 13.4 µmol), triethylamine (112 µL, 0.801 mmol) and 1-(vinyloxy)butane (2.0 mL). The resulting mixture was degassed for 5 min by bubbling argon through the reaction . The reaction was heated to 80 °C and stirred ght before being cooled to room temperature then filtered directly through a pad of dicalite. The filter cake was rinsed with Et2O and the filtrate concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica, gradient: 0% to 7% EtOAc in heptane) to afford the title compound (113 mg, 66%) as a yellow crystalline solid. MS (ESI): 158.1 ([M-C4H8+H]+). b) trans-tert-butyl N-(3-cyclopropoxycyclobutyl)carbamate To a stirred solution of diethylzinc (1.0 m solution in heptane, 1.04 mL, 1.04 mmol) in anhydrous CH2Cl2 (1 mL) under argon at 0 °C was added a solution of TFA (80 µL, 1.04 mmol) in anhydrous CH2Cl2 (1 mL) over a period of 20 min. The resulting white suspension was stirred for 20 min at 0 °C, then a solution of diiodomethane (279 mg, 84 µL, 1.04 mmol) in anhydrous CH2Cl2 (1 mL) was added dropwise to form a colorless on which was d for r 20 min. Finally, a solution of trans-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate (110.5 mg, 0.518 mmol) in anhydrous CH2Cl2 (1.50 mL) was added dropwise and the resulting light red solution was d at 0 °C for 1 hours then allowed to warm to room temperature and stirred overnight. The reaction was re-cooled to 0 °C then quenched by the addition of saturated aqueous Na2CO3 (0.6 mL). After 5 min, triethylamine (144 µL, 1.04 mmol) was added followed by di-tert-butyl dicarbonate (226 mg, 1.04 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 20 mL). The combined c extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash tography a, gradient: 0% to 9% EtOAc in heptane) afforded the title compound (91 mg, 77%) as a white needles. MS (ESI): 172.1 ([MC4H8 +H]+). c) transcyclopropoxycyclobutanamine 2,2,2-trifluoroacetate In y to experiment of e 163b, trans-tert-butyl N-(3- cyclopropoxycyclobutyl)carbamate instead of trans-tert-butyl N-(3- methoxycyclobutyl)carbamate was ted into the title compound (43 mg, quantitative) which was obtained as an off-white. MS (ESI): 128.1 ([M+H]+). d) trans-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using transcyclopropoxycyclobutanamine 2,2,2- trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (42 mg, 70%) which was obtained as a ess amorphous.

MS (ESI): 436.3 ([M+H]+).

Example 176 cis-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) cis-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate In analogy to experiment of example 175a, cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate was converted into the title compound (107 mg, 63%) which was obtained as a yellow crystalline solid. MS (ESI): 158.1 ([M-C4H8+H]+). b) cis-tert-butyl N-(3-cyclopropoxycyclobutyl)carbamate In analogy to experiment of example 175b, cis-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate was converted into the title compound (91 mg, 81%) which was obtained as a white needles. MS (ESI): 172.1 ([MC4H8 +H]+). c) ciscyclopropoxycyclobutanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, cis-tert-butyl N-(3- cyclopropoxycyclobutyl)carbamate instead of tert-butyl N-(3- ycyclobutyl)carbamate was converted into the title compound (44 mg, tative) which was obtained as an off-white amorphous. MS (ESI): 128.1 ([M+H]+). d) cis-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using cyclopropoxycyclobutanamine 2,2,2- trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (43 mg, 71%) which was obtained as a white foam. MS (ESI): 436.3 ([M+H]+).

Example 177 6-((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide In y to experiment of example 183, (3-(6-chloropyridyl)cyclopropyl-isoxazol yl)methanol (building block G) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol hanol (building block D), using 6-chloro-N-(3-methyloxetanyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (8.5 mg, 16%) which was obtained as a white solid. MS (ESI): 442.2 ([M+H]+).

Example 178 6-((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan- 6-yl)pyridazinecarboxamide In analogy to ment of example 183, (3-(6-chloropyridyl)cyclopropyl-isoxazol yl)methanol (building block G) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using 6-chloro-N-(2-oxaspiro[3.3]heptanyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (13 mg, 23%) which was obtained as a pink solid. MS (ESI): 468.3 ([M+H]+).

Example 179 (S)((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(tetrahydrofuran idazinecarboxamide In analogy to experiment of example 183, (3-(6-chloropyridyl)cyclopropyl-isoxazol yl)methanol (building block G) instead of lopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using (S)chloro-N-(tetrahydrofuranyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title nd (14 mg, 27%) which was ed as a white solid. MS (ESI): 442.2 ([M+H]+).

Example 180 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide In analogy to experiment of example 183, (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using 6-chloro-N-(3-methyloxetanyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (27 mg, 49%) which was obtained as a white solid. MS (ESI): 422.3 +).

Example 181 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2- oxaspiro[3.3]heptanyl)pyridazinecarboxamide In analogy to experiment of example 183, (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using 6-chloro-N-(2-oxaspiro[3.3]heptanyl)pyridazine carboxamide instead of 6-chloro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (6.5 mg, 11%) which was obtained as a white solid. MS (ESI): 448.3 ([M+H]+).

Example 182 (S)((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran- 3-yl)pyridazinecarboxamide In analogy to experiment of example 183, (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D), using 6-chloro-N-((3S)-tetrahydrofuranyl)pyridazine carboxamide instead of ro-N-(tetrahydropyranyl)pyridazinecarboxamide, was converted into the title compound (10 mg, 21%) which was ed as a white solid. MS (ESI): 422.3 ([M+H]+).

Example 183 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide To a stirred solution of (5-cyclopropyl(6-methylpyridyl)isoxazolyl)methanol (building block D, 30 mg, 0.130 mmol) and ro-N-(tetrahydropyranyl)pyridazinecarboxamide (35 mg, 0.130 mmol) in anhydrous N,N-dimethylacetamide (0.60 mL) was added Cs2CO3 (46.7 mg, 0.143 mmol). The reaction mixture was stirred at room temperature for 15 hours then filtered and purified ly by preparative HPLC (column: C-18, eluent: H2O and CH3CN with 0.05 % HCO2H) to afford the title compound as a white solid (23 mg, 40%). MS (ESI): 436.3 ([M+H]+).

Example 184 (fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-(fluoromethyl)(6-methylpyridyl)isoxazol- 4-yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylic acid, using 1- (trifluoromethyl)cyclopropanamine instead of transmethoxycyclobutanamine 2,2,2- trifluoroacetate, was converted into the title compound (10 mg, 51%) which was obtained as a colorless amorphous. MS (ESI): 452.3 ([M+H]+).

Example 185 6-((5-methyl(6-(trifluoromethyl)pyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide To a stirred on of (5-methyl(6-(trifluoromethyl)pyridinyl)isoxazolyl)methanol (building block E, 56 mg, 0.217 mmol) and 6-chloro-N-(tetrahydropyranyl)pyridazine amide (62.9 mg, 260 µmol) in ous N,N-dimethylacetamide (0.60 mL) at room temperature was added Cs2CO3 (141 mg, 0.434 mmol). After 17 hours, the reaction mixture was diluted with EtOAc (15 mL) and the organic layer was washed with aqueous Na2CO3 (1.0 m, 10 mL), half saturated brine (15 mL) and brine (15 mL). The aqueous layers were extracted with EtOAc (15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo.

Purification by flash chromatography (silica, gradient: 15% to 100% EtOAc in heptane) afforded the title compound (32 mg, 32%) as an off-white solid. MS (ESI): 464.2 ([M+H]+).

Example 186 N-((2S)oxabicyclo[2.2.1]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In y to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (1R,2S,4S)oxabicyclo[2.2.1]heptanamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the racemic title compound (48 mg, 80%) which was obtained as a white foam. MS (ESI): 422.2 ([M+H]+).

Example 187 -((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxepan yl)pyridazinecarboxamide In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using racemic (RS)-oxepanamine d of (1,1- dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride, was converted into the racemic title nd (48 mg, 72%) which was obtained as a white foam. MS (ESI): 424.2 ([M+H]+).

Example 188 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1R,3S,4R) oxabicyclo[2.2.1]heptanyl)pyridazinecarboxamide or enantiomer In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid using racemic (1R*,3S*,4R*) yclo[2.2.1]heptanamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride was converted into the racemic title compound (48 mg, 80%) which was obtained as a white solid. MS (ESI): 422.2 +). Separation of the enantiomers by chiral HPLC (column: Reprosil Chiral-NR) afforded the enantiopure (+)-title compound (17 mg) which was obtained as a light-brown gum. MS (ESI): 422.2 ([M+H]+).

Example 189 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S,3R,4S) oxabicyclo[2.2.1]heptanyl)pyridazinecarboxamide or enantiomer In analogy to experiment of example 30, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid using racemic (1S*,3R*,4S*) oxabicyclo[2.2.1]heptanamine instead of (1,1-dioxidotetrahydro-2H-thiopyranyl)amine hydrochloride was converted into the racemic title compound (48 mg, 80%) which was obtained as a white solid. MS (ESI): 422.2 ([M+H]+). Separation of the enantiomers by chiral HPLC (column: Reprosil Chiral-NR) afforded the enantiopure (–)-title compound (16 mg) which was obtained as a light-brown gum. MS (ESI): 422.2 ([M+H]+). e 190 ,3R)ethoxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide a) tert-butyl ((1R,3R)ethoxycyclopentyl)carbamate In analogy to experiment of example 163a, tert-butyl ((1R,3R)hydroxycyclopentyl)carbamate, using hane instead of iodomethane, was ted into the title compound (35 mg, 31%) which was obtained as colorless oil. MS (ESI): 174.1 ([M-C4H8+H]+). b) (1R,3R)ethoxycyclopentanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, tert-butyl R)ethoxycyclopentyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted into the title nd (33 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 130.1 ([M+H]+). c) N-((1R,3R)ethoxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyridazinecarboxylic acid, using (1R,3R)ethoxycyclopentanamine 2,2,2- trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (39 mg, 83%) which was obtained as a colorless amorphous.

MS (ESI): 438.3 ([M+H]+).

Example 191 N-((1R,3R)(2,2-difluoroethoxy)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide a) tert-butyl ((1R,3R)(2,2-difluoroethoxy)cyclopentyl)carbamate In analogy to experiment of example 163a, tert-butyl ((1R,3R)hydroxycyclopentyl)carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate instead of iodomethane, was converted into the title compound (88 mg, 67%) which was obtained as white ls. MS (ESI): 210.1 ([MC4H8 +H]+). b) (1R,3R)(2,2-difluoroethoxy)cyclopentanamine 2,2,2-trifluoroacetate In analogy to ment of example 163b, tert-butyl ((1R,3R)(2,2- difluoroethoxy)cyclopentyl)carbamate instead of trans-tert-butyl N-(3- ycyclobutyl)carbamate was converted into the title compound (38 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 166.2 ([M+H]+). c) N-((1R,3R)(2,2-difluoroethoxy)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide In y to experiment of e 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using (1R,3R)(2,2- difluoroethoxy)cyclopentanamine 2,2,2-trifluoroacetate instead of trans methoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (37 mg, 73%) which was obtained as a colorless amorphous: 474.3 ([M+H]+).

Example 192 6-((5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide In analogy to experiment of example 183, (5-(fluoromethyl)(6-methylpyridazinyl)isoxazol- ethanol (building block P) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D) was converted into the title compound (15 mg, 31%) which was obtained as a white powder. MS (ESI): 429.2 ([M+H]+). e 193 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide In analogy to experiment of example 183, (5-methyl(6-methylpyridazinyl)isoxazol yl)methanol (building block I) instead of (5-cyclopropyl(6-methylpyridyl)isoxazol yl)methanol (building block D) was converted into the title compound (8.8 mg, 15%) which was obtained as a light yellow powder. MS (ESI): 411.2 ([M+H]+).

Example 194 trans-N-(4-(2,2-difluoroethoxy)cyclohexyl)((5-methyl(6-methylpyridinyl)-1,2- oxazolyl)methoxy)pyridazinecarboxamide a) trans-tert-butyl N-(4-(2,2-difluoroethoxy)cyclohexyl)carbamate In analogy to experiment of example 163a, trans-tert-butyl N-(4-hydroxycyclohexyl) carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate instead of iodomethane, was converted into the title compound (69 mg, 53%) which was obtained as white crystals. MS (ESI): 224.1 ([MC4H8 +H]+). b) 4-(2,2-difluoroethoxy)cyclohexanamine 2,2,2-trifluoroacetate In y to ment of example 163b, trans-tert-butyl N-(4-(2,2- difluoroethoxy)cyclohexyl)carbamate d of trans-tert-butyl N-(3- methoxycyclobutyl)carbamate was converted into the title compound (72 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 180.1 ([M+H]+). c) trans-N((2,2-difluoroethoxy)cyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, 6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using trans(2,2-difluoroethoxy)cyclohexanamine 2,2,2-trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (15 mg, 17%) which was ed as a white powder. MS (ESI): 488.2 ([M+H]+).

Example 195 N-(4-ethoxycyclohexyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridazinecarboxamide a) trans-tert-butyl thoxycyclohexyl)carbamate In analogy to experiment of example 163a, trans-tert-butyl N-(4-hydroxycyclohexyl) carbamate, using iodoethane instead of thane, was converted into the title compound (20 mg, 18%) which was obtained as white solid. MS (ESI): 188.1 ([M-C4H8+H]+). b) transethoxycyclohexanamine 2,2,2-trifluoroacetate In analogy to experiment of example 163b, trans-tert-butyl N-(4-ethoxycyclohexyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted into the title compound (21 mg, quantitative) which was obtained as a light yellow oil. MS (ESI): 144.1 ([M+H]+). c) trans-N-(4-ethoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide In analogy to experiment of example 163c, methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxylic acid, using 4-ethoxycyclohexanamine 2,2,2- trifluoroacetate instead of transmethoxycyclobutanamine 2,2,2-trifluoroacetate, was converted into the title compound (15 mg, 55%) which was obtained as a white powder. MS (ESI): 452.2 ([M+H]+).

Reference Example A 6-((5-methyl(3-pyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridazine carboxamide a) -hydroxypyridinecarboximidoyl chloride To a stirred solution of (3E)-pyridinecarbaldehyde oxime (25.0 g, 205 mmol) in DMF (205 mL) at room temperature was added in small portion (caution: reaction exotermic) N- chlorosuccinimide (27.34 g, 205 mmol). The reaction mixture was stirred at room temperature for 20 hours then poured into water and ice (200 mL). The resulting light brown precipitate was collected through filtration on a sintered funnel then washed with water (50 mL) and dried at high vacuum to afford the title compound (16.53 g, 52%) as a light brown solid. MS (ESI): 157.0 ([M+H]+). b) ethyl 5-methyl(3-pyridyl)isoxazolecarboxylate To a stirred suspension of (3Z)-N-hydroxypyridinecarboximidoyl de (18.6 g, 119 mmol) in Et2O (202 mL) at 0 °C was added ethyl butynoate (13.9 mL, 119 mmol) followed by Et3N (19.9 mL, 143 mmol). After 30 min, the mixture was allowed to warm to room temperature and the ing suspension was stirred overnight. The reaction mixture was poured into a 1 : 1 mixture of brine and water (150 mL) and extracted with EtOAc (2 x 100 mL). The organic phase was filtered off through a sintered funnel to remove an insoluble brown precipitate then the filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography a, gradient: 20% to 80% EtOAc in heptane) afforded the title compound (8.11 g, 29%) as an off-white solid. MS (ESI): 233.1 +). c) (5-methyl(3-pyridyl)isoxazolyl)methanol In analogy to experiment of building block M c, ethyl 5-methyl(3-pyridyl)isoxazole ylate instead of ethyl 3-(6-methoxypyridyl)methyl-isoxazolecarboxylate was converted into the title compound (4.32 mg, 66%) which was obtained as a light yellow solid.

MS (ESI): 191.2 ([M+H]+). d) 4-((6-chloropyridazinyl)oxymethyl)methyl(3-pyridyl)isoxazole In analogy to experiment of example 23a, (5-methyl(3-pyridyl)isoxazolyl)methanol instead of hyl(6-methylpyridinyl)isoxazolyl)methanol (building block A) was converted into the title compound (2.53 g, 81%) which was obtained as a light yellow solid. MS (ESI): 303.1 ([M+H]+). e) ethyl methyl(3-pyridyl)isoxazolyl)methoxy)pyridazinecarboxylate In analogy to experiment of example 23b, 4-((6-chloropyridazinyl)oxymethyl)methyl(3- pyridyl)isoxazole instead of 4-((6-chloropyridazinyloxy)methyl)methyl(6- methylpyridinyl)isoxazole was converted into the title compound (1.91 g, 69%) which was obtained as a light yellow solid. MS (ESI): 341.2 ([M+H]+). f) 6-((5-methyl(3-pyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridazine carboxamide In analogy to experiment of example 1b, ethyl 6-((5-methyl(3-pyridyl)isoxazol yl)methoxy)pyridazinecarboxylate instead of methyl 6-((5-methyl(6-methyl pyridyl)isoxazolyl)methoxy)pyridinecarboxylate was converted into the title nd (122 mg, 77%) which was obtained as an ite solid. MS (ESI): 396.2 ([M+H]+).

Reference Example RE-B 6-((3-(5-chloropyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyranylpyridazinecarboxamide a) (2E)chloropyridinecarbaldehyde oxime In y to experiment of building block I a, 5-chloropyridinecarbaldehyde was converted into the title compound (6.74 g, 89%) which was obtained as a light brown solid. MS (ESI): 157.0 ([M+H]+). b) ethyl 3-(5-chloropyridyl)methyl-isoxazolecarboxylate To a stirred suspension of (2E)chloropyridinecarbaldehyde oxime (1.00 g, 6.40 mmol) in CHCl3 (20 mL) at room temperature was added a solution of N-chlorosuccinimide (853 mg, 6.40 mmol) in CHCl3 (20 mL) followed by a catalytic amount of pyridine (51 mL, 0.64 mmol). After min, the mixture was heated to 50 °C for 3 hours. The resulting brown suspension was allowed to warm to room ature before the on of a solution of (E)-ethyl 3-(pyrrolidin- 1-yl)butenoate (1.170 g, 6.40 mmol) in CHCl3 (0.8 mL). The reaction mixture was heated to 50 °C followed by the addition of a solution of Et3N (0.890 mL, 6.4 mmol) in CHCl3 (0.8 mL).

The reaction was stirred at 50 °C for 30 min before being poured into ice and water (50 mL) and extracted with CH2Cl2 (2 x 50mL). The combined c extracts were washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo. cation by flash chromatography (silica, gradient: 0% to 50% EtOAc in heptane) afforded the title compound (1.35 g, 79%) as a light yellow oil. MS (ESI): 267.1 ([M+H]+). c) (3-(5-chloropyridyl)methyl-isoxazolyl)methanol In analogy to experiment of building block M c, ethyl 3-(5-chloropyridyl)methyl- isoxazolecarboxylate instead of ethyl 3-(6-methoxypyridyl)methyl-isoxazole carboxylate was converted into the title compound (773 mg, 73%) which was obtained as an offwhite solid. MS (ESI): 225.0 ([M+H]+). d) 4-((6-chloropyridazinyl)oxymethyl)(5-chloropyridyl)methyl-isoxazole In analogy to experiment of example 23a, (3-(5-chloropyridyl)methyl-isoxazol yl)methanol instead of (5-methyl(6-methylpyridinyl)isoxazolyl)methanol (building block A) was converted into the title compound (2.47 g, 83%) which was obtained as a light brown solid. MS (ESI): 337.0 ([M+H]+). e) ethyl 6-((3-(5-chloropyridyl)methyl-isoxazolyl)methoxy)pyridazinecarboxylate In analogy to experiment of example 23b, 4-((6-chloropyridazinyl)oxymethyl)(5-chloro pyridyl)methyl-isoxazole instead of 4-((6-chloropyridazinyloxy)methyl)methyl(6- methylpyridinyl)isoxazole was converted into the title compound (1.89 g, 72%) which was obtained as a white solid. MS (ESI): 375.1 ([M+H]+). f) 6-((3-(5-chloropyridyl)methyl-isoxazolyl)methoxy)pyridazinecarboxylic acid In analogy to experiment of example 23c, ethyl 6-((3-(5-chloropyridyl)methyl-isoxazol hoxy)pyridazinecarboxylate instead of ethyl 6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxylate was ted into the title nd (1.57 g, 93%) which was obtained as a white solid. MS (ESI): 347.1 ([M+H]+). g) 6-((3-(5-chloropyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyranylpyridazinecarboxamide In analogy to experiment of example 23d, 6-((3-(5-chloropyridyl)methyl-isoxazol yl)methoxy)pyridazinecarboxylic acid instead of 6-((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxylic acid was converted into the title compound (69 mg, 64%) which was obtained as a white solid. MS (ESI): 430.1 ([M+H]+).

Claims (15)

Claims 1. Compounds of formula (I) wherein 5 X is selected from i) N, and ii) CH; Y is ed from i) N, and 10 ii) CR10; Z is selected from i) N, and ii) CR11; R1 is selected from 15 i) C1alkyl, ii) halo-C1alkyl, iii) C1alkoxy, iv) halo-C1alkoxy, v) hydroxy-C1alkyl, vi) C3cycloalkyl, vii) halogen, and viii) amino substituted on the en atom by one or two substituents 5 independently selected from a. H, b. C1alkyl, and c. C3cycloalkyl; R2 is selected from 10 i) H, and ii) halogen; R3 is selected from i) H, ii) C1alkyl, 15 iii) C3cycloalkyl, iv) hydroxy-C1alkyl, and v) halo-C1alkyl; R4 is selected from i) H, 20 ii) C1alkyl, iii) lkoxy, iv) C3cycloalkyl, and v) halogen; R5 is H; R6 is selected from i) H, 5 ii) C1alkyl, iii) C3cycloalkyl substituted with R7, R8 and R9, iv) C3cycloalkyl-C1alkyl substituted with R7, R8 and R9, v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, 10 vii) hydroxy-C1alkyl, viii) dihydroxy-C1alkyl, ix) halo-C1alkyl, x) heterocycloalkyl substituted with R7, R8 and R9, and xi) heterocycloalkyl-C1alkyl substituted with R7, R8 and R9; 15 R7, R8 and R9 are independently selected from i) H, ii) lkyl, iii) C1alkoxy, iv) C1alkoxyalkyl, 20 v) lkoxycarbonyl, vi) cyano, vii) C3cycloalkoxy, viii) C3cycloalkyl, ix) 1alkoxy, x) halo-C1alkyl, xi) halogen, 5 xii) hydroxy, xiii) hydroxy-C1alkyl, and xiv) oxo; R10 is selected from i) H, 10 ii) C1alkyl, iii) lkoxy, iv) C3cycloalkyl, and v) halogen; R11 is selected from 15 i) H, ii) C1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, and v) halogen; 20 or R5 and R10 together form -(CH2)n-; or R5 and R11 together form -(CH2)n-; or R5 and R6 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R7, R8 and R9; n is selected from 1 and 2; or pharmaceutically able salts. 5 2. A compound according to claim 1, wherein X is selected from i) N, and ii) CH; Y is selected from 10 i) N, and ii) CR10; Z is selected from i) N, and ii) CR11; 15 R1 is selected from i) C1alkyl, ii) halo-C1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, 20 v) n, and vi) amino substituted on the nitrogen atom by two independently selected C1 alkyl; R2 is selected from i) H, ii) halogen; R3 is selected from i) H, 5 ii) C1alkyl, iii) C3cycloalkyl, and iv) halo-C1alkyl; R4 is selected from i) H, and 10 ii) C1alkyl; R5 is H; R6 is selected from i) H, ii) C1alkyl, 15 iii) ycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxy, 20 d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, h. halo-C1alkoxy, i. 1alkyl, j. halogen, 5 k. hydroxy, and
1. l. hydroxy-C1alkyl; iv) C3cycloalkyl-C1alkyl tuted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, 10 b. C1alkyl, c. C1alkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, 15 g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and 20 l. hydroxy-C1alkyl; v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, vii) dihydroxy-C1alkyl, viii) 1alkyl, ix) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from 5 a. H, b. C1alkyl, c. hydroxy, and d. oxo; and wherein the heterocycloalkyl is selected from 10 a. oxetanyl, b. tetrahydrofuranyl, c. tetrahydropyranyl, d. oxepanyl, e. oxabicyclo[2.2.1]heptanyl, 15 f. oxaspiro[3.3]heptanyl, g. azetidinyl, h. tetrahydrothiophenyl, and i. tetrahydrothiopyranyl; and x) oxetanyl-C1alkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are 20 independently selected from a. H, b. y; R10 is selected from i) H, and ii) halogen; R11 is selected from i) H, 5 ii) C1alkyl, and iii) C1alkoxy; or R5 and R10 er form -(CH2)n-; or R5 and R11 together form -(CH2)n-; or R5 and R6 together with the nitrogen atom to which they are attached form a 10 heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are ndently selected from a. H, b. C1alkyl, c. C1alkoxy, 15 d. cyano, e. halogen, f. hydroxy, and g. oxo; and wherein the heterocycloalkyl is selected from 20 a. azetidinyl, b. pyrrolidinyl, c. piperidinyl, d. morpholinyl, e. thiomorpholinyl, f. oxaazabicyclo[3.1.1]heptanyl, g. oxaazabicyclo[2.
2. 2.1]heptanyl, h. azaspiro[3.3]heptanyl, 5 i. oxaazaspiro[3.3]heptanyl, j. thiaazaspiro[3.3]heptanyl; n is 1; or pharmaceutically acceptable salts.
3. 3. A compound according to claim 1, wherein 10 X is selected from i) N, and ii) CH; Y is selected from i) N, and 15 ii) CR10; Z is selected from i) N, and ii) CR11; R1 is selected from 20 i) lkyl, ii) halo-C1alkyl, iii) C1alkoxy, iv) C3cycloalkyl, v) halogen, and vi) amino substituted on the nitrogen atom by two independently selected C1 alkyl; 5 R2 is selected from i) H, ii) n; R3 is selected from i) H, 10 ii) C1alkyl, iii) C3cycloalkyl, and iv) halo-C1alkyl; R4 is selected from i) H, and 15 ii) C1alkyl; R5 is H; R6 is ed from i) H, ii) C1alkyl, 20 iii) C3cycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, c. C1alkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, 5 g. C3cycloalkoxy, h. halo-C1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and 10 l. hydroxy-C1alkyl; iv) C3cycloalkyl-C1alkyl tuted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. C1alkyl, 15 c. C1alkoxy, d. C1alkoxyalkyl, e. C1alkoxycarbonyl, f. cyano, g. C3cycloalkoxy, 20 h. 1alkoxy, i. halo-C1alkyl, j. halogen, k. hydroxy, and l. hydroxy-C1alkyl; v) C1alkylsulfonyl-C1alkyl, vi) cyano-C1alkyl, 5 vii) dihydroxy-C1alkyl, viii) halo-C1alkyl, ix) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are ndently selected from a. H, 10 b. C1alkyl, c. hydroxy, and d. oxo; and wherein the heterocycloalkyl is selected from a. yl, 15 b. tetrahydrofuranyl, c. tetrahydropyranyl, d. oxepanyl, e. oxabicyclo[2.2.1]heptanyl, f. oxaspiro[3.3]heptanyl, 20 g. azetidinyl, h. tetrahydrothiophenyl, and i. tetrahydrothiopyranyl; and x) oxetanyl-C1alkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, b. hydroxy; 5 R10 is selected from i) H, and ii) n; R11 is selected from i) H, 10 ii) C1alkyl, and iii) C1alkoxy; or pharmaceutically able salts.
4. 4. A compound according to claim 1, wherein X is selected from 15 i) N, and ii) CH; Y is selected from i) N, and ii) CR10; 20 Z is CR11; R1 is C1alkyl; R2 is selected from i) H, ii) halogen; R3 is selected from i) C1alkyl, 5 ii) C3cycloalkyl, and iii) halo-C1alkyl; R4 is selected from i) H, and ii) lkyl; 10 R5 is H; R6 is selected from i) lkyl, ii) C3cycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from 15 a. H, b. C1alkyl, c. C1alkoxyalkyl, and d. halo-C1alkyl; iii) hydroxy-C1alkyl, 20 iv) halo-C1alkyl, v) heterocycloalkyl substituted with R7, R8 and R9, wherein R7, R8 and R9 are independently selected from a. H, and b. C1alkyl; and wherein the cycloalkyl is selected from a. oxetanyl, b. tetrahydrofuranyl, 5 c. tetrahydropyranyl, d. oxepanyl, and e. oxaspiro[3.3]heptanyl; R10 is H; R11 is H; 10 or pharmaceutically acceptable salts.
5. 5. A compound according to claim 1, wherein X is CH; Y is N; Z is CR11; 15 R1 is C1alkyl; R2 is H; R3 is C1alkyl; R4 is H; R5 is H; 20 R6 is heterocycloalkyl substituted with R7, R8 and R9; R7, R8 and R9 are H; R11 is H; or ceutically acceptable salts.
6. 6. A compound according to claim 1, wherein X is CH; Y is N; 5 Z is CR11; R1 is C1alkyl; R2 is H; R3 is C1alkyl; R4 is H; 10 R5 is H; R6 is tetrahydropyranyl substituted with R7, R8 and R9; R7, R8 and R9 are H; R11 is H; or pharmaceutically acceptable salts. 15
7. 7. A compound according to any one of claims 1 to 6, selected from 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide N-(cyclopropylmethyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; 20 l((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyridine carboxamide; N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((5-cyclopropyl(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide 5 (1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyridazinecarboxamide; 2-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- 10 c]pyridin-3(2H)-one; 2-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one; N-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)nicotinamide; 2-(2-hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-1H- 15 pyrrolo[3,4-c]pyridin-3(2H)-one; (S)(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; (S)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyrazinecarboxamide; 20 5-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyrazinecarboxamide; N-(1,1-dioxothiolanyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)nicotinamide; 25 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinecarboxamide; N-((3S)-1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide; )-1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide; 5 N-(1,1-dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-pyran yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; N-((1S,2R)Hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol 10 yl)methoxy)pyridazinecarboxamide; N-((1S,2S)Hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1R,2R)Hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 15 N-cyclopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-((1R,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((3S,4R)hydroxytetrahydropyranyl)((5-methyl(6-methylpyridinyl)isoxazol- 20 4-yl)methoxy)pyridazinecarboxamide; N-(2-hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; -dioxothianyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyridazinecarboxamide; 25 N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(2-cyanoethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine- 3-carboxamide; 5 (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1- trifluoropropanyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxetanyl)pyridazine carboxamide; (RS)-N-(1,1-dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol 10 yl)methoxy)pyridazinecarboxamide; l((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; ropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; 15 N-isobutyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2,2,2- trifluoroethyl)pyridazinecarboxamide; N-tert-butyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine 20 carboxamide; N-(3,3-difluorocyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 25 6-((3-(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyranyl-pyridine carboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; N-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; 5 (3,3-difluoroazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3,3-difluoropyrrolidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((3-methyloxetan 10 yl)methyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(oxetan ylmethyl)pyridazinecarboxamide; N-((3-hydroxyoxetanyl)methyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 15 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((3R,4R) tetrahydropyranyl)pyridazinecarboxamide; (4,4-difluoropiperidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; N-(1-(methoxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol 20 yl)methoxy)pyridazinecarboxamide; (3-methoxyazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3-hydroxymethylazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; 25 inyl(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazin yl)methanone; (RS)-N-(2,2-dimethyltetrahydropyranyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide; 5 (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazin yl)(morpholino)methanone; (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinyl)(2-oxa azaspiro[3.3]heptanyl)methanone; yl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- 10 (tetrahydropyranyl)pyridazinecarboxamide; (6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazinyl)(6-oxa azaspiro[3.3]heptanyl)methanone; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1-trifluoro methylpropanyl)pyridazinecarboxamide; 15 (3-fluoroazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3-hydroxyazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; (3-fluoromethylazetidinyl)(6-((5-methyl(6-methylpyridinyl)isoxazol 20 yl)methoxy)pyridazinyl)methanone; ethyl 1-(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine amido)cyclopropanecarboxylate; N-(1-cyanocyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 25 5-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; 5-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide; -dioxothianyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide; 5 N-(2-hydroxy-1,1-dimethyl-ethyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide; N-cyclopropyl((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)pyrazine carboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- 10 methyltetrahydrofuranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclopropyl)pyridazinecarboxamide; 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(oxetanyl)pyrazine carboxamide; 15 5-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-(2,2,2- trifluoroethyl)pyrazinecarboxamide; N-(4-hydroxymethylbutanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-methyl 20 (methylsulfonyl)butanyl)pyridazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; 25 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; 1-(6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carbonyl)azetidinecarbonitrile; N-(1-(hydroxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 5 N-(4,4-difluorocyclohexyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyrazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; (S)-N-(1-cyanobutanyl)((5-methyl(6-methylpyridinyl)isoxazol 10 hoxy)pyridazinecarboxamide; (R)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyrazinecarboxamide; N-(2-Hydroxyethyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyrazine- 2-carboxamide; 15 2-(1,1-Dioxothianyl)[[5-methyl(6-methylpyridinyl)-1,2-oxazolyl]methoxy]- 1#H!-pyrrolo[3,4-c]pyridinone; (S)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyrazinecarboxamide; 2-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy]tetrahydropyranyl-7H- 20 pyrrolo[3,4-b]pyridinone; N-(1,1-Dioxothiolanyl)((5-methyl(6-methylpyridinyl)-1,2-oxazol yl)methoxy)pyrazinecarboxamide; N-(Cyclopropylmethyl)((5-methyl(6-methylpyridinyl)isoxazol hoxy)pyrazinecarboxamide; 25 2-(4,4-Difluorocyclohexyl)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one; 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydro-2H- pyranyl)pyridazinecarboxamide; (R)((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran- 3-yl)pyrazinecarboxamide; 5 (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan idazinecarboxamide; 5-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan 10 yl)pyrazinecarboxamide; 5-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-((cis) (trifluoromethyl)cyclohexyl)pyrazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 15 N-((cis)Hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyrazinecarboxamide; N-((trans)Hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyrazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydro-2H- 20 pyranyl)nicotinamide; 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)(tetrahydro-2H-thiopyran- 4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide 25 N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridazinyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4- tetrahydrothiopyranyl)pyridazinecarboxamide; N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; 5 (2,2-dioxidothiaazaspiro[3.3]heptanyl)(6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinyl)methanone; (2,2-Dioxidothiaazaspiro[3.3]heptanyl)(5-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyrazinyl)methanone; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- 10 methylcyclopentyl)pyridazinecarboxamide; 5-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4,4,4- trifluorobutyl)pyrazinecarboxamide; N-(1-isopropylazetidinyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 15 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)(2-oxaspiro[3.3]heptan yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclobutyl)pyridazinecarboxamide; 6-((5-Ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran 20 yl)nicotinamide; -Dioxidotetrahydro-2H-thiopyranyl)((5-ethyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)nicotinamide; 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 25 6-((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; N-cyclopropyl((5-ethyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; (R)-N-(1-hydroxypentanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide; 5 (difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((5-(difluoromethyl)(6-methylpyridyl)isoxazolyl)methoxy)-N-tetrahydropyran yl-pyridinecarboxamide; N-((3R,4S)hydroxytetrahydropyranyl)((5-methyl(6-methylpyridyl)isoxazol 10 hoxy)pyridinecarboxamide; 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyranylpyridinecarboxamide 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 15 6-((3-(6-cyclopropylpyridyl)methyl-isoxazolyl)methoxy)-N-(1,1-dioxothian yl)pyridinecarboxamide; N-((1R,2S)-3,3-difluorohydroxycyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; N-((1R,2R)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol 20 yl)methoxy)nicotinamide; N-((1S,2R)-3,3-difluorohydroxycyclohexyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; N-((3S,4R)hydroxytetrahydro-2H-pyranyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)nicotinamide; 25 N-((1S,2S)hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide; 2-fluoro-N-methyl((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)nicotinamide; 6-((3-(6-methoxypyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)nicotinamide; 5 N-isopropyl((3-(6-methoxypyridinyl)methylisoxazolyl)methoxy)nicotinamide; (S)-N-(1-hydroxypentanyl)((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)nicotinamide; ioxidothiomorpholino)(6-((3-(6-methoxypyridinyl)methylisoxazol yl)methoxy)pyridinyl)methanone; 10 (S)((3-(6-(dimethylamino)pyridinyl)methylisoxazolyl)methoxy)-N-(1- hydroxypentanyl)nicotinamide; 4-methoxy((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro- 2H-pyranyl)nicotinamide; 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-tetrahydropyran 15 yl-pyridinecarboxamide; 6((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-isopropyl-pyridine- 3-carboxamide; 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 20 N-((1r,4r)hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; N-(1,3-dihydroxymethylpropanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1s,4s)hydroxymethylcyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol- 25 ethoxy)pyridazinecarboxamide; N-((1R,3S)hydroxy(trifluoromethyl)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; ,3R)hydroxy(trifluoromethyl)cyclopentyl)((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinecarboxamide; (1S,4S)oxaazabicyclo[2.2.1]heptanyl(6-((5-methyl(6-methylpyridin yl)isoxazolyl)methoxy)pyridazinyl)methanone; 5 N-((1RS,3RS)hydroxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; trans-N-(4-hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; trans-N-(4-methoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol 10 yl)methoxy)pyridazinecarboxamide; (6,6-difluoroazaspiro[3.3]heptanyl)(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; N-(3-hydroxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 15 3-oxaazabicyclo[3.1.1]heptanyl(6-((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinyl)methanone; cis-N-(4-methoxycyclohexyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydro-2H-pyran 20 yl)pyridazinecarboxamide; (S)((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(tetrahydrofuran idazinecarboxamide; 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; 25 6-((3-(6-chloropyridinyl)methylisoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide; trans-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide; cis-N-(3-methoxycyclobutyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridazinecarboxamide; 5 6-((5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; trans-N-((1RS,3RS)methoxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; N-(6,6-difluorospiro[3.3]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol 10 yl)methoxy)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran- 4-yl)pyridazinecarboxamide; cis-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 15 trans-N((2,2-difluoroethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol- 4-yl)methoxy)pyridazinecarboxamide; cis-N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-(3-ethoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol 20 hoxy)pyridazinecarboxamide; cis-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; trans-N-(3-(difluoromethoxy)cyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 25 trans-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; cis-N-(3-cyclopropoxycyclobutyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 6-((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; 5 6-((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(2- oxaspiro[3.3]heptanyl)pyridazinecarboxamide; (S)((3-(6-chloropyridinyl)cyclopropylisoxazolyl)methoxy)-N-(tetrahydrofuran- 3-yl)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan 10 yl)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2- oxaspiro[3.3]heptanyl)pyridazinecarboxamide; (S)((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran- yridazinecarboxamide; 15 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran idazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide; 6-((5-methyl(6-(trifluoromethyl)pyridinyl)isoxazolyl)methoxy)-N- 20 (tetrahydropyranyl)pyridazinecarboxamide; N-((2S)oxabicyclo[2.2.1]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxepan yl)pyridazinecarboxamide; 25 6-((5-methyl(6-methylpyridyl)isoxazolyl)methoxy)-N-((1R,3S,4R) oxabicyclo[2.2.1]heptanyl)pyridazinecarboxamide; N-((2R)oxabicyclo[2.2.1]heptanyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; N-((1R,3R)ethoxycyclopentyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 5 N-((1R,3R)(2,2-difluoroethoxy)cyclopentyl)((5-methyl(6-methylpyridin xazolyl)methoxy)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran 10 yl)pyridazinecarboxamide; N-[4-(2,2-difluoroethoxy)cyclohexyl][[5-methyl(6-methylpyridinyl)-1,2-oxazol yl]methoxy]pyridazinecarboxamide; N-(4-ethoxycyclohexyl)[[5-methyl(6-methylpyridinyl)-1,2-oxazol yl]methoxy]pyridazinecarboxamide; 15 or pharmaceutically acceptable salts.
8. 8. A compound ing to any one of claims 1 to 7, selected from N-((1S)(hydroxymethyl)butyl)((5-methyl(6-methylpyridyl)isoxazol yl)methoxy)pyridinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran 20 yl)pyridazinecarboxamide; N-cyclopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1,1,1- trifluoropropanyl)pyridazinecarboxamide; 25 N-isopropyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; N-tert-butyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)pyridazine carboxamide; methoxymethyl)cyclopropyl)((5-methyl(6-methylpyridinyl)isoxazol yl)methoxy)pyridazinecarboxamide; 5 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- (trifluoromethyl)cyclopropyl)pyridazinecarboxamide; 5-methyl((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N- (tetrahydropyranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- 10 cyclopropyl)pyridazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3- methyltetrahydrofuranyl)pyridazinecarboxamide; 15 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; (S)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydrofuran yl)pyridazinecarboxamide; 6-((5-Methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(4-methyltetrahydro-2H- 20 pyranyl)pyridazinecarboxamide; (R)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran yl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(2-oxaspiro[3.3]heptan yl)pyridazinecarboxamide; 25 6-((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(1- methylcyclobutyl)pyridazinecarboxamide; 6-((3-(5-fluoromethylpyridyl)methyl-isoxazolyl)methoxy)-N-((1S) (hydroxymethyl)butyl)pyridinecarboxamide; 6-((5-cyclopropyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; 5 6-((5-(fluoromethyl)(6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydropyran- 4-yl)pyridazinecarboxamide; 6-((5-cyclopropyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(3-methyloxetan yl)pyridazinecarboxamide; (RS)((5-methyl(6-methylpyridinyl)isoxazolyl)methoxy)-N-(oxepan 10 yl)pyridazinecarboxamide; 6-((5-(fluoromethyl)(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H- pyranyl)pyridazinecarboxamide; 6-((5-methyl(6-methylpyridazinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyran yl)pyridazinecarboxamide; 15 or pharmaceutically acceptable salts.
9. 9. A compound according to any one of claims 1 to 8, wherein the compound is 6-((5-methyl (6-methylpyridinyl)isoxazolyl)methoxy)-N-(tetrahydro-2H-pyranyl)pyridazine carboxamide or pharmaceutically acceptable salts.
10. 10. A nd ing to any one of claims 1 to 9 for use as therapeutically active 20 substance.
11. 11. A pharmaceutical composition comprising a compound ing to any one of claims 1 to 9 and a therapeutically inert carrier.
12. 12. The use of a compound according to any one of claims 1 to 9 for the treatment or prophylaxis of Alzheimer’s disease, mild cognitive impairment, age-related ive decline, negative 25 and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder Angelman me, Rett syndrome, Prader-Willi syndrome, epilepsy, posttraumatic stress disorder, amyotrophic lateral sclerosis, fragile-X disorder.
13. 13. A compound according to any one of claims 1 to 9 for the treatment or prophylaxis of Alzheimer’s disease, mild ive impairment, lated cognitive decline, ve and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder Angelman syndrome, Rett syndrome, Prader-Willi syndrome, sy, post- 5 traumatic stress disorder, amyotrophic lateral sclerosis, fragile-X er.
14. 14. The use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or laxis of Alzheimer’s disease, mild cognitive impairment, age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder Angelman syndrome, Rett 10 syndrome, -Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, fragile-X disorder.
15. 15. A method for the treatment or prophylaxis of Alzheimer’s e, mild cognitive impairment, age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder Angelman syndrome, Rett 15 syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, fragile-X disorder, which method ses administering an effective amount of a compound according to any one of claims 1 to 9.