RU2772862C2 - New eterial derivatives of isoxazole as positive allosteric modulators of the gaba a alfa 5 receptor - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where X is selected from N and CH; Y is selected from N and CR¹⁰; Z is selected from N and CR¹¹; R¹ is selected from i) C_1-6-alkyl, ii) halo- C_1-6-alkyl, iii) C_1-6-alkoxy, iv) halo- C_1-6-alkoxy, v) hydroxy-C1-6-alkyl, vi ) C_3-8-cycloalkyl, vii) halogen and viii) amino substituted on the nitrogen atom with one or two substituents independently selected from H, C1-6-alkyl and C_3-8-cycloalkyl; R² is selected from H and halo; R³ is selected from i) H, ii) C_1-6 alkyl, iii) C_3-8 cycloalkyl, iv) hydroxy C_1-6 alkyl, and v) halo C_1-6 alkyl; R⁴ is selected from i) H, ii C_1-6 alkyl, iii) C_1-6 alkoxy, iv) C_3-8 cycloalkyl, and v) halogen; R⁵ is H; R⁶ is selected from i) H, ii) C_1-6 alkyl, iii) C_3-8 cycloalkyl substituted with R⁷, R⁸ and R⁹, iv) C_3-8-cycloalkyl-C1-6-alkyl substituted with R⁷, R⁸ and R⁹, v) C_1-6-alkylsulfonyl- C_1-6-alkyl, vi) cyano- C_1-6-alkyl, vii) hydroxy- C_1-6-alkyl, viii) dihydroxy- C_1-6-alkyl, ix) halo- C_1-6-alkyl, x) heterocycloalkyl substituted with R⁷, R⁸ and R⁹, where heterocycloalkyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiolanyl, oxaspiro- [3.3]-heptanyl, tetrahydrothiopyranyl, 7-oxabicyclo[2.2.1]heptanyl and oxepanyl, and xi) heterocycloalkyl- C_1-6-alkyl substituted with R⁷, R⁸ and R⁹, where heterocycloalkyl is oxetanyl; R¹⁰ is selected from i) H, ii) C_1-6 alkyl, iii) C_1-6 alkoxy, iv) C_3-8 cycloalkyl, and v) halogen; ^R11 is selected from i) H, ii) C_1-6 alkyl, iii) C_1-6 alkoxy, iv) C_3-8 cycloalkyl, 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, where the heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptanyl,3-oxa-6-azabicyclo[3.1.1]heptanyl,thiomorpholinyl or azaspiro[3.3]heptanyl; n is selected from 1 and 2; or pharmaceutically acceptable salts. The invention also relates to the use of compounds of formula (I) for the use or prevention of diseases associated with GABA α5 receptors.

EFFECT: compounds that are selective positive allosteric modulators (PAM) of GABAA α5 receptors.

15 cl, 2 tbl, 193 ex

Description

The present invention relates to organic compounds useful for the treatment or prevention in mammals, and in particular to positive allosteric modulators (PAMs) of the GABA _A α5 receptor (GABA A alpha 5) for the treatment or prevention of GABA _A receptor associated α5 diseases and disorders or conditions. that can be treated by modulating GABA _A α5 receptor activity, such as Alzheimer's disease, mild cognitive impairment (MCl), age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorders (ASD) , Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile X syndrome.

The present invention provides new compounds of formula (I)

where

X selected from

i) N, and

ii) CH;

Y is selected from

i) N, and

ii) CR ¹⁰ ;

Z is selected from

i) N, and

ii) CR ¹¹ ;

R ¹ is selected from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) halo-C _1-6 -alkoxy,

v) hydroxy-C _1-6 -alkyl,

vi) C _3-8 -cycloalkyl,

vii) halogen, and

viii) amino substituted on the nitrogen atom with one or two substituents independently selected from

a. H,

b. C _1-6 -alkyl, and

With. C _3-8 -cycloalkyl;

R ² is selected from

i) H, and

ii) halogen;

R ³ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 -cycloalkyl,

iv) hydroxy-C _1-6 -alkyl, and

v) halo-C _1-6 -alkyl;

R ⁴ selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl, and

v) halogen;

R ⁵ is H;

R ⁶ selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ ,

iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ ,

v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl,

vii) hydroxy-C _1-6 -alkyl,

viii) dihydroxy-C _1-6 -alkyl,

ix) halo-C _1-6 -alkyl,

x) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , and

xi) heterocycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _1-6 alkoxyalkyl,

v) C _1-6 alkoxycarbonyl,

vi) cyano,

vii) C _3-8 -cycloalkoxy,

viii) C _3-8 -cycloalkyl,

ix) halo-C _1-6 -alkoxy,

x) halo-C _1-6 -alkyl,

xi) halogen,

xii) hydroxy,

xiii) hydroxy-C _1-6 -alkyl, and

xiv) oxo;

R ¹⁰ selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl, and

v) halogen;

R ¹¹ selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl, and

v) halogen;

or R ⁵ and R ¹⁰ together form -(CH ₂ ) _n -;

or R ⁵ and R ¹¹ together form -(CH ₂ ) _n -;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ ;

n is selected from 1 and 2;

or their pharmaceutically acceptable salts.

Receptors for the main inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), fall into two main classes: (1) GABA receptors, which are members of the ligand-gated ion channel superfamily, and (2) GABA receptors, which are members of the G- protein-coupled receptors. The GABAd receptor complex, which is a membrane-bound heteropentameric protein polymer, consists mainly of α, β, and γ subunits. GABA receptors are ligand-gated chloride channels and are the main mediators of inhibitory neurotransmission in the human brain.

There are 19 genes encoding GABA _A receptor subunits, which assemble as pentamers, with the most common stoichiometry being two α, two β, and one γ subunit. Combinations of GABA _A subunits give functional, schema, and behavioral specificity (Sieghart, 2006; Vithlani et al., 2011). GABA receptors containing the α5 subunit (GABA _A α5) are of particular interest due to their limited expression region and unique physiological and pharmacological properties (Sur et al., 1999; Mohler, 2011). Receptors containing the α5 GABA _A subunit are predominantly localized in the hippocampus, prefrontal cortex, nucleus accumbens, and amygdala, which are believed to be key regions involved in the neuropathology and pathophysiology of various CNS diseases.

Hyperactivity of the hippocampus as a result of reduced expression of GABA _A α5 or GABAergic deficiency or other conditions is a common hallmark of various CNS disorders characterized by cognitive decline (memory and executive functions). In such a disease state, GABA _A α5-positive allosteric modulator (PAM), rather than negative allosteric modulator (NAM), may be an effective treatment for cognitive impairment associated with such diseases.

Ample evidence suggests that an imbalance between excitatory/inhibitory neurotransmission resulting from dysfunction of the GABAergic signaling system, the major inhibitory neurotransmitter system in the brain, underlies the pathogenesis of various CNS disorders. Given the distribution of GABA _A α5 receptors, they are very attractive targets for restoring levels of intracortical inhibition and hence (E/I) chain balance under these conditions. Therefore, the compounds described herein and their pharmaceutically acceptable salts and esters can be used, alone or in combination with other drugs, as disease modifying or symptomatic agents for the treatment or prevention of acute neurological disorders, chronic neurological 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 syndrome, Down syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ALS), fragile X syndrome, AIDS-related dementia, age-related memory impairment, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder (PTSD), drug addiction, movement disorder, Parkinson's disease, restless leg syndrome, mild cognitive impairment (MCl), cognitive impairment, age-related cognitive decline, multi-infarction dementia, dementia, mood disorders, depression, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, epilepsy, stroke and attention disorder.

The most preferred indication according to the present invention is autism spectrum disorder (ASD). ASD is a complex, heterogeneous neurodevelopmental disorder characterized by impairments to three main symptoms: social interactions, repetitive behavior, and cognitive deficits. The estimated prevalence of ASD in the United States is 1 in 68 children (CDC, 2014), and it is estimated that 1% of the world's population has ASD (WHO, 2013).

There is no approved pharmacological treatment for basic social communication and repetitive behavior in autism spectrum disorder, and the disorder continues to be an area of high unmet medical need. Currently approved treatments for ASD-associated symptoms are limited to antipsychotics (risperidone and aripiprazole) for the treatment of irritability associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, the major inhibitory 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 (PET) and magnetic resonance spectroscopy (MRS) suggest changes in GABAergic signaling in ASD. GABA receptor binding has been reported to be dramatically reduced in the superior and medial frontal cortex of ASD patients using [123I]-iomazenil PET (Moi et al., 2012). In addition, a pilot study of [11C]-RO154513 PET found reduced binding of this tracer, suggesting lower levels of the GABA _A α5 receptor in ASD (Mendez et al., 2012). MRS studies have found altered GABA levels in ASD (Gaetz et al., 2014; Rojas et al., 2014), and in particular, some recent studies have shown a decrease in GABA and somatosensory function in children with ASD and (Puts et al., 2016 ; Robertson et al., 2016). Consistent with these observations, postmortem downregulation of GABA _A receptor subunits, including GABRB3 (DeLorey, 2005; Abrahams and Geschwind, 2008) and the GABA-synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and 67, was found in the parietal and cerebellar cortices. patients with autism (Fatemi et al., 2002). Importantly, a decrease in GABAergic inhibitory activity leads to the increased excitability seen in ASD, including a high incidence of seizures and auditory-tactile hypersensitivity (Rubenstein and Merzenich, 2003; Frye et al., 2016). Altered GABAergic function can lower the seizure threshold, as evidenced by the high comorbidity of epilepsy in ASD, occurring in one third of patients. Finally, enhancement of GABA _A receptor activity by non-selective BZDs has been shown to improve behavioral deficits in a mouse model of ASD, however, very narrow therapeutic margins are observed due to sedation mediated by the GABA _A α1 subtype (Man et al., 2012, 2014; Soto et al. et al. 2013). These data support the notion that restoring the balance between GABAergic transmission via GABA _A α5 receptors can improve symptoms in ASD without the side effects of non-selective benzodiazepines.

The objects of the present invention are the compounds of formula (I) and their pharmaceutically acceptable salts and esters, the preparation of the above compounds, containing their drugs and their production, as well as the use of the above compounds in the treatment or prevention of diseases associated with GABA _A α5 receptors or diseases or conditions, which can be treated by modulating GABA _A α5 receptor activity, such as Alzheimer's disease, mild cognitive impairment (MCl), age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorders (ASD), Angelman syndrome , Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile X syndrome.

The compounds of the present invention are selective positive allosteric modulators (PAM) of α5 GABA _A receptors because they enhance the function of α5-containing GABA _A receptors by increasing GABAergic (chloride influx) at a given concentration of gamma-aminobutyric acid (GABA) EC ₂₀ . Most preferred are compounds with Ki (nM) <35 relative to the α5 subunit. In a preferred embodiment, the compounds of the invention are selective binding for the α5 subunit relative to the α1, α2 and α3 subunits. Consistent with the brain distribution of the α5 subtype, selective GABA _A α5 PAMs will restore GABAergic signaling in key brain regions (eg, hippocampus, amygdala, nucleus accumbens, and prefrontal cortex) without the side effects of non-selective GABA _A modulators (eg, benzodiazepines).

The term "C _1-6 -alkoxy" means a group of the formula -O-R', where R' represents a C _1-6 -alkyl group. Examples of C _1-6 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Specific examples are methoxy and ethoxy. In the case of R ¹ , a specific example is methoxy.

The term "C _1-6 -alkoxy-C _1-6 -alkyl" means a C _1-6 -alkyl group, where one of the hydrogen atoms of the C _1-6 -alkyl group is replaced by a C _1-6 -alkoxy group. Examples of C _1-6 -alkoxy-C _1-6 -alkyl groups include methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl. Specific alkoxyalkyl groups are methoxyethyl.

The term "C _1-6 -alkoxycarbonyl" means a group of the formula -C(O)-R', where R' represents a C _1-6 -alkoxy group. Examples of C _1-6 alkoxycarbonyl groups include those where R' is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy. A specific example of C _1-6 alkoxycarbonyl is a group where R' is ethoxy.

The term "C _1-6 -alkyl" means a monovalent linear or branched saturated hydrocarbon group of 1-6 carbon atoms. Examples of C _1-6 alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl. Specific C _1-6 alkyl groups are methyl, ethyl, isopropyl and tert-butyl. In the case of R ¹ , a more specific example is methyl. In the case of R ³ , more specific examples are methyl and ethyl. In the case of R ³ , an even more specific example is methyl.

The term "C _1-6 -alkylsulfonyl" denotes a group of the formula -S(O) ₂ -R', where R' represents a C _1-6 -alkyl group. Examples of C _1-6 alkylsulfonyl include groups where R' is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl or pentyl.

The term "C _1-6 -alkylsulfonyl-C _1-6 -alkyl" means a C _1-6 -alkyl group, where one of the hydrogen atoms of the C _1-6 -alkyl group is replaced by a C _1-6 -alkylsulfonyl group. Specific C _1-6 alkylsulfonyl-C _1-6 alkyl is methylsulfonyl (methyl) butanyl.

The term "amino" means a -NH ₂ group.

The term "bicyclic ring system" means two rings that are fused to each other through a common single or double bond (annelated ring bicyclic system), through a sequence of three or more common atoms (bridged bicyclic ring system), or through a common one atom (spiro bicyclic ring system). system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic. Bicyclic ring systems may contain heteroatoms selected from N, O and S.

The term "carbonyl" means a -C(O)- group.

The term "cyano" means a -C≡N- group.

The term "cyano-C _1-6 -alkyl" means a -C _1-6 -alkyl group, where one of the hydrogen atoms of the C _1-6 -alkyl group is replaced by a cyano group. Examples of cyano-C _1-6 -alkyl include cyanomethyl, cyanoethyl, cyanopropyl and cainobutyl. Specific examples are cyanoethyl and cyanobutyl.

The term "cyano-C _1-6 -alkoxy" means -C _1-6 -alkoxy group, where one of the hydrogen atoms of the C _1-6 -alkoxy group is replaced by a cyano group.

The term "C _3-8 -cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3-8 ring carbon atoms. Bicyclic means a ring system of two saturated carbocycles sharing one or two atoms. Examples of monocyclic C _3-8 cycloalkyls are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Specific monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More specifically, the monocyclic cycloalkyl group is cyclopropyl. An example of a bicyclic C _3-8 cycloalkyl is spiro[3.3]-heptanyl. In the case of R ¹ and R ³ a specific example of C _3-8 cycloalkyl is cyclopropyl.

The term "C _3-8 -cycloalkyl-C _1-6 -alkyl" means a -C _1-6 -alkyl group, where one of the hydrogen atoms of the C _1-6 -alkyl group is replaced by a C _3-8 -cycloalkyl group. Examples of C _3-8 -cycloalkyl-C _1-6 -alkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0.0]heptanylmethyl, bicyclo 2.2.2]octanylmethyl and bicyclo[ 2.2.2] octanylethyl. A specific example of C _3-8 -cycloalkyl-C _1-6 -alkyl is cyclopropylmethyl.

The term "dihydroxy-C1-6-alkyl" means a C _1-6 alkyl group in which two hydrogen atoms in the C _1-6 alkyl group have been replaced by a hydroxy group. Examples of dihydroxy-C _1-6 -alkyl include dihydroxyethyl, dihydroxypropyl, dihydroxy(methyl)propyl and dihydroxybutyl. A specific example is dihydroxy(methyl)propyl.

The term "halo-C _1-6 -alkoxy" means a group of C _1-6 -alkoxy, where at least one of the hydrogen atoms of the C _1-6 -alkoxy group is replaced by the same or different halogen atoms. The term "perhaloalkoxy" means an alkoxy group in which all hydrogen atoms of the alkoxy group are 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-C _1-6 alkyl" means a C 1-6 alkyl group wherein at least one of the hydrogen atoms in the C _1-6 alkyl group is replaced by the same or different halogen atoms. The term "perhalo-C _1-6 -alkylalkyl" means -C _1-6 -alkylalkyl group, where all hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, and pentafluoroethyl. A particular halo C _1-6 alkyl group is fluoromethyl, difluoromethyl trifluoromethyl. Specifically, the halo-C1-6-alkyl group is trifluoromethyl.

The terms "halo" and "halogen" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. A specific halogen is fluorine. In the case of R ¹ , the specific halogen is chlorine.

The term "heterocycloalkyl" means a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 4-9 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 rings sharing one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thioxydolidyl hydrate, vinyl oxyhydrate. piperazinil, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanil, diazepanil, homopiperazinil or oxazepanil.

Examples of bicyclic saturated heterocycloalkyl are oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9 -aza-bicyclo [3.3.1] nonyl, 3-oxa-9-aza-bicyclo [3.3.1] nonyl, or 3-thia-9-aza-bicyclo [3.3.1] nonyl. Examples of partially unsaturated heterocycloalkyls are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl. Specific heterocycloalkyls are oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, oxabicpo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, azetidinyl, tetrahydrothiophenyl and tetrahydrothiopyranyl. More specifically, heterocycloalkyl is tetrahydropyranyl.

When heterocycloalkyl is formed by R ⁵ and R ⁶ together with the nitrogen atom to which they are attached, specific examples of heterocycloalkyl are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxaazabicyclo[3.1.1]heptanyl, oxaazabicyclo[2.2.1]heptanyl , azaspiro[3.3]heptanil, oxaazaspiro[3.3]heptanil and thiaazaspiro[3.3]heptanil.

The term "heterocycloalkyl-C _1-6 -alkyl" means a C _1-6 -alkyl group, where one of the hydrogen atoms of the C _1-6 -alkyl group is replaced by a heterocycloalkyl group. A specific heterocycloalkyl-C _1-6 -alkyl is oxetanylmethyl.

The term "hydroxy" means a -OH group.

The term "hydroxy-C _1-6 -alkylalkyl" means a C _1-6 -alkyl alkyl group, where at least one of the hydrogen atoms in the C _1-6 -alkyl alkyl group is replaced by a hydroxy group. Examples of hydroxy-C _1-6 -alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, hydroxybutyl and hydroxypentyl. A specific example is hydroxypentyl.

The term "oxo" means a =O group.

The term "sulfonyl" means a -S(O) ₂ - group.

The term "pharmaceutically acceptable salts" refers to salts that retain the biological efficacy and free base or free acid properties that are not biologically or otherwise undesirable. Salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably 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-acetylcysteine, etc. .P. In addition, these salts can be obtained by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, without limitation, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine , arginine, N-ethylpiperidine, piperidine, polyamine resins, and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric acid, methanesulfonic acid and citric acid.

"Pharmaceutical esters" means that the compounds of general formula (I) can be functionally derivatized to give derivatives that are capable of being converted back to the parent compounds under in vivo conditions. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ethers, methylthiomethyl ethers and pivaloyloxymethyl ethers. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), analogous to metabolically labile esters, which are capable of being converted to the parent compounds of general formula (I) in vivo, are included within the scope of the present invention.

The term "protecting group" means a group that selectively 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 sense commonly associated with it in synthetic chemistry. The protecting groups may be removed at an appropriate stage. Typical protecting groups are amino protecting groups, carboxy protecting groups or hydroxy protecting groups. Specific protecting groups are tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ or Z), fluorenylmethyloxycarbonyl (Fmoc) and benzyl (Bn). Additionally specific protecting groups are tert-butoxycarbonyl (BOC) and fluorenylmethyloxycarbonyl (Fmoc). A more specific protecting group is a tert-butoxycarbonyl (BOC) group.

The abbreviation µM stands for micromole and is equivalent to µM.

The abbreviation µl stands for microliter and is equivalent to uL.

The abbreviation µg stands for microgram and is equivalent to µg

The compound of formula (I) may contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereomeric racemates, or mixtures of diastereomeric racemates.

According to the Kahn-Ingold-Prelog rules, an asymmetric carbon atom can be in the "R" or "S" configuration.

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

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein X is CH.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein Y is N.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein Z is CR ¹¹ .

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹ is selected from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) halogen, and

vi) amino substituted on the nitrogen atom with one or two substituents selected from

a. H,

b. C _1-6 -alkyl, and

With. C _3-8 -cycloalkyl.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹ is selected from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) halogen, and

vi) amino substituted on the nitrogen atom with two independently selected C _1-6 alkyl substituents.

In a more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹ is C _1-6 alkyl.

In a further more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹ is methyl.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ² is H.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ³ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 -cycloalkyl, and

iv) halo-C _1-6 -alkyl.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ³ is selected from

i) H,

ii) C _1-6 -alkyl, and

iii) C _3-8 cycloalkyl.

In a more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ³ is C _1-6 alkyl.

In a further more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ³ is methyl.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁴ is selected from

i) H, and

ii) C _1-6 alkyl.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁴ is H.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁶ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. C _1-6 -alkoxyalkyl,

e. C _1-6 alkoxycarbonyl,

f. cyano,

g. C _3-8 -cycloalkoxy,

h. halo-C _1-6 -alkoxy,

i. halo-C _1-6 -alkyl,

j. halogen,

k. hydroxy, and

l. hydroxy-C _1-6 -alkyl;

iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. C _1-6 -alkoxyalkyl,

e. C _1-6 alkoxycarbonyl,

f. cyano,

g. C _3-8 -cycloalkoxy,

h. halo-C _1-6 -alkoxy,

i. halo-C _1-6 -alkyl,

j. halogen,

k. hydroxy, and

l. hydroxy-C _1-6 -alkyl;

v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl,

vii) hydroxy-C _1-6 -alkyl,

viii) dihydroxy-C _1-6 -alkyl,

ix) halo-C _1-6 -alkyl,

x) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

c. hydroxy, and

d. oxo;

and where heterocycloalkyl is selected from

a. oxetanil,

b. tetrahydrofuranyl,

With. tetrahydropyranyl,

d. oxepanil,

e. oxabicyclo[2.2.1]heptanil,

f. oxaspiro[3.3]heptanil,

g. azetidinil,

h. tetrahydrothiophenyl, and

i. tetrahydrothiopyranil; and

xi) oxetanyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H, and

b. hydroxy.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁶ is selected from

i) C _1-6 -alkyl,

ii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

c. C _1-6 -alkoxyalkyl,

d. halo-C _1-6 -alkyl;

iii) hydroxy-C _1-6 -alkyl,

iv) halo-C _1-6 -alkyl,

v) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H, and

b. C _1-6 -alkyl,

and where heterocycloalkyl is selected from

a. oxetanil,

b. tetrahydrofuranyl,

With. tetrahydropyranyl, and

d. oxaspiro[3.3]heptanil.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁷ , R ⁸ and R ⁹ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _1-6 alkoxyalkyl,

v) C _1-6 alkoxycarbonyl,

vi) cyano,

vii) C _3-8 -cycloalkoxy,

viii) halo-C _1-6 -alkoxy,

ix) halo-C _1-6 -alkyl,

x) halogen,

xi) hydroxy,

xii) hydroxy-C _1-6 -alkyl, and

xiii) oxo.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁷ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _1-6 alkoxyalkyl,

v) C _1-6 alkoxycarbonyl,

vi) cyano,

vii) C _3-8 -cycloalkoxy,

viii) halo-C _1-6 -alkoxy,

ix) halo-C _1-6 -alkyl,

x) halogen,

xi) hydroxy,

xii) hydroxy-C _1-6 -alkyl, and

xiii) oxo.

In a more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁷ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxyalkyl, and

iv) halo-C _1-6 -alkyl.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁸ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) halo-C _1-6 -alkyl,

iv) halogen, and

v) oxo.

In a more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁸ is H.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁹ is selected from

i) H, and

ii) halogen.

In a more specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ⁹ is H.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹⁰ is selected from

i) H, and

ii) halogen.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹⁰ is H.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹¹ is selected from

i) H,

ii) C _1-6 -alkyl, and

iii) C _1-6 alkoxy.

In a further specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein R ¹¹ is H.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein n is 1.

In a further specific embodiment, 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) CR ¹⁰ ;

Z is selected from

i) N, and

ii) CR ¹¹ ;

R ¹ is selected from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) halogen, and

vi) amino substituted on the nitrogen atom with two independently selected C _1-6 alkyls;

R ² is selected from

i) H,

ii) halogen;

R ³ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 -cycloalkyl, and

iv) halo-C _1-6 -alkyl;

R ⁴ selected from

i) H, and

ii) C _1-6 -alkyl;

R ⁵ is H;

R ⁶ selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. C _1-6 -alkoxyalkyl,

e. C _1-6 alkoxycarbonyl,

f. cyano,

g. C _3-8 -cycloalkoxy,

h. halo-C _1-6 -alkoxy,

i. halo-C _1-6 -alkyl,

j. halogen,

k. hydroxy, and

l. hydroxy-C _1-6 -alkyl;

iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. C _1-6 -alkoxyalkyl,

e. C _1-6 -alkoxycarbonyl,

f. cyano,

g. C _3-8 -cycloalkoxy,

h. halo-C _1-6 -alkoxy,

i. halo-C _1-6 -alkyl,

j. halogen,

k. hydroxy, and

l. hydroxy-C _1-6 -alkyl;

v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl,

vii) dihydroxy-C _1-6 -alkyl,

viii) halo-C _1-6 -alkyl,

ix) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. C _1-6 -alkyl,

c. hydroxy, and

d. oxo;

and where heterocycloalkyl is selected from

a. oxetanil,

b. tetrahydrofuranyl,

With. tetrahydropyranyl,

d. oxepanil,

e. oxabicyclo[2.2.1]heptanyl,

f. oxaspiro[3.3]heptanil,

g. azetidinil,

h. tetrahydrothiophenyl, and

i. tetrahydrothiopyranil; and

x) oxetanyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. hydroxy;

R ¹⁰ selected from

i) H, and

ii) halogen;

R ¹¹ selected from

i) H,

ii) C _1-6 -alkyl, and

iii) C _1-6 alkoxy;

or R ⁵ and R ¹⁰ together form -(CH ₂ ) _n -;

or R ⁵ and R ¹¹ together form -(CH ₂ ) _n -;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. cyano,

e. halogen,

f. hydroxy, and

g. oxo;

and where heterocycloalkyl is selected from

a. azetidinil,

b. pyrrolidinyl,

With. piperidinil,

d. morpholinyl,

e. thiomorpholinil,

f. oxaazabicyclo[3.1.1]heptanyl,

g. oxaazabicyclo[2.2.1]heptanyl,

h. azaspiro[3.3]heptanil,

i. oxaazaspiro[3.3]heptanil,

j. thiaazaspiro[3.3]heptanil;

n is 1;

or pharmaceutically acceptable salts.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein

X selected from

i) N, and

ii) CH;

Y is selected from

i) N, and

ii) CR ¹⁰ ;

Z is selected from

i) N, and

ii) CR ¹¹ ;

R ¹ is selected from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) halogen, and

vi) amino substituted on the nitrogen atom with two independently selected C _1-6 alkyls;

R ² is selected from

i) H,

ii) halogen;

R ³ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 -cycloalkyl, and

iv) halo-C _1-6 -alkyl;

R ⁴ selected from

i) H, and

ii) C _1-6 -alkyl;

R ⁵ is H;

R ⁶ selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. C _1-6 -alkoxyalkyl,

e. C _1-6 -alkoxycarbonyl,

f. cyano,

g. C _3-8 -cycloalkoxy,

h. halo-C _1-6 -alkoxy,

i. halo-C _1-6 -alkyl,

j. halogen,

k. hydroxy, and

l. hydroxy-C _1-6 -alkyl;

iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. C _1-6 -alkyl,

With. C _1-6 -alkoxy,

d. C _1-6 -alkoxyalkyl,

e. C _1-6 -alkoxycarbonyl,

f. cyano,

g. C _3-8 -cycloalkoxy,

h. halo-C _1-6 -alkoxy,

i. halo-C _1-6 -alkyl,

j. halogen,

k. hydroxy, and

l. hydroxy-C _1-6 -alkyl;

v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl,

vii) dihydroxy-C _1-6 -alkyl,

viii) halo-C _1-6 -alkyl,

ix) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. C _1-6 -alkyl,

With. hydroxy, and

d. oxo;

and where heterocycloalkyl is selected from

a. oxetanil,

b. tetrahydrofuranyl,

With. tetrahydropyranyl,

d. oxepanil,

e. oxabicyclo[2.2.1]heptanil,

f. oxaspiro[3.3]heptanil,

g. azetidinil,

h. tetrahydrothiophenyl, and

i. tetrahydrothiopyranil; and

x) oxetanyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. hydroxy;

R ¹⁰ selected from

i) H, and

ii) halogen;

R ¹¹ selected from

i) H,

ii) C _1-6 -alkyl, and

iii) C _1-6 alkoxy;

or pharmaceutically acceptable salts.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein

X selected from

i) N, and

ii) CH;

Y is selected from

i) N, and

ii) CR ¹⁰ ;

Z is CR ¹¹ ;

R ¹ is C _1-6 alkyl;

R ² is selected from

i) H,

ii) halogen;

R ³ is selected from

i) C _1-6 -alkyl,

ii) C _3-8 -cycloalkyl, and

iii) halo-C _1-6 -alkyl;

R ⁴ selected from

i) H, and

ii) C _1-6 -alkyl;

R ⁵ is H;

R ⁶ selected from

i) C _1-6 -alkyl,

ii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. h,

b. C _1-6 -alkyl,

With. C _1-6 alkoxyalkyl, and

d. halo-C _1-6 -alkyl;

iii) hydroxy-C _1-6 -alkyl,

iv) halo-C _1-6 -alkyl,

v) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from

a. H, and

b. C _1-6 -alkyl;

and where heterocycloalkyl is selected from

a. oxetanil,

b. tetrahydrofuranyl,

With. tetrahydropyranyl,

d. oxepanil, and

e. oxaspiro[3.3]heptanil;

R ¹⁰ is H;

R ¹¹ is H;

or pharmaceutically acceptable salts.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein

X is CH;

Y is N;

Z is CR ¹¹ ;

R ¹ is C _1-6 alkyl;

R ² is H;

R ³ is C _1-6 alkyl;

R ⁴ is H;

R ⁵ is H;

R ⁶ is heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are H;

R ¹¹ is H;

or pharmaceutically acceptable salts.

In a specific embodiment, the present invention provides compounds according to formula (I) as described herein, wherein

X is CH;

Y is N;

Z is CR ¹¹ ;

R ¹ is C _1-6 alkyl;

R ² is H;

R ³ is C _1-6 alkyl;

R ⁴ is H;

R ⁵ is H;

R ⁶ is tetrahydropyranyl substituted with R ⁷ , R ⁸ and R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are H;

R ¹¹ is H;

or pharmaceutically acceptable salts.

Specific examples of compounds of formula (I) as described herein are selected from

6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;

N-ethyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;

N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;

6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;

6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

(S)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;

2-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one ;

2-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one ;

N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

2-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine-3( 2H)-he;

(S)-2-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3, 4-c]pyridine-3(2H)-one;

(S)-N-(1-hydroxypentan-2-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;

N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-((3S)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridine-3-carboxamide;

N-((3R)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridine-3-carboxamide;

N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridin-3- carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,4- c]pyridine-3(2H)-one;

N-((1S,2R)-2-Hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-((1S,2S)-2-Hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-((1R,2R)-2-Hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-((1R,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-((3S,4R)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide ;

N-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazin-3- carboxamide;

N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(2-cyanoethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazin-3 -carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyridazin-3-carboxamide;

(RS)-N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridazine-3-carboxamide;

N-ethyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide;

N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(3,3-difluorocyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;

N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(3,3-difluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

(3,3-difluoropyrrolidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3-methyloxetan-3-yl)methyl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-ylmethyl)pyridazine-3-carboxamide;

N-((3-hydroxyoxetan-3-yl)methyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3R,4R)-3-methyltetrahydropyran-4-yl)pyridazine-3-carboxamide ;

(4,4-difluoropiperidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(3-methoxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

(3-hydroxy-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

azetidin-1-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

(RS)-N-(2,2-dimethyltetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide ;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide;

(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(morpholino)methanone;

(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl ) methanone;

4-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl ) methanone;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridazin-3 -carboxamide;

(3-fluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

(3-hydroxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

(3-fluoro-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone;

ethyl 1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamido)cyclopropanecarboxylate;

N-(1-cyanocyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

N-(1,1-dioxothian-4-yl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

N-(2-hydroxy-1,1-dimethyl-ethyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

N-cyclopropyl-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazine-3-carboxamide;

5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyrazine-2-carboxamide;

5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide;

N-(4-hydroxy-2-methylbutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)pyridazin-3- carboxamide;

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;

(R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;

1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carbonyl)azetidine-3-carbonitrile;

N-(1-(hydroxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(4,4-difluorocyclohexyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;

(S)-N-(1-cyanobutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(R)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide;

N-(2-Hydroxyethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

2-(1,1-Dioxothian-4-yl)-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]-1H-pyrrolo [3,4-c]pyridin-3-one;

(S)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide;

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy]-6-tetrahydropyran-4-yl-7H-pyrrolo[3,4-b]pyridin-5- he;

N-(1,1-Dioxothiolan-3-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyrazin-2- carboxamide;

N-(cyclopropylmethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

2-(4,4-Difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine- 3(2H)-one;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

(R)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-3-yl)pyrazine-2-carboxamide ;

(R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyrazine-2-carboxamide;

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((cis)-4-(trifluoromethyl)cyclohexyl)pyrazine-2-carboxamide;

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide;

N-((cis)-4-hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

N-((trans)-4-hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)nicotinamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrolo[3,4- c]pyridine-3(2H)-one;

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

N-((13)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydrothiopyran-4-yl)pyridazine-3-carboxamide;

N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide;

(2,2-dioxydo-2-thia-6-azaspiro[3.3]heptan-6-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyridazin-3-yl)methanone;

(2,2-dioxydo-2-thia-6-azaspiro[3.3]heptan-6-yl)(5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyrazin-2-yl)methanone;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopentyl)pyridazine-3-carboxamide;

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4,4,4-trifluorobutyl)pyrazine-2-carboxamide;

N-(1-isopropylazetidin-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3, 4-c]pyridine-3(2H)-one;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazin-3-carboxamide;

6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide;

N-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;

N-cyclopropyl-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(R)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;

6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

N-((3R,4S)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide ;

6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide;

6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-(1,1-dioxothian-4-yl)pyridine-3-carboxamide;

N-((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

N-((1R,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide ;

N-((1S,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

2-fluoro-N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide;

6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide;

N-isopropyl-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)nicotinamide;

(S)-N-(1-hydroxypentan-2-yl)-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)nicotinamide;

(1,1-dioxidothiomorpholino)(6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone;

(S)-6-((3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(1-hydroxypentan-2-yl)nicotinamide;

4-methoxy-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide;

6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide;

6((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-isopropyl-pyridine-3-carboxamide;

6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3 -carboxamide;

N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide ;

N-(1,3-dihydroxy-2-methylpropan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide ;

N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide ;

N-((1R,3S)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide;

N-((1S,3R)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide;

(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyridazin-3-yl)methanone;

N-((1RS,3RS)-3-hydroxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

trans-N-(4-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

trans-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3 -yl) methanone;

N-(3-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

3-oxa-6-azabicyclo[3.1.1]heptan-6-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl ) methanone;

cis-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;

(S)-6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;

6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;

trans-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

cis-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

trans-N-((1RS,3RS)-3-methoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-(6,6-difluorospiro[3.3]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide ;

6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

cis-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

trans-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

cis-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

trans-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

cis-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

trans-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

trans-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

cis-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazin-3-carboxamide;

6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;

(S)-6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;

(S)-6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

N-((2S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide;

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1R,3S,4R)-7-oxabicyclo[2.2.1]heptan-3 -yl)pyridazine-3-carboxamide;

N-((2R)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide;

N-((1R,3R)-3-ethoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide;

N-((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide;

6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

N-[4-(2,2-difluoroethoxy)cyclohexyl]-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridazin-3 -carboxamide;

N-(4-ethoxycyclohexyl)-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridazin-3-carboxamide;

or pharmaceutically acceptable salts.

Additional specific examples of compounds of formula (I) as described herein are selected from

N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide;

N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazin-3 -carboxamide;

N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide;

5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazine-3-carboxamide;

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;

(R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

(R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide;

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazin-3-carboxamide;

6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3 -carboxamide;

6-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide;

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide;

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazin-3-carboxamide;

6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide;

or their pharmaceutically acceptable salts.

Additional specific examples of compounds of formula (I) as described herein are selected from

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide

or its pharmaceutically acceptable salts.

Methods for the preparation of compounds of formula (I) as described herein are the subject of the present invention.

The preparation of the compounds of formula (I) of the present invention may be carried out by sequential or convergent synthetic routes. The syntheses of the invention are shown in the following general schemes. The skills required to carry out the reaction and purify the resulting products are known to those skilled in the art. Substituents and indices used in the following description of the methods have the meanings given here, unless otherwise indicated.

In more detail, the compounds of formula (I) can be obtained by the methods below, the methods given in the examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to that shown in Schemes 1-7, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely changed. Starting materials are either commercially available or can be obtained by methods similar to those below, by methods described in the references given in the description or in the examples, or by methods known in the art.

Compounds of the present invention of formula (I) and their pharmaceutically acceptable salts can be obtained by the method as described below (Scheme 1)

Scheme 1: where Y is CH or N; Z is CH or N; with the proviso that no 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 a conventional amide coupling reaction between a primary (R ⁵ ═H) or secondary amine HNR ⁵ R ⁶ and a carboxylic acid of formula (II). Carboxylic acids (II) can be conveniently obtained by hydrolysis of the corresponding methyl esters (III) under standard conditions. Alternatively, a compound of formula (I) can be prepared in one step from methyl esters (III) and a primary amine (H ₂ NR ⁶ ) by treatment with Me ₃ Al in 1,4-dioxane or DBU in toluene.

Alternatively, according to Scheme 2, compounds of formula (I) can be prepared by a nucleophilic aromatic substitution reaction between a primary alcohol (IV) and an aryl chloride (V) in the presence of a base (Cs ₂ CO ₃ ).

Scheme 2: where Y is CH or N; Z is CH or N; with the proviso that no more than one of Y and Z is N; all other definitions are as described above and in the claims

In some embodiments of the present invention, R ^z or R ^y and R ⁵ are connected together to form -CH ₂ -, thus forming a 5-membered heterocycloalkyl together with interconnected atoms. In such a case, the compounds of formula (I-a) can be obtained by the method described in Scheme 3.

Scheme 3: where all definitions are as described above and in the claims

Intermediate γ-lactams (2) can be prepared using a two step one pot procedure involving reductive amination between commercially available 6-chloro-4-formylnicotinic acid and a primary amine (H ₂ NR ⁶ ) followed by intramolecular lactam formation. The esterification reaction between γ-lactams (5) and alcohols (IV) can be carried out by a palladium-catalyzed reaction in the presence of a base (Cs ₂ CO ₃ ) to form compounds of formula (I-a).

In turn, regioisomeric compounds of formula (I-b) can be obtained by the method described in Scheme 4.

Scheme 4: where all definitions are as described above and in the claims.

Intermediate γ-lactams (5) can be obtained in two steps from commercially available ethyl 6-chloro-2-methylnicotinate by radical bromination to form bromide (4). This is followed by a reaction with a primary amine (H ₂ NR ⁶ ) followed by intramolecular lactam formation to give γ-lactams (5). The final esterification between γ-lactams (5) and alcohols (IV) can be carried out again by a palladium-catalyzed reaction in the presence of a base (Cs ₂ CO ₃ ) to form compounds of formula (Ib).

Scheme 5: where Y is CH or N; Z is CH or N; with the proviso that no more than one of Y and Z is N; all other definitions are as described above and in the claims

As shown in Scheme 5, methyl esters of formula (III) can be conveniently prepared by a nucleophilic aromatic substitution reaction between a commercially available heteroaryl chloride or fluoride and an alcohol of formula (IV) in the presence of a base (NaH or Cs ₂ CO ₃ ).

Scheme 6: where all definitions are as described above and in the claims

Alternatively, according to Scheme 6, the pyridazine esters of formula (III) can be obtained in a two-step process. First, the alcohol of formula (IV) is reacted with commercially available 3,6-dichloropyridazines (7) in the presence of a base (NaH). Finally, the resulting aryl chloride of formula (VI) undergoes a palladium-catalyzed carbonylation reaction (CO _(g) in EtOH) to give ethyl esters (III).

The synthesis of structural blocks (A-P) of formula (IV) is shown in Scheme 7.

Scheme 7: synthesis of structural blocks (A-P); where all definitions are as described above and in the claims

Commercially available aldehydes (8) are converted to the corresponding oximes (9) by treating hydroxylamine with hydrochloride in the presence of a base (NaOH). After electrophilic chlorination with N-chlorosuccinimides, intermediate chlorooximes (10), depending on the base (Et3N), undergo a 1,3-dipolar cycloaddition reaction with readily available enamines (11) or enols (12) to give isoxazoles. formula (VII). Their final reduction with LiAlH4 or DIBAL-H at controlled temperature gives the desired alcohols (IV). Alternatively, the alcohols of formula (IV) can be obtained in a two-step synthesis from ethyl esters (VII). The reaction of saponification (LiOH, water) of ethyl esters (VII) to the corresponding carboxylates (VIII) followed by reduction by treatment with ethyl chloroformate in the presence of a base (Et3N) and NaBH4 gives the building blocks (AP) of formula (IV).

Also an embodiment of the present invention is a process for the preparation of a compound of formula (I) as defined above, comprising

i) reacting a compound of formula (II) with a compound of formula (III)

or

ii) reacting a compound of formula (IV) with a compound of formula (V)

Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y and Z are as defined here and R ³ is C _1-6 alkyl and R ^b is bromine, chlorine or iodine.

Also an object of the present invention is a compound according to formula I for use as a therapeutically active substance.

In addition, the subject of the present invention is a pharmaceutical composition containing a compound of compounds of formula (I) as described herein and a therapeutically inert carrier.

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

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

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

Also an embodiment of the present invention are compounds of formula (I) as described here, obtained in accordance with any of the methods described.

Analysis Method

Membrane preparation and binding analysis

The affinity of compounds for GABA _A receptor subtypes was measured by competition for [3H]flumazenil (85 Cu/mmol; Roche) binding to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors of the following 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 MgCl ₂ , 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized on a polytron for approximately 20 sec on ice, and centrifuged for 60 min at 4°C (50,000 g; Sorvall, rotor: SM24=20,000 rpm). Cell pellets were resuspended in Krebs-Tris buffer and homogenized on a polytron for approximately 15 seconds on ice. The protein content was measured (according to Bradford, Bio-Rad) and 1 ml aliquots were obtained and stored at -80°C.

The radioligand binding assay was performed in a volume of 200 ml (96-well plates), which contained 100 ml of cell membranes, [ ³ H]-Flumazenil at a concentration of 1 nM for the α1, α2, α3 subunits and 0.5 nM for the α5 subunit, and test compounds in the range 10-10 ^-3 ×10 ^-6 M. Non-specific binding was determined using diazepam 10 ^-5 M and it was usually present in a ratio of not more than 5% of the total binding. Analyzed samples were incubated to equilibrium for 1 hour at 4° C. and placed on GF/C unifilters (Packard) by filtration using a Packard harvester and washed with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, the radioactivity remaining on the filter was determined by liquid scintillation counting. The K _i values were calculated using Excel-Fit (Microsoft) and are the average of two measurements.

Compounds from the appended examples were tested in the assay described above and the preferred compounds were found to have a Ki value for displacing [ ³ H]-flumazenil from the α 5 subunits of the human GABA _A receptor of 100 nM or less. Most preferred are compounds with Ki (nM) <35. In a preferred embodiment, the compounds of the invention are selective binding for the α5 subunit over the α1, α2 and α3 subunits. Representative test results obtained by the above assay measuring binding affinity to HEK293 cells expressing human (h) receptors are shown in the table below.

Functional expression of GABA _A receptors:

Obtaining Xenopus oocytes

Xenopus laevis oocytes at maturation stages V-VI were used to express the cloned mRNA encoding the GABA _A receptor subunits. Oocytes ready for RNA microinjection were obtained from Ecocyte, Castrop-Rauxel, Germany and stored in modified Barth's medium in mM: NaCl 88, KCl 1, NaHCO ₃ 2.4, HEPES 10, MgSO ₄ 0.82, CaNO ₃ 0.33, CaCl2 0.33, pH =7.5) at 20°C before the experiment.

Microinjection into Xenopus oocytes

Oocytes were placed in 96-well plates for use in an automated instrument (Robo-ocyte, MultiChannelSystems, Reutlingen, Germany) for microinjection and recording of electrophysiological parameters. Approximately 50 nl of an aqueous solution containing RNA transcripts for the required GABA _A receptor subunits was injected into each oocyte. The RNA concentration ranged between 0.3 and 16 ng/μl/subunit and was adjusted in pilot experiments to obtain GABA responses of suitable strength and maximize the effect of the reference modulator, Beta-CCM (β-CCM), betacarbonyl negative allosteric modulator (NAM) at the site GABA _A receptor binding to benzodiazepine (BZD) or Midazolam, a benzodiazepine positive allosteric modulator (PAM) at the GABA _A receptor binding site to benzodiazepine (BZD). The concentration of RNA encoding the γ2 subunit was typically 5-10 times higher than that of RNA encoding other subunits. Oocytes were maintained in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO ₃ 4, HEPES 10, MgSO ₄ 0.82, CaNO ₃ 0.33, CaCl ₂ 0.33, pH=7.5) at 20°C until the experiment.

electrophysiology

Electrophysiological experiments were performed 3-5 days after mRNA microinjection. During the experiment, oocytes were constantly superfused with a solution containing (in mM) NaCl 90, KCl 1, HEPES 5, MgCl ₂ 1, CaCl ₂ 1 (pH 7.4). The oocytes are pierced with two glass microelectrodes (resistance: 0.4 MΩ) which are filled with a solution containing 1 M KCl + 1.5 M acetate K and fixed with a voltage of -80 mV. The recording was carried out at room temperature using a two-electrode Roboocyte voltage fixation system (Multichannelsystem). After an initial equilibration period of 1.5 min, GABA was added over 1.5 min at a concentration inducing approximately 20% of the maximum current response (EC20). After another rest interval of 2.5 minutes, GABA was added again, causing a response of similar amplitude and shape. 0.5 min after the start of this second application of GABA, the test compound at a concentration of about 30 times its Ki was added while GABA was still present. Current traces were recorded at a sampling rate of 10 Hz during and shortly before and after GABA application.

Each compound and concentration was tested on at least 3 oocytes. Different oocytes were used for different compound concentrations. β-CCM, negative allosteric modulator, or Midazolam, positive allosteric modulator, was tested on multiple (3-6) oocytes per 96-well plate as a positive control at maximum efficacy. β-CSM reduced the current induced by GABA by about 50% (increase, times ~ 0.5), while Midazolam increased the current caused by GABA by about 150% (increase, times ~ 2.5).

Data analysis

For analysis, the digitized current traces of the first and second GABA responses were superimposed and, if necessary, scaled to equal maximum amplitudes. The ratio between the two responses during the test compound application time interval was calculated point by point. The extremum of the "trace ratio" obtained was taken as the potency ("fold increase") of the compound, expressed as "% modulation of GABA EC20" (100*(fold increase-1)). The results are shown in Table 1.

WO 2009/071476 discloses the reference compound RO-159 as example 159, RO-251 as example 251, RO-272 as example 272 and RO-301 as example 301.

WO 2009/071477 discloses the reference compound RO-094 as Example 94.

Reference examples RE-A and RE-B were prepared as described here.

The reference compounds were also tested for their affinity for the α5β3γ2 GABA _A receptor subtype as well as their efficacy in oocytes overexpressing GABA _A α5β3γ2. The results are shown in Table 2.

The compounds of formula I and their pharmaceutically acceptable salts can be used as drugs (for example, in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered orally, for example, orally (for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, in the form of nasal sprays), rectally (for example, in the form of suppositories) or topically through the eyes (for example, in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can be done parenterally, eg intramuscularly, intravenously or intraocularly (eg in the form of sterile injectable solutions).

The compounds of formula I and their pharmaceutically acceptable salts can be formulated with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical compositions. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as adjuvants for tablets, dragees and hard gelatine capsules.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols, etc.

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

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

Suitable adjuvants for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-liquid and liquid polyols, and the like.

Suitable adjuvants for topical ophthalmic compositions are, for example, cyclodextrins, mannitol, or a variety of other carriers and excipients known in the art.

In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosifiers, stabilizers, wetting agents, emulsifiers, sweeteners, colors, flavors, osmotic salts, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within a wide range and will naturally be adjusted to the individual requirements in each particular case. In general, in the case of oral administration, a suitable daily dose for one individual would be about 0.1 to 20 mg per kg body weight, preferably about 0.5 to 4 mg per kg body weight (e.g. about 300 mg per individual), preferably divided into 1-3 separate doses, which may consist, for example, of equal amounts, if appropriate. In the case of topical administration, the composition may contain 0.001% - 15% by weight of the drug and the required dose, which may be between 0.1 and 25 mg and may be administered either as a single dose per day or per week or multiple doses (2-4) per day , or multiple doses per week. However, it is clear that the above upper and lower values can be extended if necessary.

Preparation of pharmaceutical compositions containing compounds of the invention:

Tablets of the following composition are produced in the usual way:

Manufacturing technique

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable grinding equipment.

4. Ingredient 5 is added and mixed for three minutes; pressed on a suitable press.

Produce capsules of the following composition:

Manufacturing technique

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 in suitable capsules.

The compound of formula I, lactose and starch are first mixed in a mixer and then in a grinder. The mixture is returned to the mixer; talc is added there and thoroughly mixed. The mixture is filled into suitable capsules by means of an apparatus, for example hard gelatine capsules.

Produce solutions for injection of the following composition:

The present invention is illustrated by Examples, which are non-limiting.

In the case where the formulations are obtained as a mixture of enantiomers, the pure enantiomers may be obtained by the methods described herein or by methods known to those skilled in the art such as chiral chromatography or crystallization.

Examples

Structural block A

(5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol

a) (3E)-6-methylpyridine-3-carbaldehyde oxime

To a solution of 6-methylnicotinaldehyde (9.86 g, 77.3 mmol) in methanol (35 mL) was added hydroxylamine (50 wt % in water, 5.93 mL, 101 mmol) under nitrogen. The resulting suspension was stirred for 3 hours at 40° C. and for 20 hours at room temperature. Concentration by rotary evaporation under reduced pressure gave the title compound (10.89 g, 98%) as a grey-white precipitate. MS (ESI): 137.0 ([M+H] ⁺ ).

b) ethyl 5-methyl-3-(6-methylpyridin-3-yl)isoxazole-4-carboxylate

N-chlorosuccinimide (11.7 g, 88.0 mmol) was added to a solution of (E)-6-methylnicotinaldehyde oxime (10.89 g, 80.0 mmol) in DMF (95 ml) at 6°C. After the addition, the color of the reaction mixture changed from yellow to orange and the reaction mixture 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 again cooled to 6°C, then (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (17.6 g, 96.0 mmol) was added and the reaction mixture was stirred at 50°C overnight. After cooling to room temperature, water (95 ml) was added dropwise and the resulting brown suspension was filtered through a schott funnel. The residue was washed with water then dried under high vacuum to give the title compound (11.80 g, 60%) as a brown precipitate. MS (ESI): 247.1 ([M+H] ⁺ ).

c) (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol

LiAlH ₄ (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 stirred for an additional 50 minutes before being quenched by adding aqueous NaOH (15 wt.%, 2.61 ml). The reaction mixture was stirred for 30 min at room temperature before adding water (7.8 ml). After stirring for 1 hour, the resulting suspension was filtered through a schott funnel and the residue was washed with THF (20 ml) to give the title compound (9.08 g, 93%) as an orange precipitate. MS (ESI): 205.1 ([M+H] ⁺ ).

Structural block B

(5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol

a) ethyl 5-ethyl-3-(6-methylpyridin-3-yl)isoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, (E)-6-methylnicotinaldehyde oxime, using ethyl 3-(pyrrolidin-1-yl)pent-2-enoate instead of (E)-ethyl 3-(pyrrolidin-1-yl) but-2-enoate was converted to the title compound (1.81 g, 63%) which was obtained as a yellow oil. MS (ESI): 261.3 ([M+H] ⁺ ).

b) (5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol

By analogy with the experiment for the structural block A c, ethyl 5-ethyl-3-(6-methylpyridin-3-yl)isoxazole-4-carboxylate instead of ethyl 5-methyl-3-(6-methylpyridin-3-yl)isoxazol- The 4-carboxylate was converted to the title compound (1.44 g, 95%) which was obtained as an orange precipitate. MS (ESI): 219.2 ([M+H] ⁺ ).

Structural block C

(5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol

a) ethyl 4-fluoro-3-oxo-butanoate

To a stirred solution of ethyl acetate (9.59 g, 10.7 ml, 109 mmol) in anhydrous Et ₂ O (100 ml) under argon at -78°C (CO ₂ -acetone bath) was added LDA (2.0 M solution in cyclohexane /ethylbenzene/THF, 59 ml, 118 mmol). The reaction 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 minutes. The CO2-acetone bath was removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was slowly poured into cold aqueous HCl (10 wt.%, 100 ml) and was extracted with Et ₂ O (3×50 ml). The combined organic extracts were washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered and evaporated at 35° C. by rotary evaporation under reduced pressure (650 mbar-200 mbar). The resulting colorless liquid was purified by distillation under reduced pressure using a 30 cm Vigreux column. Collection of fractions at 13 mbar at 71° C. (evaporating temperature) gave the title compound (12.67 g, 86.4%) as a colorless liquid. MS (ESI): 149.1 ([M+H] ⁺ ).

b) ethyl 5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazole-4-carboxylate

N-chlorosuccinimide (1.10 g, 8.08 mmol) was added to a stirred solution of (E)-6-methylnicotinaldehyde oxime (1.00 g, 7.34 mmol) in anhydrous THF (6.7 mL) at 6°C. 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 (chloro-oxime) was dissolved in EtOH (6.7 ml) and stirred at room temperature for 30 min. In a separate flask, Et ₃ N (2.05 ml, 14.7 mmol) was added to a solution of ethyl 4-fluoro-3-oxobutanoanate (1.65 g, 7.34 mmol) in THF (6.6 ml) and the resulting suspension was stirred at room temperature. After 30 minutes, the suspension was cooled to 0°C and the previously prepared suspension of chloroxime in EtOH was slowly added via cannula. The resulting yellow suspension was stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc (100 ml) and the organic phase was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 50% EtOAc in heptane) gave the title compound (1.1 g, 57%) as a white precipitate. MS (ESI): 265.2 ([M+H] ⁺ ).

c) (5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol

DIBAL- H (1.0 M in toluene, 1.84 ml, 1.84 mmol). The reaction mixture was stirred at -78°C for 30 min before being extinguished by adding EtOAc (0.5 ml). After 15 min the reaction mixture was allowed to warm to 0°C and saturated aqueous NaHCO ₃ (5 ml) was added. The mixture was stirred vigorously for 20 min, then diluted with EtOAc (30 ml) and the organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 100% EtOAc in heptane) gave the title compound (193 mg, 57%) as a white precipitate. MS (ESI): 223.2 ([M+H] ⁺ ).

Structural block D

(5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol

a) ethyl 5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, (E)-6-methylnicotinaldehyde oxime, using (Z)-ethyl 3-cyclopropyl-3-(pyrrolidin-1-yl)acrylate instead of (E)-ethyl 3-(pyrrolidin- 1-yl)but-2-enoate was converted to the title compound (0.215 g, 43%) which was obtained as a yellow oil. MS (ESI): 273.2 ([M+H] ⁺ ).

b) (5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol

By analogy with the experiment for the structural block A c, ethyl 5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-carboxylate instead of ethyl 5-methyl-3-(6-methylpyridin-3-yl)isoxazol- The 4-carboxylate was converted to the title compound (0.52 g, 83%) which was obtained as a yellow precipitate. MS (ESI): 231.2 ([M+H] ⁺ ).

Structural block E

(5-methyl-3-(6-(trifluoromethyl)-3-pyridyl)isoxazol-4-yl)methanol

a) (3E)-6-(trifluoromethyl)pyridine-3-carbaldehyde oxime

By analogy with the experiment for building block A a, 6-(trifluoromethyl)pyridine-3-carboxaldehyde was converted instead of 6-methylnicotinaldehyde into the title compound (10.94 g, 96%), which was obtained as a light yellow precipitate. MS (ESI): 191.1 ([M+H] ⁺ ).

b) ethyl 5-methyl-3-(6-(trifluoromethyl)-3-pyridyl)isoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate, using (3E)-6-(trifluoromethyl)pyridine-3-carbaldehyde oxime instead of (E) -6-methylnicotinaldehyde oxime was converted to the title compound (7.95 g, 96%) which was obtained as a yellow precipitate. MS (ESI): 301.1 ([M+H] ⁺ ).

c) 5-methyl-3-(6-(trifluoromethyl)-3-pyridyl)isoxazole-4-carboxylic acid

To a stirred solution of ethyl 5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-carboxylate (5.91 g, 19.7 mmol) in a mixture of THF (21 ml), MeOH (21 ml) and water ( 21 ml) LiOH⋅H ₂ O monohydrate (2.03 g, 48.4 mmol) was added at 0°C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was again cooled to 0°C, then acidified with aqueous citric acid (5 wt.%) to pH~5 (precipitate formed). Organic solvents were removed by rotary evaporation under reduced pressure. The resulting aqueous suspension was cooled to 0°C, then filtered on a funnel with a Schott filter. The collected precipitate was washed with ice water (50 ml) and dried under high vacuum to give the title compound (4.88 g, 91% yield) as a light yellow precipitate. MS (ESI): 273.1 ([M+H] ⁺ ).

d) (5-methyl-3-(6-(trifluoromethyl)-3-pyridyl)isoxazol-4-yl)methanol

By analogy with the experiment for the structural block H c, 5-methyl-3-(6-(trifluoromethyl)-3-pyridyl)isoxazole-4-carboxylic acid instead of 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylic the acids were converted to the title compound (3.87 g, 84%) which was obtained as a light yellow precipitate. MS (ESI): 259.1 ([M+H] ⁺ ).

Structural block F

(3-(6-chloro-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

a) (E)-6-chloronicotinaldehyde oxime

Hydroxylamine hydrochloride (73.6 mg, 1.06 mmol) and tribasic potassium phosphate (75 mg, 0.353 mmol) were added to a solution of 6-chloronicotinaldehyde (100 mg, 0.706 mmol) in acetonitrile (1 mL). The mixture was stirred at room temperature for 30 min before water (0.2 ml) was added. After 1 hour, the resulting suspension was diluted with water (5 ml) and the precipitate was collected by filtration on a Schott funnel, then dried under vacuum to give the title compound (57 mg, 51%) as a white precipitate. MS(ESI): 157.0([M+H] ⁺ ).

b) ethyl 3-(6-chloropyridin-3-yl)-5-methylisoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate, using (E)-6-chloronicotinaldehyde oxime instead of (E)-6-methylnicotinaldehyde oxime, converted to the title compound (92 mg, 78%) which was obtained as a white precipitate. MS (ESI): 267.1 ([M+H] ⁺ ).

c) (3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methanol

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 cooled back to 0° C. (ice bath) and quenched by addition of aqueous Na/K tartrate (10 wt%, 7 ml). The mixture was stirred vigorously at room temperature (ice bath removed) for 30 minutes, then diluted with EtOAc (10 ml). After addition of aqueous NH ₄ Cl (20 wt.%, 3 ml) and aqueous HCl (1.0 m, 1 ml) the aqueous layer was separated and was extracted with EtOAc (2×15 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 100% EtOAc in heptane) gave the title compound (48 mg, 74%) as a white precipitate. MS (ESI): 225.0 ([M+H] ⁺ ).

Structural block G

(3-(6-chloro-3-pyridyl)-5-cyclopropyl-isoxazol-4-yl)methanol

a) ethyl 3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, (E)-6-chloronicotinaldehyde oxime, using (Z)-ethyl 3-cyclopropyl-3-(pyrrolidin-1-yl)acrylate instead of (E)-ethyl 3-(pyrrolidin- 1-yl)but-2-enoate was converted to the title compound (317 mg, 85%) which was obtained as a light yellow precipitate. MS (ESI): 293.1 ([M+H] ⁺ ).

b) (3-(6-chloro-3-pyridyl)-5-cyclopropyl-isoxazol-4-yl)methanol

By analogy with the experiment for the structural block F c, ethyl 3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazole-4-carboxylate instead of ethyl 3-(6-chloropyridin-3-yl)-5-methylisoxazol-4- the carboxylate was converted to the title compound (177 mg, 82%) which was obtained as a light yellow precipitate. MS (ESI): 251.1 ([M+H] ⁺ ).

Structural block H

(3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol

a) ethyl 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, (E)-6-methylnicotinaldehyde oxime, using ethyl (E)-3-(dimethylamino)prop-2-enoate instead of (E)-ethyl 3-(pyrrolidin-1-yl) but-2-enoate was converted to the title compound (2.45 g, 57%) which was obtained as a light brown oil. MS (ESI): 233.1 ([M+H] ⁺ ).

b) 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylic acid

By analogy with the experiment for the structural block E c, ethyl 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylate instead of ethyl 5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4 α-carboxylate was converted to the title compound (1.48 g, 70%) which was obtained as a grey-white precipitate. MS (ESI): 205.0 ([M+H] ⁺ ).

c) (3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol

To a stirred suspension of 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylic 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 schott funnel and the collected precipitate was washed with a minimum amount of THF. The filtrate was again cooled to -15°C (NaCl/ice bath) and a solution of NaBH ₄ (686 mg, 18.1 mmol) in water (16 ml) was added dropwise. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Additional NaBH ₄ (137 mg, 3.62 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding aqueous NaOH (2.0 M, 30 ml), then was extracted with EtOAc (2×160 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 100% EtOAc in heptane) gave the title compound (606 mg, 44%) as a grey-white precipitate. MS (ESI): 191.1 ([M+H] ⁺ ).

Structural block I

(5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol

a) (E)-6-methylpyridazine-3-carbaldehyde oxime

To a stirred solution of 6-methylpyridazine-3-carbaldehyde (880 mg, 7.21 mmol) in EtOH (1.25 mL) was added hydroxylamine hydrochloride (551 mg, 7.93 mmol) followed by aqueous NaOH (2.0 M, 9.2 mL, 18.4 mmol). The reaction mixture 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 under high vacuum to give the title compound (943 mg, 95%) as a gray-white precipitate . MS (ESI): 138.1 ([M+H] ⁺ ).

b) ethyl 5-methyl-3-(6-methylpyridazin-3-yl)isoxazole-4-carboxylate

By analogy with the experiment for building block A b, (E)-6-methylpyridazine-3-carbaldehyde oxime was converted instead of (E)-6-methylnicotinaldehyde oxime to the title compound (1.15 g, 67%), which was obtained as brown oil. MS (ESI): 248.1 ([M+H] ⁺ ).

c) (5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol

Ethyl 5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4 -carboxylate (1.0 g, 4.04 mmol) followed by NaBH ₄ (1.22 g, 32.4 mmol, added in portions). The mixture was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature and stirred for an additional 1 hour. The reaction mixture was again cooled to 0°C and extinguished by adding saturated aqueous NH ₄ Cl. Organic solvents were removed by rotary evaporation under reduced pressure, and the resulting aqueous layer was extracted with CH ₂ Cl ₂ (2×50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 20% to 100% EtOAc in heptane) gave the title compound (407 mg, 49%) as a yellow precipitate. MS (ESI): 206.1 ([M+H] ⁺ ).

Building Block J

(5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol

a) (Z)-4,4-difluoro-3-pyrrolidin-1-yl-but-2-enoate

To a stirred solution of ethyl 4,4-difluoro-3-oxobutanoanate (1.6 ml, 15.5 mmol) in cyclohexane (11 ml) was added pyrrolidine (1.4 ml, 16.9 mmol). The reaction mixture was heated to 110° C. overnight using a Dean Stark trap before being cooled to room temperature. The reaction mixture was immediately filtered through a pad of Na ₂ SO ₄ and the filtrate was concentrated in vacuo to give the title compound (2.49 g, 62%) as a brown oil. MS (ESI): 220.2 ([M+H] ⁺ ).

b) ethyl 5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole-4-carboxylate

By analogy with the experiment for structural block A b, (3E)-6-methylpyridine-3-carbaldehyde oxime, using ethyl (Z)-4,4-difluoro-3-pyrrolidin-1-yl-but-2-enoate instead of ( E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate was converted to the title compound (362 mg, 58%) which was obtained as an orange oil. MS (ESI): 283.2 ([M+H] ⁺ ).

c) (5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol

DIBAL- H (1.0 m in toluene, 3.2 ml, 3.2 mmol). The reaction mixture was stirred at -78°C for 3.5 hours before adding additional DIBAL-H (1.0 M in toluene, 0.78 ml, 0.78 mmol). After 1.5 hours, the reaction mixture was carefully quenched by adding 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 (2×40 ml). The combined organic extracts were washed with water (5 ml) and brine (5 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 70% EtOAc in heptane) gave the title compound (165 mg, 44%) as a light yellow precipitate. MS (ESI): 241.1 ([M+H] ⁺ ).

Structural block K

(3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

a) (Z)-N-((6-bromopyridin-3-yl)methylidene)hydroxylamine

To a stirred solution of hydroxylamine hydrochloride (11.0 g, 161 mmol) in EtOH (300 mL) was added triethylamine (33.0 mL, 242 mmol) and the reaction mixture was stirred at room temperature for 30 min before adding 6-bromo-pyridine-3-carbaldehyde ( 15.0 g, 80.6 mmol). The reaction mixture was heated at the boil under reflux for 1 hour, then all volatile components were removed by rotary evaporation under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, 10% EtOAc in hexane) gave the title compound (12.5 g, 77%) as a white precipitate. MS (ESI): 201.3 ([M+H] ⁺ ).

b) ethyl 3-(6-bromo-3-pyridyl)-5-methyl-isoxazole-4-carboxylate

Similar to the experiment for building block A b, (Z)-N-((6-bromopyridin-3-yl)methylidene)hydroxylamine instead of (E)-6-methylnicotinaldehyde oxime was converted to the title compound (16 g, 86%) which was obtained as a brown oil. MS (ESI): 311.0 ([M+H] ⁺ ).

c) ethyl 3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazole-4-carboxylate

A round bottom flask was filled with ethyl 3-(6-bromo-3-pyridyl)-5-methyl-isoxazole-4-carboxylate (8.00 g, 25.7 mmol), cyclopropylboronic acid (8.80 g, 102 mmol), K ₃ PO ₄ (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 alternately evacuating and backfilling with argon with argon. A pre-degassed 10:1 toluene/water solution (264 ml) was added and the resulting mixture was purged with argon for 15 minutes. The reaction mixture was stirred at 100°C for 3 hours before being cooled to room temperature and filtered immediately through a pad of celite. The filter cake was washed with EtOAc and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica gel, 10% EtOAc in hexanes) gave the title compound (5.5 g, 78%) as a yellow precipitate. MS (ESI): 272.7 ([M+H] ⁺ ).

d) (3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

LiAlH ₄ ( 1.0 m in THF, 13.7 ml, 13.7 mmol). After 30 minutes, the reaction mixture was allowed to warm to 0° C. before being quenched by the addition of sodium sulfate decahydrate. The reaction mixture was filtered immediately through a pad of celite. The filter cake was washed with EtOAc and the filtrate concentrated in vacuo to give the title compound (1.8 g, 81%) as a grey-white precipitate. MS (ESI): 236.1 ([M+H] ⁺ ).

Structural block L

(5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol

ethyl 5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazole-4-carboxylate

By analogy with the experiment for the structural block A b, 6-methylpyridazin-3-carbaldehyde oxime, using ethyl 3-cyclopropyl-3-(pyrrolidin-1-yl)acrylate instead of (E)-ethyl 3-(pyrrolidin-1-yl) but-2-enoate was converted to the title compound (352 mg, 42%) which was obtained as an orange oil. MS (ESI): 274.1 ([M+H] ⁺ ).

5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazole-4-carboxylic acid

By analogy with the experiment for the structural block E c, ethyl 5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-carboxylate instead of ethyl 5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl )isoxazole-4-carboxylate was converted to the title compound (260 mg, 95%) which was obtained as an orange precipitate. MS (ESI): 246.1 ([M+H] ⁺ ).

(5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol

By analogy with the experiment for the Hc structural block, 5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazole-4-carboxylic acid was converted instead of 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylic acid to the title compound (85 mg, 47%) which was obtained as an orange precipitate. MS (ESI): 232.1 ([M+H] ⁺ ).

Structural block M

(3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

a) (3E)-6-methoxypyridine-3-carbaldehyde oxime

To a stirred suspension of 6-methoxypyridine-3-carbaldehyde (1.50 g, 10.9 mmol) in ethanol (2 ml) was added ice-cold water (11 ml) and hydroxylamine hydrochloride (836 mg, 12 mmol) under argon. After 10 min, aqueous NaOH (2.0 m, 13.9 ml, 27.9 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The resulting colorless solution was treated with acetic acid to pH~5 (a white precipitate formed). The resulting precipitate was collected by filtration and dried under high vacuum to give the title compound (1.47 g, 88%) as a white precipitate. MS (ESI):153.1 ([M+H] ⁺ ).

b) ethyl 3-(6-methoxy-3-pyridyl)-5-methyl-isoxazole-4-carboxylate

N-chlorosuccinimide (1.4 g, 10.5 mmol) was added to a stirred solution of (3E)-6-methoxypyridine-3-carbaldehyde oxime (1.45 g, 9.53 mmol) in DMF (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 3.5 hours before (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (2.1 g, 11.4 mmol) was added. The mixture was heated to 50° C. overnight to give 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 (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 30% EtOAc in heptane) gave the title compound (2.31 g, 92%) as a light brown precipitate. MS (ESI): 263.1 ([M+H] ⁺ ).

c) (3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

To a stirred solution of ethyl 3-(6-methoxy-3-pyridyl)-5-methyl-isoxazole-4-carboxylate (2.3 g, 8.77 mmol) in anhydrous THF (30 ml) at 0°C was added under argon and in portions LiAlH ₄ (466 mg, 12.3 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours before being cooled back to 0° C. and carefully quenched by adding water (0.5 ml). After gas evolution 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 hour. 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 gel, gradient: 0% to 5% MeOH in CH ₂ Cl ₂ ) to give the title compound (1.44 g, 75%) as a yellow precipitate. MS (ESI ): 221.2 ([M+H] ⁺ ).

Structural block N

(3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

a) (3E)-6-(dimethylamino)pyridine-3-carbaldehyde oxime

To a stirred suspension of 6-(dimethylamino)pyridine-3-carbaldehyde (1.71 g, 11.4 mmol) in ethanol (2 mL) was added ice-cold water (11 mL) and hydroxylamine hydrochloride (871 mg, 12.5 mmol) under argon. 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 colorless solution was treated with acetic acid to pH ~ 5 (a white precipitate formed) then diluted with water (15 ml). After stirring for 15 minutes, the precipitate was collected by filtration on a sintered glass funnel, washed with water and dried under high vacuum. The resulting precipitate was triturated in a 1:1 mixture of CH ₂ Cl ₂ and heptane (30 ml), then filtered and dried to give the title compound (1.54 g, 82%) as a grey-white precipitate. MS (ESI): 166.2 ([M+H] ⁺ ).

b) ethyl 3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazole-4-carboxylate

N-chlorosuccinimide (0.967 g, 7.24 mmol) was added to a stirred solution of (3E)-6-(dimethylamino)pyridine-3-carbaldehyde oxime (1.09 g, 6.58 mmol) in DMF (15 mL) at room temperature. The reaction mixture was heated to 50°C for 3 hours before being cooled back to room temperature and (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (1.45 g, 7.9 mmol) was added in one portion. The mixture was heated again to 50° C. overnight to give a clear brown solution. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml) and washed with water (50 ml) and brine (50 ml), dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 50% EtOAc in heptane) gave the title compound (0.632 g, 33%) as a yellow precipitate. MS (ESI): 276.2 ([M+H] ⁺ ).

c) (3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol

To a stirred solution of ethyl 3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazole-4-carboxylate (220 mg, 0.799 mmol) in anhydrous THF (5 ml) at 0°C was carefully added under argon LiAlH ₄ (42.5 mg, 1.12 mmol). The reaction mixture was stirred for 2 hours before being carefully quenched by adding water (0.05 ml). After gas evolution 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 suspension was filtered and the filter residue was washed with THF. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) to give the title compound (140 mg, 75%) as a gray-white precipitate. MS (ESI): 234.2 ([M+H] ⁺ ).

Structural block O

(3-(5-fluoro-6-methylpyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methanol

a) (3E)-5-fluoro-6-methyl-pyridine-3-carbaldehyde oxime

To a stirred suspension of 5-fluoro-6-methyl-pyridine-3-carbaldehyde (450 mg, 3.23 mmol) in ethanol (0.7 ml) was added ice-cold water (4.3 ml) and hydroxylamine hydrochloride (247 mg, 3.56 mmol) under argon. ). 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 colorless solution was treated with acetic acid to pH~5 (a white precipitate formed). After stirring for 15 minutes, the precipitate was collected by filtration on a sintered glass funnel, washed with water and dried under high vacuum to give the title compound (383 mg, 77%) as a white precipitate. MS (ESI): 155.1 ([M+H] ⁺ ).

b) ethyl 3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazole-4-carboxylate

To a stirred solution of (3E)-5-fluoro-6-methyl-pyridine-3-carbaldehyde oxime (380 mg, 2.47 mmol) in DMF (5 mL) was added N-chlorosuccinimide (329 mg, 2.47 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3.5 hours before (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (452 mg, 2.47 mmol) was added. The mixture was heated to 50° C. overnight to give a clear brown solution. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml) and washed with water (50 ml) and brine (50 ml), dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 30% EtOAc in heptane) gave the title compound (475 mg, 73%) as a light brown precipitate. MS (ESI): 265.2 ([M+H] ⁺ ).

c) (3-(5-fluoro-6-methylpyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methanol

Water was carefully added to a stirred solution of ethyl 3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazole-4-carboxylate (470 mg, 1.78 mmol) in anhydrous THF (10 ml) at 0°C. LiAlH ₄ (94.5 mg, 2.49 mmol) in an argon atmosphere. The reaction mixture was allowed to warm to room temperature for 2 hours before being cooled back to 0° C. and carefully quenched by adding water (0.1 ml). After gas evolution ended, aqueous 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 and the filter residue was washed with THF. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient: 0% to 5% MeOH in CH ₂ Cl ₂ ) to give the title compound (221 mg, 56%) as a yellow precipitate. MS (ESI): 223.2 ([M+H] ⁺ ).

Structural block P

(5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol

a) ethyl (E)-4-fluoro-3-pyrrolidin-1-yl-but-2-enoate

To a stirred solution of ethyl 4-fluoro-3-oxo-butanoate (1.0 g, 6.75 mmol) in cyclohexane (10 ml) was added dropwise (caution: exothermic) pyrrolidine (0.60 ml, 7.22 mmol) followed by a catalytic amount of p-toluenesulfonic acid monohydrate (64.2 mg, 0.338 mmol). The mixture was stirred at room temperature for 30 minutes, then the flask was fitted with a Dean Stark trap and heated at reflux overnight.

The reaction mixture was cooled to room temperature, and all volatile components were removed by rotary evaporation under reduced pressure. The resulting crude residue (orange oil) was used directly in the next step without further purification.

b) ethyl 5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazole-4-carboxylate

N-chlorosuccinimide (375 mg, 2.81 mmol) was added to a stirred suspension of (E)-6-methylpyridazine-3-carbaldehyde oxime (350 mg, 2.55 mmol) in DMF (5 mL) at 6°C. After the addition, the color of the reaction mixture changed from yellow to orange and the reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was heated to 50°C for 2 hours. The resulting brown suspension was cooled again to 6°C, then a solution of ethyl (E)-4-fluoro-3-pyrrolidin-1-yl-but-2-enoate (685 mg, 3.06 mmol, 90% purity) 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 mixture was diluted with water (20 ml) and was extracted with EtOAc (3×40 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 50% EtOAc in heptane) gave the title compound (498 mg, 74%) as an orange oil. MS (ESI): 266.1 ([M+H] ⁺ ).

c) (5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol

DIBAL- H (1.0 m in toluene, 5.63 ml, 5.63 mmol). The reaction mixture 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 extinguished by adding aqueous NaOH (1.0 m, 15 ml) followed by EtOAc (20 ml). The mixture was diluted with water (20 ml) and extracted with EtOAc (3×40 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 100% EtOAc in heptane) gave the title compound (105 mg, 25%) as a light yellow powder. MS (ESI): 224.2 ([M+H] ⁺ ).

Example 1

6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

a) methyl 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

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 minutes before being cooled back to 0°C. Methyl 6-chloronicatanate (1.28 g, 7.49 mmol) was added over a period of 5 minutes and the reaction mixture was stirred for 5 hours. The reaction mixture was poured into a mixture of aqueous citric acid (5 wt.%, 30 ml) and ice, then was extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 30% to 100% EtOAc in heptane) gave the title compound (2.07 g, 90%) as a light yellow precipitate. MS (ESI): 340.2 ([M+H] ⁺ ).

b) 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

Trimethylaluminum (2.0 M solution in heptane, 0.60 ml, 1.2 mmol) was added dropwise to a stirred solution of tetrahydropyran-4-amine (119 mg, 1.18 mmol) in anhydrous 1,4-dioxane (10 mL) at room temperature. After 1 hour, a solution of methyl 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate (100 mg, 0.295 mmol) in anhydrous 1,4- dioxane (5 ml) was added dropwise. The reaction mixture was heated to 90°C for 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 minutes of vigorous stirring, the reaction mixture was extracted with dichloromethane (2×30 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 3% MeOH in CH ₂ Cl ₂ ) gave the title compound (89 mg, 74%) as a white solid MS (ESI): 409.4 ([M+H ] ⁺ ).

Example 2

N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 1b, methyl 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate using cyclopropylmethanamine instead of tetrahydropyran-4-amine, was converted to the title compound (60 mg, 54%) which was obtained as a white precipitate. MS (ESI): 379.4 ([M+H] ⁺ ).

Example 3

N-ethyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 1b, methyl 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate, using ethylamine instead of tetrahydropyran-4-amine, was converted to the title compound (62 mg, 60%) which was obtained as a white precipitate. MS (ESI): 353.3 ([M+H] ⁺ ).

Example 4

(S)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide

a) 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

To a stirred solution of methyl 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate (1.43 g, 3.49 mmol, 83% purity) in THF (10 ml), MeOH (10 ml) and water (10 ml) were added LiOH (335 mg, 14.0 mmol). The reaction mixture was stirred at room temperature for 2 hours before being quenched by adding an aqueous citric acid solution (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 glass funnel and the collected precipitate was washed with ice water (2×10 ml) and dried under high vacuum to give the title compound (1.08 g, 95%) as a white precipitate. MS (ESI): 326.1 ([M+H] ⁺ ).

b) (S)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide

To a stirred solution of 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid (92 mg, 0.284 mmol) and (S)-2- aminopentan-1-ol (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 (2×20 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, gradient: 95% to 100% EtOAc in heptane, then 5% MeOH in EtOAc) to give the title compound (67 mg, 57%) as a gray-white precipitate. . MS (ESI): 411.3 ([M+H] ⁺ ).

Example 5

6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide

a) methyl 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 1a, (5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block D) instead of (5-methyl-3-(6-methylpyridin-3- yl)isoxazol-4-yl)methanol (building block A) was converted to the title compound (632 mg, 71%) which was obtained as a light yellow oil. MS (ESI): 366.2 ([M+H] ⁺ ).

b) 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 4a, methyl 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (632 mg, 71%) which was obtained as a white precipitate. MS (ESI): 352.2 ([M+H] ⁺ ).

c) 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid was converted to the title compound (96 mg, 96%) which was obtained as a white precipitate. MS (ESI): 437.2 ([M+H] ⁺ ).

Example 6

6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using tetrahydropyran-4-amine instead of (S)-2-aminopentan-1-ol, was converted to the compound indicated in title (64 mg, 63%) which was obtained as a white precipitate. MS (ESI): 435.3 ([M+H] ⁺ ).

Example 7

(S)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

a) methyl 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

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-chloropyridazine-3-carboxylate (187 mg, 1.08 mmol) was added and the reaction mixture was kept at 0° C. overnight using a melting ice bath. After adding more methyl 6-chloropyridazine-3-carboxylate (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 again cooled to room temperature then poured into ice water and extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, gradient: 5% to 100% EtOAc in heptane, then 5% MeOH in EtOAc) to give the title compound (132 mg, 47%) as a gray-white precipitate. . MS (ESI): 341.1 ([M+H] ⁺ ).

b) (S)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

To a stirred solution of methyl 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate (70 mg, 0.206 mmol) in toluene (0.5 ml) was added in an argon atmosphere (S)-2-aminopentan-1-ol (25.5 mg, 0.247 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (17.2 mg, 0.123 mmol). The reaction mixture was stirred at room temperature for 6 hours before additional (S)-2-aminopentan-1-ol (25.5 mg, 0.247 mmol) was added. After 16 hours, the resulting solution was concentrated in vacuo to give a brown oil which was purified by flash chromatography (silica gel, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) to give the title compound (45 mg, 43 %) as a gray-white precipitate. MS (ESI): 412.3 ([M+H] ⁺ ).

Example 8

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 4b, methyl 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using tetrahydropyran-4-amine instead of (S)-2-aminopentan-1-ol, was converted to the compound indicated in title (6 mg, 8%), which was obtained as a gray-white precipitate. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 9

2-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

a) 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one

To a suspension of 6-chloro-4-formylnicotinic acid (520 mg, 2.8 mmol) in acetic acid (1.12 ml, 19.6 mmol) was added isobutylamine (0.323 ml, 3.22 mmol) under nitrogen -dioxane, 0.771 ml, 3.08 mmol) and sodium triacetoxyborohydride (891 mg, 4.2 mmol). The reaction mixture was stirred at room temperature for 18 hours, then heated to 60°C for 5 hours. After this time, the second part 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 an additional 18 hours. The mixture was diluted with EtOAc (30 ml) and the organic layer was washed with aqueous Na ₂ CO ₃ (1.0 m solution, 30 ml), water (30 ml) and brine (30 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the title compound as a white solid (438 mg, 70%). MS (ESI): 410.3 ([M+H] ⁺ ).

b) 2-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine-3(2H) -he

A round bottom flask was filled with (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A, 107 mg, 0.524 mmol), 6-chloro-2-isobutyl-1H-pyrrolo[ 3,4-c]pyridin-3(2Н)-one (177 mg, 0.786 mmol), Cs ₂ CO ₃ (333 mg, 1.02 mmol), rac-2-(di-tert-butylphosphino)-1,1' -binaphthyl (20.9 mg, 52.4 µmol) and Pd(OAc) ₂ (9.41 mg, 41.9 µmol). The flask was degassed by alternately evacuating and backfilling with argon before adding anhydrous toluene (2.0 ml). The mixture was purged with argon for 15 minutes, then stirred at 90° C. for 18 hours before being concentrated in vacuo. The resulting crude brown oil was purified by flash chromatography (silica gel, gradient: 30% to 100% EtOAc in heptane) to give the title compound (166 mg, 81%) as a white precipitate. MS (ESI): 393.2 ([M+H] ⁺ ).

Example 10

2-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

a) 6-chloro-2-methyl-1H-pyrrolo[3,4-c]pyridin-3-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using methylamine instead of isobutylamine, was converted to the title compound (408 mg, 69%), which was obtained as a light yellow precipitate. MS (ESI): 183.0 ([M+H] ⁺ ).

b) 2-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine-3(2H) -he

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol using 6-chloro-2-methyl-1H-pyrrolo[3,4-c] pyridin-3-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the title compound (89 mg, 78%) which was obtained as white foam. MS (ESI): 351.2 ([M+H] ⁺ ).

Example 11

N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using isobutylamine instead of (S)-2- aminopentan-1-ol was converted to the title compound (67 mg, 74%) which was obtained as a white precipitate. MS (ESI): 381.2 ([M+H] ⁺ ).

Example 12

2-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine-3( 2Н)-one

a) 6-chloro-2-(2-hydroxyethyl)-1H-pyrrolo[3,4-c]pyridin-3-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using 2-aminoethanol instead of isobutylamine, was converted to the title compound (466 mg, 81%), which was obtained as a white precipitate. MS (ESI): 213.1 ([M+H] ⁺ ).

b) 2-(6-chloro-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)ethyl acetate

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 give the title compound (369 mg, 100%, 87% purity) as a white precipitate. MS (ESI): 255.0 ([M+H] ⁺ ).

c) 2-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine- 3(2Н)-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) using 2-(6-chloro-3-oxo-1H- pyrrolo[3,4-c]pyridin-2-yl)ethyl acetate instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the title compound (12 mg , 12%), which was obtained as a white precipitate. MS (ESI): 381.2 ([M+H] ⁺ ).

Example 13

(S)-2-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3, 4-c]pyridine-3(2Н)-one

a) 6-chloro-2-((1S)-1-(hydroxymethyl)butyl)-1H-pyrrolo[3,4-c]pyridine-3-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using (S)-2-aminopentan-1-ol instead of isobutylamine, was converted to the title compound (693 mg, 100%, 50% purity), which was obtained in the form of a light brown foam. MS (ESI): 253.1 ([M+H] ⁺ ).

b) ((2S)-2-(6-chloro-3-oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)pentyl)acetate

By analogy with the experiment of Example 12b, 6-chloro-2-((1S)-1-(hydroxymethyl)butyl)-1H-pyrrolo[3,4-c]pyridin-3-one instead of 6-chloro-2-(2 -hydroxyethyl)-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the title compound (560 mg, 70%) which was obtained as a white precipitate. MS (ESI): 297.1 ([M+H] ⁺ ).

c) (S)-2-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[ 3,4-c]pyridine-3(2Н)-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A), using ((2S)-2-(6-chloro-3 -oxo-1H-pyrrolo[3,4-c]pyridin-2-yl)pentyl)acetate instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one, converted to compound , indicated in the header (140 mg, 73%), which was obtained as a white foam. MS (ESI): 423.2 ([M+H] ⁺ ).

Example 14

N-((1S)-1-(hydroxymethyl)butyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

a) methyl 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylate

Cs ₂ CO ₃ (491 mg, 1.51 mmol) followed by methyl 5-chloropyrazine-2-carboxylate (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 Na ₂ CO ₃ (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 (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, 30% to 100% EtOAc in heptane) gave the title compound (199 mg, 78%) as a white precipitate MS (ESI): 341.2 ([M+H] ⁺ )

b) 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy]pyrazine-2-carboxylic acid

To a stirred solution of methyl 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazin-2-carboxylate (2.09 g, 6.14 mmol) in THF (17 mL) , MeOH (17 ml) and water (17 ml) LiOH monohydrate (773 mg, 18.4 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes before being quenched by adding an aqueous citric acid solution (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 glass funnel and the collected precipitate was washed with ice water (2×10 ml) and dried under high vacuum to give the title compound (1.47 g, 74%) as a white precipitate. MS (ESI): 327.1 ([M+H] ⁺ ).

c) N-((1S)-1-(hydroxymethyl)butyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

To a stirred solution of 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid (51 mg, 0.16 mmol) and (S)-2- aminopentan-1-ol (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 temperature, then poured into water (20 ml) and extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, gradient: 80% to 100% EtOAc in heptane, then 5% MeOH in EtOAc) to give the title compound (60 mg, 93%) as a white precipitate. MS (ESI): 412.2 ([M+H] ⁺ ).

Example 15

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid, using tetrahydropyran-4-amine instead of (1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (52 mg, 92%) which was obtained as a white precipitate. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 16

N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using 1,1-dioxothiolan-3- amine instead of (S)-2-aminopentan-1-ol was converted to the title compound (66 mg, 80%) which was obtained as a white precipitate. MS (ESI): 443.2 ([M+H] ⁺ ).

Example 17

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide

To a stirred solution of 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid (86.8 mg, 0.267 mmol) in anhydrous DMF (2 mL) 1,1'-carbonyldiimidazole (56.2 mg, 0.347 mmol) was added at room temperature. The reaction mixture was heated to 60°C for 1 hour before being cooled back to room temperature. After 15 min ammonium hydroxide (25 wt.%, 0.416 ml, 2.67 mmol) was added and the reaction mixture was stirred at room temperature. After 1 hour, Isolate® was added and the resulting slurry was dried under vacuum then immediately purified by flash chromatography (silica gel, gradient: 0% to 10% MeOH) to give the title compound (70 mg, 81%), in the form of a white precipitate. MS (ESI): 325.1 ([M+H] ⁺ ).

Example 18

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

To a suspension of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (structural block A, 54 mg, 0.226 mmol) and 6-chloropyridazin-3-carbonitrile (44.3 mg, 0.317 mmol ) in THF (2 mL) was added under nitrogen at room temperature with 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 an additional 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 mixture was quenched by adding an aqueous solution of citric acid (5 wt.%, 2 ml) followed by the addition of 1.0 M aqueous NaHCO ₃ to bring the pH lj ~7. The aqueous layer was extracted with EtOAc (2×30 ml) and the combined organic extracts were washed with saline, dried (MgSO ₄ ) and concentrated under vacuum. Purification by flash chromatography (silica gel, gradient: 0% to 5% MeOH in EtOAc) gave the title compound (17 mg, 20%) as a grey-white precipitate. MS (ESI): 326.1 ([M+H] ⁺ ).

Example 19

N-((3S)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using 1,1-dioxothiolan-3- amine instead of (S)-2-aminopentan-1-ol was converted to the racemic title compound (66 mg, 80%) which was obtained as a white precipitate. MS (ESI): 443.2 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Chiralcel OD) gave the (+)-title compound (16 mg) which was obtained as a white precipitate. MS (ESI): 443.2 ([M+H] ⁺ ).

Example 20

N-((3R)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridine-3-carboxamide

By analogy with the experiment of Example 19, resolution of the enantiomers by chiral HPLC (column: Chiralcel OD) gave the (-)-title compound (16 mg) which was obtained as a white precipitate. MS (ESI): 443.2 ([M+H] ⁺ ).

Example 21

N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridin-3- carboxamide

a) 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydrothiopyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using tetrahydrothiopyran-4-amine instead of (S )-2-aminopentan-1-olo was converted to the title compound (136 mg, 91%) which was obtained as a grey-white precipitate. MS (ESI): 425.2 ([M+H] ⁺ ).

b) N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridine- 3-carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydrothiopyran-4-yl-pyridine-3-carboxamide (122 mg, 0.287 mmol ) in a mixture of MeOH (3 ml) and water (3 ml) at room temperature was added oxon® (353 mg, 0.575 mmol). After 3 hours, the suspension was made basic by adding aqueous Na ₂ CO ₃ (0.5 m, 4 ml) and the mixture was stirred at room temperature for 1 hour. The suspension was filtered through a schott funnel and the collected precipitate was washed with water (5 ml) and TBME (2 ml), then dried under high vacuum to give the title compound (118 mg, 90%) as a white precipitate. MS (ESI): 457.2 ([M+H] ⁺ ).

Example 22

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,4- c]pyridine-3(2Н)-one

a) 6-chloro-2-tetrahydropyran-4-yl-1H-pyrrolo[3,4-c]pyridin-3-one

In analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using tetrahydropyran-4-amine instead of isobutylamine, was converted to the title compound (544 mg, 75%), which was obtained as a white precipitate. MS (ESI): 253.1 ([M+H] ⁺ ).

b) 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3, 4-c]pyridine-3(2Н)-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) using 6-chloro-2-tetrahydropyran-4-yl-1H -pyrrolo[3,4-c]pyridin-3-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the title compound (99 mg, 83%), which was obtained as a white precipitate. MS (ESI): 421.2 ([M+H] ⁺ ).

Example 23

N-((1S,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) 4-((6-chloropyridazin-3-yloxy)methyl)-5-methyl-3-(6-methylpyridin-3-yl)isoxazole

NaH ( 60% dispersion in mineral oil, 4.05 g, 101 mmol). The resulting solution was warmed to room temperature and stirred for 30 minutes before being cooled to 0°C. 3,6-dichloropyridazine (13.9 g, 93.4 mmol) was added over a period of 5 minutes and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into ice water and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 10% to 20% EtOAc in heptane) gave the title compound (18.7 g, 76% yield) as a yellow precipitate. MS (ESI): 317.1 ([M+H] ⁺ ).

b) ethyl 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

Na ₂ CO ₃ (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 slurry was evacuated and then refilled with a stream of CO _(g) (cylinder, 1.3 L) three times before being heated to 50° C. overnight under a CO _(gas) atmosphere. The reaction mixture was immediately filtered through a pad of dicalite and the filter cake was washed with EtOH (200 ml) followed by EtOAc (200 ml). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, gradient: 0% to 20% EtOAc in heptane) to give the title compound (14.8 g, 75%) as a light yellow solid. MS (ESI): 355.2 ([M+H] ⁺ ).

c) 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid

To a stirred solution of ethyl 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate (2.20 g, 6.21 mmol) in THF (7 mL) and MeOH (7 ml) and water (7 ml) were added LiOH⋅H ₂ O (782 mg, 18.6 mmol). The reaction mixture was stirred at room temperature overnight. The pH was adjusted to ~5 by adding aqueous citric acid (5 wt.%), then the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic extracts were washed with water (~20 ml) and brine (~20 ml) and the resulting precipitate precipitated during the reaction was collected by filtration on a Schott funnel. The precipitate was combined with the organic layers and concentrated under vacuum. The residue was triturated with EtOAc, then filtered and dried under high vacuum to give the title compound (1.51 g, 75%) as a gray-white precipitate. MS (ESI): 327.1 ([M+H] ⁺ ).

d) N-((1S,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid (35 mg, 0.107 mmol) and (1R,2S)- 2-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 (3×10 ml). The combined organic extracts were washed with water (3×3 ml), brine (~3 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting precipitate was triturated with TBME and EtOAc, then filtered and dried under high vacuum to give the title compound (39 mg, 86%) as a grey-white precipitate. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 24

N-((1S,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1S,2S)-2- aminocyclohexanol hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (29 mg, 64%) which was obtained as a grey-white precipitate. MS (ESI): 424.2 ([M+H] ⁺ ).

Example 25

N-((1R,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1R,2R)-2- aminocyclohexanol hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (37 mg, 82%) which was obtained as a grey-white precipitate. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 26

N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cyclopropylamine instead of (1R,2S)- 2-aminocyclohexanol hydrochloride was converted to the title compound (51 mg, 80%) which was obtained as a white precipitate. MS (ESI): 366.2 ([M+H] ⁺ ).

Example 27

N-((1R,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1S,2R)-2- aminocyclohexanol hydrochloride instead of (1R,2R)-2-aminocyclohexanol hydrochloride was converted to the title compound (31 mg, 68%) which was obtained as a light brown precipitate. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 28

N-((3S,4R)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (19 mg, 42%) which was obtained as a grey-white foam. MS (ESI): 426.2 ([M+H] ⁺ ).

Example 29

N-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid (35 mg, 0.107 mmol) in DMF (0.75 ml) was added 1,1'-carbonyldiimidazole (23 mg, 0.142 mmol) and the reaction mixture was heated to 60°C for 1 hour. After cooling to room temperature, ethanolamine (65 μl, 0.107 mmol) was added and the mixture was stirred for an additional 2 hours. The reaction mixture was poured into water (~3 ml) and extracted with TBME (2×10 ml). The combined organic extracts were washed with water (3×3 ml), brine (3×3 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The aqueous layers were extracted with CH ₂ Cl ₂ (2×20 ml) and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification of the combined precipitates by flash chromatography (silica gel, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (25 mg, 63%) as a white precipitate. MS (ESI): 370.2 ([M+H] ⁺ ).

Example 30

N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazin-3- carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid (40 mg, 0.123 mmol) and (1,1-dioxidotetrahydro -2H-thiopyran-4-yl)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 cycloanhydride in EtOAc (50 wt.%, 160 mg, 150 µl, 0.252 mmol). The reaction mixture was heated to 50°C overnight before being cooled to room temperature, diluted with EtOAc (~50 ml) and washed with saturated aqueous NaHCO ₃ (2×10 ml). The aqueous layers were extracted with EtOAc (~50 ml). The combined organic extracts were washed with water (~5 ml) and brine (~5 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (40 mg, 68%) as a grey-white precipitate. MS (ESI): 458.2 ([M+H] ⁺ ).

Example 31

N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using (aminomethyl)-cyclopropane instead of ethanolamine, was converted to the title compound (39 mg, 80%) which was obtained as a grey-white precipitate. MS (ESI): 380.2 ([M+H] ⁺ ).

Example 32

N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2-amino-2-methylpropan- 1-ol instead of ethanolamine was converted to the title compound (35 mg, 82%) which was obtained as a white foam. MS (ESI): 398.2 ([M+H] ⁺ ).

Example 33

N-(2-cyanoethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using 3-aminopropionitrile instead of ethanolamine, was converted to the title compound (34 mg, 84%) which was obtained as a grey-white precipitate. MS (ESI): 379.2 ([M+H] ⁺ ).

Example 34

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazin-3 -carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (RS)-1,1, 1-trifluoropropane-2-amine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (19 mg, 42%) which was obtained as a grey-white precipitate. MS (ESI): 422.2 ([M+H] ⁺ ).

Example 35

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using oxetan-3-amine hydrochloride instead of ( 1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (36 mg, 57%) which was obtained as a grey-white precipitate. MS (ESI): 382.2 ([M+H] ⁺ ).

Example 36

(RS)-N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (RS)-1,1- dioxothiolan-3-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (89 mg, 82%) which was obtained as a gray-white precipitate. MS (ESI): 444.2 ([M+H] ⁺ ).

Example 37

N-ethyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using ethylamine (2.0 M in THF) instead of ethanolamine was converted to the title compound (42 mg, 86%) which was obtained as a grey-white precipitate. MS (ESI): 354.2 ([M+H] ⁺ ).

Example 38

N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using isopropylamine instead of ethanolamine, was converted to the compound, indicated in the header (44 mg, 87%), which was obtained as a gray-white precipitate. MS (ESI): 368.2 ([M+H] ⁺ ).

Example 39

N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using isobutylamine instead of ethanolamine, was converted to the compound, indicated in the header (46 mg, 83%), which was obtained as a gray-white precipitate. MS (ESI): 382.2 ([M+H] ⁺ ).

Example 40

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2,2,2-trifluoroethanamine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride, was converted to the title compound (34 mg, 61%), which was obtained as a gray-white precipitate. MS (ESI): 408.2 ([M+H] ⁺ ).

Example 41

N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using tert-butylamine instead of ethanolamine, was converted to the title compound (46 mg, 83%) which was obtained as a grey-white precipitate. MS (ESI): 382.2 ([M+H] ⁺ ).

Example 42

N-(3,3-difluorocyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3,3-difluorocyclobutanmine hydrochloride instead of ( 1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (36 mg, 63%) which was obtained as a grey-white precipitate. MS (ESI): 416.2 ([M+H] ⁺ ).

Example 43

N-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4,4-difluorocyclohexanamine hydrochloride instead of ( 1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (51 mg, 79%) which was obtained as a grey-white precipitate. MS (ESI): 444.2 ([M+H] ⁺ ).

Example 44

6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

a) methyl 6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 1a, (3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block H) instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol- 4-yl)methanol (building block A) was converted to the title compound (821 mg, 48%) which was obtained as a white precipitate. MS (ESI): 326.1 ([M+H] ⁺ ).

b) 6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 4a, methyl 6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((5-methyl-3-(6 -methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (837 mg, 88%) which was obtained as a white precipitate. MS (ESI): 312.1 ([M+H] ⁺ ).

c) 6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3-(6- methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using tetrahydropyran-4-amine instead of (S)-2-aminopentan-1-ol was converted to the title compound (65 mg , 80%), which was obtained as a white precipitate. MS (ESI): 395.2 ([M+H] ⁺ ).

Example 45

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using (RS)-tetrahydrofuran-3- amine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (33 mg, 58%) which was obtained as a grey-white precipitate. MS (ESI): 396.3 ([M+H] ⁺ ).

Example 46

N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using methylamine (2.0 M solution in THF) instead of ethanolamine was converted to the title compound (38 mg, 73%) which was obtained as a grey-white precipitate. MS (ESI): 340.2 ([M+H] ⁺ ).

Example 47

(3,3-difluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3,3-difluoroazetidine hydrochloride instead of ( 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (53 mg, 82%) which was obtained as a grey-white precipitate. MS (ESI): 402.2 ([M+H] ⁺ ).

Example 48

(3,3-difluoropyrrolidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3,3-difluoropyrrolidine hydrochloride instead of ( 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (46 mg, 80%) which was obtained as a grey-white precipitate. MS (ESI): 416.2 ([M+H] ⁺ ).

Example 49

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3-methyloxetan-3-yl)methyl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using (3-methyloxetan-3-yl )methanamine instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (40 mg, 71%) which was obtained as a grey-white precipitate. MS (ESI): 410.2 ([M+H] ⁺ ).

Example 50

6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-ylmethyl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-aminomethyloxetane instead of (1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (33 mg, 58%) which was obtained as a grey-white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 51

N-((3-hydroxyoxetan-3-yl)methyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-(aminomethyl)oxetan-3 -ol in place of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (44 mg, 74%) which was obtained as a grey-white foam. MS (ESI): 412.2 ([M+H] ⁺ ).

Example 52

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3R,4R)-3-methyltetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (3R,4R)-3- methyltetrahydro-2H-pyran-4-amine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (44 mg, 75%) which was obtained as a grey-white foam. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 53

(4,4-difluoropiperidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4,4-difluoropiperidine hydrochloride instead of ( 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (41 mg, 59%) which was obtained as a white precipitate. MS (ESI): 430.2 ([M+H] ⁺ ).

Example 54

N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using 1-(methoxymethyl)cyclopropanamine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (41 mg, 59%) which was obtained as a grey-white precipitate. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 55

(3-methoxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-methoxyazetidine hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (45 mg, 74%) which was obtained as a grey-white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 56

(3-hydroxy-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-methylazetidin-3-ol hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (27 mg, 45%) which was obtained as a grey-white foam. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 57

azetidin-1-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using azetidine instead of ethanolamine, was converted to the compound, indicated in the header (26 mg, 44%), which was obtained as a gray-white precipitate. MS (ESI): 366.2 ([M+H] ⁺ ).

Example 58

(RS)-N-(2,2-dimethyltetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (RS)-2,2- dimethyltetrahydropyran-4-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (52 mg, 78%) which was obtained as a white foam. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 59

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using 1-(trifluoromethyl)cyclopropanamine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (46 mg, 69%) which was obtained as a grey-white precipitate. MS (ESI): 434.2 ([M+H] ⁺ ).

Example 60

(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(morpholino)methanone

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using morpholine instead of ethanolamine was converted to the compound indicated in the title (41 mg, 68%) which was obtained as a gray-white precipitate. MS (ESI): 396.3 ([M+H] ⁺ ).

Example 61

(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl ) methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using 2-oxa-6-azaspiro[ 3.3]heptane hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (20 mg, 30%) which was obtained as a white foam. MS (ESI): 408.2 ([M+H] ⁺ ).

Example 62

4-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

a) 4-((6-chloro-5-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole

By analogy with the experiment of Example 23a, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A), using 3,6-dichloro-4-methylpyridazine instead of 3,6 -dichloropyridazine, was converted into a 1:1 mixture of the title compound and isomeric 4-((6-chloro-4-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3 -pyridyl)isoxazole (1.45 g, 89%) which was obtained as a light brown oil. MS (ESI): 331.1 ([M+H] ⁺ ).

b) ethyl 4-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

By analogy with the experiment of Example 23b, 4-((6-chloro-4-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole and 4-((6 -chloro-5-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole instead of 4-((6-chloropyridazin-3-yloxy)methyl)-5- methyl-3-(6-methylpyridin-3-yl)isoxazole was converted to the title compound (310 mg, 21%) as a light yellow oil, followed by separation of the regioisomers by flash chromatography (silica gel, gradient: 0 % to 80% EtOAc in heptane). MS (ESI): 369.2 ([M+H] ⁺ ).

c) 4-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid

By analogy with the experiment of Example 23c, ethyl 4-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate instead of ethyl 6-(( 5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate was converted to the title compound (213 mg, 72%) which was obtained as a white precipitate. MS (ESI): 341.1 ([M+H] ⁺ ).

d) 4-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 4-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5 -methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using tetrahydropyran-4-amine instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to compound , indicated in the header (49 mg, 89%), which was obtained as a white precipitate. MS (ESI): 424.2 ([M+H] ⁺ ).

Example 63

(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl ) methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 6-oxa-1-azaspiro[ 3.3]heptane oxalate instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (43 mg, 62%) which was obtained as a grey-white foam. MS (ESI): 408.2 ([M+H] ⁺ ).

Example 64

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridazin-3 -carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 1,1,1-trifluoro- 2-methylpropan-2-amine instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (41 mg, 62%) which was obtained as a gray-white precipitate. MS (ESI): 436.2 ([M+H] ⁺ ).

Example 65

(3-fluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-fluoroazetidine hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (52 mg, 89%) which was obtained as a grey-white precipitate. MS (ESI): 384.2 ([M+H] ⁺ ).

Example 66

(3-hydroxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-hydroxyazetidine hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (19 mg, 31%) which was obtained as a grey-white precipitate. MS (ESI): 382.2 ([M+H] ⁺ ).

Example 67

(3-Fluoro-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-fluoro-3-methylazetidine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (51 mg, 84%) which was obtained as a grey-white precipitate. MS (ESI): 398.2 ([M+H] ⁺ ).

Example 68

ethyl 1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamido)cyclopropanecarboxylate

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using ethyl 1-aminocyclopropanecarboxylate hydrochloride instead of (1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (99 mg, 92%) which was obtained as a grey-white precipitate. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 69

N-(1-cyanocyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 1-aminocyclopropanecarbonitrile hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (44 mg, 74%) which was obtained as a white precipitate. MS (ESI): 391.2 ([M+H] ⁺ ).

Example 70

5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) 4-((6-chloro-4-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole

By analogy with the experiment of Example 23a, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A), using 3,6-dichloro-4-methylpyridazine instead of 3,6 -dichloropyridazine, was converted into a 1:1 mixture of the title compound and isomeric 4-((6-chloro-5-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3 -pyridyl)isoxazole (1.45 g, 89%) which was obtained as a light brown oil. MS (ESI): 331.1 ([M+H] ⁺ ).

b) ethyl 5-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

By analogy with the experiment of Example 23b, 4-((6-chloro-4-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole and 4-((6 -chloro-5-methyl-pyridazin-3-yl)oxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole instead of 4-((6-chloropyridazin-3-yloxy)methyl)-5- methyl-3-(6-methylpyridin-3-yl)isoxazole was converted to the title compound (271 mg, 18%) as a white precipitate, followed by separation of the regioisomers by flash chromatography (silica gel, gradient: 0% to 80% EtOAc in heptane). MS (ESI): 369.2 ([M+H] ⁺ ).

c) 5-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid

By analogy with Example 23c, ethyl 5-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate instead of ethyl 6-(( 5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate was converted to the title compound (372 mg, 72%) which was obtained as a white precipitate. MS (ESI): 341.2 ([M+H] ⁺ ).

d) 5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 5-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5 -methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using ammonium hydroxide solution (~25 wt.%) instead of ethanolamine was converted to the title compound (15 mg, 31%) which was obtained as a white precipitate. MS (ESI): 340.1 ([M+H] ⁺ ).

Example 71

5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 5-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5 -methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using tetrahydropyran-4-amine instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to compound , indicated in the header (43 mg, 86%), which was obtained as a light brown oil. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 72

N-(1,1-dioxothian-4-yl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid was converted to the title compound (45 mg, 64%) which was obtained as a white precipitate. MS (ESI): 458.2 ([M+H] ⁺ ).

Example 73

N-(2-hydroxy-1,1-dimethyl-ethyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 29, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2-amino-2-methylpropan-1-ol in place of ethanolamine was converted to the title compound (51 mg , 84%), which was obtained as a white foam. MS (ESI): 398.3 ([M+H] ⁺ ).

Example 74

N-cyclopropyl-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, methyl 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cyclopropanamine instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the compound, indicated in the header (53 mg, 95%), which was obtained as a white precipitate. MS (ESI): 366.2 ([M+H] ⁺ ).

Example 75

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (RS)-3-amino- 3-methyloxolane in place of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (50 mg, 76%) which was obtained as a grey-white foam. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 76

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 1-methylcyclopropanamine hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (54 mg, 93%) which was obtained as a grey-white precipitate. MS (ESI): 380.2 ([M+H] ⁺ ).

Example 77

5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using oxetan-3-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride , was converted to the title compound (50 mg, 86%) which was obtained as a white precipitate. MS (ESI): 382.2 ([M+H] ⁺ ).

Example 78

5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2,2,2-trifluoroethanamine hydrochloride instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl) amine hydrochloride was converted to the title compound (54 mg, 87%) which was obtained as a white precipitate. MS (ESI): 408.2 ([M+H] ⁺ ).

Example 79

N-(4-hydroxy-2-methylbutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-amino-3-methylbutan- 1-ol instead of ethanolamine was converted to the title compound (45 mg, 71%) which was obtained as a grey-white precipitate. MS (ESI): 412.2 ([M+H] ⁺ ).

Example 80

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)pyridazin-3- carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2-methyl-4-methylsulfonyl- butan-2-amine instead of ethanolamine was converted to the title compound (36 mg, 47%) which was obtained as a grey-white foam. MS (ESI): 474.2 ([M+H] ⁺ ).

Example 81

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide or enantiomer

Separation of enantiomers of (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide (Example 75) by chiral HPLC (column: Chiralpak AD, 35 ml/min, i-PrOH/heptane: 40/60; 18 bar; 220 nm) gave the (+)-title compound (22 mg), which was obtained as a gray-white precipitate. MS (ESI): 410.2 ([M+H] ⁺ ).

Example 82

(R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide or enantiomer

Separation of enantiomers of (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide (Example 75) by chiral HPLC (column: Chiralpak AD, 35 ml/min, i-PrOH/heptane: 40/60; 18 bar; 220 nm) gave the (-)-title compound (20 mg), which was obtained in the form of a gray-white foam. MS (ESI): 410.2 ([M+H] ⁺ ).

Example 83

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-methyloxetan-3-amine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (61 mg, 84%) which was obtained as a grey-white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 84

1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carbonyl)azetidine-3-carbonitrile

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using azetidin-3-carbonitrile hydrochloride instead of ( 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (42 mg, 70%) which was obtained as a grey-white precipitate. MS (ESI): 391.2 ([M+H] ⁺ ).

Example 85

N-(1-(hydroxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid (78 mg, 0.191 mmol) in anhydrous THF (1.5 mL) triethylamine (30 µl, 0.215 mmol) was added. 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 dropwise. After 30 minutes, the resulting white precipitate was filtered through a schott funnel and the collected precipitate was washed with a minimal amount of anhydrous THF. The filtrate was again cooled to -16°C (NaCl/ice bath) and a solution of NaBH ₄ (18 mg, 0.476 mmol) in water (0.8 ml) was added dropwise. After adding the reaction mixture was allowed to warm to 0°C for 2 hours, then to room temperature for 1 hour. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (5 ml), then diluted with water (5 ml) and extracted with EtOAc (2×15 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 5% MeOH in CH ₂ Cl ₂ ) gave the title compound (21 mg, 27%) as a grey-white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 86

N-(4,4-difluorocyclohexyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4,4-difluorocyclohexanamine hydrochloride instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride , was converted to the title compound (41 mg, 88%) which was obtained as a grey-white precipitate. MS (ESI): 444.3 ([M+H] ⁺ ).

Example 87

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using (S)-tetrahydrofuran-3- amine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (52 mg, 82%) which was obtained as a white foam. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 88

(S)-N-(1-cyanobutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 29, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using (S)-3-aminopentanenitrile instead of ethanolamine was converted to the title compound (61 mg, 93%) which was obtained as a grey-white foam. MS (ESI): 407.2 ([M+H] ⁺ ).

Example 89

(R)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid, using (R)-tetrahydrofuran-3-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amine hydrochloride was converted to the title compound (40 mg, 73%) which was obtained as a grey-white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 90

N-(2-Hydroxyethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 14c, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid, using ethanolamine instead of (S)-2- aminopentan-1-ol was converted to the title compound (39 mg, 77%) which was obtained as a white precipitate. MS (ESI): 370.2 ([M+H] ⁺ ).

Example 91

2-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)-1H-pyrrolo [3,4-c]pyridine-3-one

a) 6-chloro-2-(1,1-dioxothian-4-yl)-1H-pyrrolo[3,4-c]pyridin-3-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride instead of isobutylamine, was converted to the title compound (137 mg, 42% ), which was obtained as a light yellow precipitate. MS (ESI): 301.0 ([M+H] ⁺ ).

b) 2-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)-1H -pyrrolo[3,4-c]pyridine-3-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A), using 6-chloro-2-(1,1-dioxothian- 4-yl)-1H-pyrrolo[3,4-c]pyridin-3-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the compound indicated in the title (15 mg, 12%) which was obtained as a yellow precipitate. MS (ESI): 469.2 ([M+H] ⁺ ).

Example 92

(S)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (S)-tetrahydrofuran-3-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amine hydrochloride was converted to the title compound (37 mg, 76%) which was obtained as a white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Example 93

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy]-6-tetrahydropyran-4-yl-7H-pyrrolo[3,4-b]pyridin-5- he

a) ethyl 2-(bromomethyl)-6-chloro-pyridine-3-carboxylate

To a stirred solution of ethyl 6-chloro-2-methylnicotinate (0.810 g, 4.06 mmol) in CCl ₄ (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 mixture was heated at the boil under reflux overnight before all volatile components were removed by rotary evaporation under reduced pressure. The resulting crude residue was purified by flash chromatography (silica gel, gradient: 0% to 15% EtOAc in heptane) to give the title compound (1.04 g, 55%, ca. 60% purity) as a light yellow oil. MS (ESI): 278.1 ([M+H] ⁺ ).

b) 2-chloro-6-tetrahydropyran-4-yl-7H-pyrrolo[3,4-b]pyridin-5-one

To a stirred solution of ethyl 2-(bromomethyl)-6-chloro-pyridine-3-carboxylate (0.380 g, 0.819 mmol, purity ca. ml, 3.28 mmol). The reaction mixture was heated to 50° C. overnight before being cooled back to room temperature. The mixture was diluted with EtOAc (40 ml) and the organic layer was 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 (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (192 mg, 93%) as a white precipitate. MS (ESI): 253.1 ([M+H] ⁺ ).

c) 2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-6-tetrahydropyran-4-yl-7H-pyrrolo[3,4-b]pyridine- 5th

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) using 2-chloro-6-tetrahydropyran-4-yl-7H -pyrrolo[3,4-b]pyridin-5-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one, was converted to the title compound (77 mg, 75%), which was obtained in the form of a light yellow precipitate. MS (ESI): 421.3 ([M+H] ⁺ ).

Example 94

N-(1,1-dioxothiolan-3-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyrazin-2- carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-aminotetrahydrothiophene 1,1-dioxide instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl) amine hydrochloride was converted to the title compound (40 mg, 65%) which was obtained as a white precipitate. MS (ESI): 444.4 ([M+H] ⁺ ).

Example 95

N-(cyclopropylmethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cyclopropylmethanamine instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the compound, indicated in the header (50 mg, 86%), which was obtained as a white precipitate. MS (ESI): 380.2 ([M+H] ⁺ ).

Example 96

2-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine- 3(2Н)-one

a) 6-chloro-2-(4,4-difluorocyclohexyl)-1H-pyrrolo[3,4-c]pyridin-3-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using 4,4-difluorocyclohexanamine hydrochloride instead of isobutylamine, was converted to the title compound (211 mg, 45%), which was obtained as a gray-white precipitate. MS (ESI): 287.1 ([M+H] ⁺ ).

b) 2-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c] pyridine-3(2Н)-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) using 6-chloro-2-(4,4-difluorocyclohexyl) -1H-pyrrolo[3,4-c]pyridin-3-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the title compound (90 mg, 81%), which was obtained as a light brown precipitate. MS (ESI): 455.3 ([M+H] ⁺ ).

Example 97

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4-methyltetrahydropyran-4-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (54 mg, 79%) which was obtained as a grey-white foam. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 98

(R)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (R)-tetrahydropyran-3-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amine hydrochloride was converted to the title compound (49 mg, 87%) which was obtained as a white precipitate. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 99

(R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using (R)-tetrahydropyran-3- amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (51 mg, 90%) which was obtained as a white precipitate. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 100

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2-oxaspiro[3.3]heptane- 6-amine hydrochloride in place of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (388 mg, 70%) which was obtained as a grey-white precipitate. MS (ESI): 422.2 ([M+H] ⁺ ).

Example 101

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using 2-oxaspiro[3.3]heptan-6-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)amine hydrochloride was converted to the title compound (355 mg, 72%) which was obtained as a white precipitate. MS (ESI): 422.3 ([M+H] ⁺ ).

Example 102

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(cis-4-(trifluoromethyl)cyclohexyl)pyrazine-2-carboxamide

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4-(trifluoromethyl)cyclohexanamine hydrochloride instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (45 mg, 34%) which was obtained as a grey-white foam. MS (ESI): 476.2 ([M+H] ⁺ ).

Example 103

(S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using (S)-tetrahydropyran-3- amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (43 mg, 76%) which was obtained as a white foam. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 104

N-(cis-4-hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 14c, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid using cis-4-amino-1- methylcyclohexanol 2,2,2-trifluoroacetate in place of (S)-2-aminopentan-1-ol was converted to the title compound (18 mg, 13%) which was obtained as a grey-white precipitate. MS (ESI): 438.2 ([M+H] ⁺ ).

Example 105

N-(trans-4-hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide

By analogy with the experiment of Example 14c, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid using trans-4-amino-1- methylcyclohexanol 2,2,2-trifluoroacetate in place of (S)-2-aminopentan-1-ol was converted to the title compound (50 mg, 37%) which was obtained as a grey-white precipitate. MS (ESI): 438.2 ([M+H] ⁺ ).

Example 106

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydropyran-4-yl)nicotinamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4-methyltetrahydropyran-4-amine hydrochloride instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl) amine hydrochloride was converted to the title compound (48 mg, 75%) which was obtained as a colorless oil. MS (ESI): 423.3 ([M+H] ⁺ ).

Example 107

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrolo[3,4- c]pyridine-3(2Н)-one

a) 6-chloro-2-tetrahydrothiopyran-4-yl-1H-pyrrolo[3,4-c]pyridin-3-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using tetrahydrothiopyran-4-amine instead of isobutylamine, was converted to the title compound (585 mg, 45%), which was obtained as a light brown precipitate. MS (ESI): 269.1 ([M+H] ⁺ ).

b) 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrolo[3, 4-c]pyridine-3(2Н)-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) using 6-chloro-2-tetrahydrothiopyran-4-yl-1H -pyrrolo[3,4-c]pyridin-3-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the title compound (379 mg, 59%), which was obtained as a yellow precipitate. MS (ESI): 437.3 ([M+H] ⁺ ).

Example 108

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

methyl 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 1a, (5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol (building block I) instead of (5-methyl-3-(6-methylpyridin-3- yl)isoxazol-4-yl)methanol (building block A) was converted to the title compound (751 mg, 60%) which was obtained as a light yellow oil. MS (ESI): 341.1 ([M+H] ⁺ ).

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 4a, methyl 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (400 mg, 83%) which was obtained as a white precipitate. MS (ESI): 327.0 ([M+H] ⁺ ).

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using tetrahydropyran-4-amine instead of (S)-2-aminopentan-1-ol, was converted to the compound indicated in title (85 mg, 67%) which was obtained as a white precipitate. MS (ESI): 410.1 ([M+H] ⁺ ).

Example 109

N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid was converted to the title compound (151 mg, 79%) which was obtained as a white precipitate. MS (ESI): 412.1 ([M+H] ⁺ ).

Example 110

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydrothiopyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 4-methyltetrahydrothiopyran-4-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (94 mg, 83%) which was obtained as a grey-white foam. MS (ESI): 440.3 ([M+H] ⁺ ).

Example 111

N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-thiopyran-4-yl)pyridazin-3- carboxamide (Example 68, 60 mg, 0.130 mmol) in a mixture of MeOH (1.4 ml) and water (0.14 ml) was added oxon® (159 mg, 0.259 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The suspension was made basic by adding aqueous Na ₂ CO ₃ (0.5 m, 3 ml) and stirred for an additional 2 hours. The reaction mixture was poured into water (5 ml) and was extracted with CH ₂ Cl ₂ (2×15 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 20% to 100% EtOAc in heptane) gave the title compound (41 mg, 64%) as a grey-white foam. MS (ESI): 472.3 ([M+H] ⁺ ).

Example 112

(2,2-dioxydo-2-thia-6-azaspiro[3.3]heptan-6-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyridazin-3-yl)methanone

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using 2-thia-6-azaspiro[ 3.3]heptane 2,2-dioxide 2,2,2-trifluoroacetate instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (53 mg, 90%) which obtained as a gray-white precipitate. MS (ESI): 456.3 ([M+H] ⁺ ).

Example 113

(2,2-dioxydo-2-thia-6-azaspiro[3.3]heptan-6-yl)(5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyrazin-2-yl)methanone

By analogy with the experiment of Example 30, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide 2,2,2-trifluoroacetate instead (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (45 mg, 80%) which was obtained as a grey-white precipitate. MS (ESI): 456.3 ([M+H] ⁺ ).

Example 114

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopentyl)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 1-methylcyclopentanamine hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (46 mg, 88%) which was obtained as a grey-white foam. MS (ESI): 408.3 ([M+H] ⁺ ).

Example 115

5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4,4,4-trifluorobutyl)pyrazine-2-carboxamide

By analogy with the experiment of Example 14c, 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxylic acid using 4,4,4-trifluorobutan- 1-amine instead of (S)-2-aminopentan-1-ol was converted to the title compound (50 mg, 94%) which was obtained as a grey-white precipitate. MS (ESI): 436.2 ([M+H] ⁺ ).

Example 116

N-(1-isopropylazetidin-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 1-isopropylazetidine-3-amine hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (25 mg, 41%) which was obtained as a white foam. MS (ESI): 423.3 ([M+H] ⁺ ).

Example 117

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3, 4-c]pyridine-3(2Н)-one

a) 6-chloro-2-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

By analogy with the experiment of Example 9a, 6-chloro-4-formylnicotinic acid, using 2-oxaspiro[3.3]heptan-6-amine hydrochloride instead of isobutylamine, was converted to the title compound (96 mg, 37%), which was obtained in as a light yellow precipitate. MS (ESI): 265.2 ([M+H] ⁺ ).

b) 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[ 3,4-c]pyridine-3(2Н)-one

By analogy with the experiment of Example 9b, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol using 6-chloro-2-(2-oxaspiro[3.3]heptan-6-yl )-1H-pyrrolo[3,4-c]pyridin-3(2H)-one instead of 6-chloro-2-isobutyl-1H-pyrrolo[3,4-c]pyridin-3-one was converted to the compound indicated in the title (59 mg, 51%) which was obtained as a light yellow precipitate. MS (ESI): 433.3 ([M+H] ⁺ ).

Example 118

6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 1-methylcyclobutanamine hydrochloride instead of (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (23 mg, 48%) which was obtained as a white foam. MS (ESI): 394.3 ([M+H] ⁺ ).

Example 119

6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

a) methyl 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 1a, (5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block B) instead of (5-methyl-3-(6-methylpyridin-3- yl)isoxazol-4-yl)methanol (building block A) was converted to the title compound (743 mg, 77%) which was obtained as a light yellow oil. MS (ESI): 354.3 ([M+H] ⁺ ).

b) 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 4a, methyl 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (591 mg, 87%) which was obtained as a gray-white precipitate. MS (ESI): 340.2 ([M+H] ⁺ ).

c) 6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using tetrahydropyran-4-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride, was converted to the title compound (56 mg, 90%) which was obtained as a grey-white precipitate. MS (ESI): 423.3 ([M+H] ⁺ ).

Example 120

N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid was converted to the title compound (44 mg, 64%) which was obtained as a grey-white precipitate. MS (ESI): 471.3 ([M+H] ⁺ ).

Example 121

6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

a) 4-((6-chloropyridazin-3-yl)oxymethyl)-5-ethyl-3-(6-methyl-3-pyridyl)isoxazole

By analogy with the experiment of Example 23a, (5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block B) instead of (5-methyl-3-(6-methylpyridin-3- yl)isoxazol-4-yl) methanol (building block A) was converted to the title compound (1.2 g, 91%) which was obtained as a yellow oil. MS (ESI): 331.2 ([M+H] ⁺ ).

b) ethyl 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

By analogy with the experiment of Example 23b, 4-((6-chloropyridazin-3-yl)oxymethyl)-5-ethyl-3-(6-methyl-3-pyridyl)isoxazole instead of 4-((6-chloropyridazin-3-yl )hydroxymethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole was converted to the title compound (272 mg, 21%) which was obtained as a light brown oil. MS (ESI): 369.2 ([M+H] ⁺ ).

c) 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid

By analogy with the experiment of Example 23c, ethyl 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate instead of ethyl 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate was converted to the title compound (192 mg, 91%) which was obtained as a gray-white precipitate. MS (ESI): 341.2 ([M+H] ⁺ ).

d) 6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using tetrahydropyran-4-amine instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (38 mg, 87%) which was obtained as a gray-white precipitate. MS (ESI): 424.3 ([M+H] ⁺ ).

Example 122

6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid, using 3-methyloxetan-3-amine hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride, was converted to the compound, indicated in the header (46 mg, 96%), which was obtained as a gray-white precipitate. MS (ESI): 410.3 ([M+H] ⁺ ).

Example 123

N-cyclopropyl-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-ethyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5-methyl-3 -(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cyclopropanamine in place of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (37 mg, 95%), which was obtained in the form of a gray-white precipitate. MS (ESI): 380.2 ([M+H] ⁺ ).

Example 124

(R)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (R)-2-aminopentan- 1-ol instead of (S)-2-aminopentan-1-ol was converted to the title compound (156 mg, 82%) which was obtained as a white precipitate. MS (ESI): 411.3 ([M+H] ⁺ ).

Example 125

6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide

a) methyl 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 1a, (5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block J) instead of (5-methyl-3-(6-methylpyridine- 3-yl)isoxazol-4-yl)methanol (building block A) was converted to the title compound (146 mg, 58%) which was obtained as a colorless oil. MS (ESI): 376.2 ([M+H] ⁺ ).

b) 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 4a, methyl 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((5- methyl 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (23 mg, 97%) which was obtained as a gray-white precipitate. MS (ESI): 362.2 ([M+H] ⁺ ).

c) 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3- carboxamide

By analogy with the experiment of Example 4b, 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl -3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid was converted to the title compound (13 mg, 50%) which was obtained as a grey-white foam. MS (ESI): 447.3 ([M+H] ⁺ ).

Example 126

6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl -3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using tetrahydropyran-4-amine instead of (S)-2-aminopentan-1-ol, was converted to the compound, indicated in the header (17 mg, 29%), which was obtained as a gray-white precipitate. MS (ESI): 445.3 ([M+H] ⁺ ).

Example 127

N-((3R,4S)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

To a stirred solution of 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid (50 mg, 0.154 mmol) in anhydrous DMF (2 ml) (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol 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 resulting clear yellow solution was poured into water (10 ml) then extracted with EtOAc (2×20 ml). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (59 mg, 90%) as a white precipitate. MS (ESI): 425.3 ([M+H] ⁺ ).

Example 128

6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

a) methyl 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 1a, (3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol (building block K) instead of (5-methyl-3-(6-methylpyridine-3 -yl)isoxazol-4-yl)methanol (building block A) using methyl 6-fluoropyridine-3-carboxylate in place of methyl 6-chloronicatanate was converted to the title compound (920 mg, 25%) which was obtained as colorless oil. MS (ESI): 365.8 ([M+H] ⁺ ).

b) 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 4a, methyl 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((5-methyl -3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (740 mg, 83%) which was obtained as a white precipitate. MS (ESI): 352.0 ([M+H] ⁺ ).

c) 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using tetrahydropyran-4-amine instead of (S)-2-aminopentan-1-ol, was converted to the compound indicated in the title (120 mg, 74%) which was obtained as a white precipitate. MS (ESI): 435.1 ([M+H] ⁺ ).

Example 129

6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid was converted to the title compound (140 mg, 59%) which was obtained as a yellow oil. MS (ESI): 437.1 ([M+H] ⁺ ).

Example 130

6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-(1,1-dioxothian-4-yl)pyridine-3-carboxamide

By analogy with the experiment of Example 4b, 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((5-methyl- 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride instead of (S)-2 -aminopentan-1-ol was converted to the title compound (110 mg, 87%) which was obtained as a white precipitate. MS (ESI): 483.1 ([M+H] ⁺ ).

Example 131

N-((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridin-3 -carboxamide

By analogy with the experiment of Example 127, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (1S,6R)-6- amino-2,2-difluorocyclohexanol instead of (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride was converted to the title compound (50 mg, 70%) which was obtained as a white precipitate. MS (ESI): 459.5 ([M+H] ⁺ ).

Example 132

N-((1R,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 127, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (1R,2R)-2- aminocyclohexanol hydrochloride instead of (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride was converted to the title compound (39 mg, 60%) which was obtained as a white precipitate. MS (ESI): 423.4 ([M+H] ⁺ ).

Example 133

N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridin-3 -carboxamide

By analogy with the experiment of Example 127, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (1R,6S)-6- amino-2,2-difluorocyclohexanol instead of (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride was converted to the title compound (66 mg, 94%) which was obtained as a white precipitate. MS (ESI): 459.4 ([M+H] ⁺ ).

Example 134

N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridine -3-carboxamide

By analogy with the experiment of Example 127, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol hydrochloride instead of (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride was converted to the title compound (51 mg, 78%) which was obtained as white draft. MS (ESI): 425.3 ([M+H] ⁺ ).

Example 135

N-((1S,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with the experiment of Example 127, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (1S,2S)-2- aminocyclohexanol hydrochloride instead of (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride was converted to the title compound (30 mg, 46%) which was obtained as a white precipitate. MS (ESI): 423.4 ([M+H] ⁺ ).

Example 136

2-fluoro-N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

a) methyl 2-fluoro-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-pyridine-3-carboxylate

Methyl 2, 6-difluoropyridine-3-carboxylate (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% dispersion 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 (2×30 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 40% EtOAc in heptane) gave the title compound (323 mg, 37%, white precipitate) as a 2:5 mixture with its regioisomer methyl 6-fluoro-2 -((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate. MS (ESI): 358.2 ([M+H] ⁺ ).

b) 2-fluoro-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

To a stirred solution of methyl 2-fluoro-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-pyridine-3-carboxylate and methyl 6-fluoro-2-( (5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate (418 mg, 1.17 mmol) in a mixture of MeOH (3 ml) and THF (3 ml) at room temperature, water (0.9 ml) was added followed by aqueous NaOH (1.0 m, 1.64 mmol, 1.64 ml). The reaction mixture was stirred at room temperature for 1 hour before being quenched by adding aqueous HCl (1.0 m, 1.64 ml). The mixture was evaporated to dryness by rotary evaporation under reduced pressure to give the title compound (546 mg, quantitatively, white precipitate) as a 2:5 mixture with its regioisomer 6-fluoro-2-((5-methyl-3-(6- methyl-3-pyridyl)isoxazol-4-yl)methoxy)-pyridine-3-carboxylic acid. MS (ESI): 344.1 ([M+H] ⁺ ).

c) 2-fluoro-N-methyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with Example 127, 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using methylamine hydrochloride instead of (3R,4S) -4-aminotetrahydro-2H-pyran-3-ol hydrochloride was converted to the title compound (35 mg, 7%) which was obtained as a white precipitate after preparative HPLC removal of the unwanted regioisomer. MS (ESI): 357.1 ([M+H] ⁺ ).

Example 137

6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

a) methyl 6-((3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate

To a stirred solution of (3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methanol (structural block M, 1.44 g, 6.54 mmol) in anhydrous THF (30 mL) at 0°C was added under atmospheric argon methyl 6-chloropyridine-3-carboxylate (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 pouring into water (50 ml), then was extracted with EtOAc (2×50 ml). The combined organic extracts were washed with water, dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 30% EtOAc in heptane) gave the title compound (1.51 g, 65%) as a white precipitate. MS (ESI): 356.1 ([M+H] ⁺ ).

b) 6-((3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

To a stirred solution of methyl 6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridine-3-carboxylate (1.51 g, 4.25 mmol) in a mixture of MeOH (11 ml) and THF (11 ml) at room temperature was 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 to form a solution. The mixture was cooled to room temperature, then quenched by adding aqueous HCl (1.0 m, 8.5 ml). The resulting suspension was diluted with water (10 ml) and filtered on a sintered glass funnel. The collected precipitate was washed with water (40 ml) and heptane (20 ml), then dried under high vacuum to give the title compound (1.39 g, 96%) as a white precipitate. MS (ESI): 342.1 ([M+H] ⁺ ).

c) 6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridin-3-carboxamide

To a stirred solution of 6-((3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid (200 mg, 586 µmol) in anhydrous DMF (3 ml ) were added at room temperature under argon atmosphere tetrahydropyran-4-amine (72.8 µl, 0.703 mmol), N-ethyldiisopropylamine (512 µl, 2.93 mmol) and HATU (267 mg, 0.703 mmol). The resulting yellow solution was stirred at room temperature overnight before being poured into water (20 ml), then extracted with EtOAc (2×30 ml). The combined organic extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 5% MeOH in CH ₂ Cl ₂ ) gave the title compound (230 mg, 92%) as a white precipitate. MS (ESI): 425.2 ([M+H] ⁺ ).

Example 138

N-isopropyl-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with Example 137, 6-((3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using isopropylamine instead of tetrahydropyran-4-amine , was converted to the title compound (218 mg, 97%) which was obtained as a white precipitate. MS (ESI): 383.2 ([M+H] ⁺ ).

Example 139

(S)-N-(1-hydroxypentan-2-yl)-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridine-3-carboxamide

By analogy with Example 137, 6-((3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (S)-2-aminopentane -1-ol in place of tetrahydropyran-4-amine was converted to the title compound (131 mg, 52%) which was obtained as a white precipitate. MS (ESI): 427.3 ([M+H] ⁺ ).

Example 140

(1,1-dioxidothiomorpholino)(6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone

By analogy with the experiment of Example 137, 6-((3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid, using thiomorpholine 1,1-dioxide instead of tetrahydropyran-4-amine was converted to the title compound (244 mg, 91%) which was obtained as a white precipitate. MS (ESI): 459.2 ([M+H] ⁺ ).

Example 141

(S)-6-((3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(1-hydroxypentan-2-yl)nicotinamide

a) methyl 6-((3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with Example 137a, (3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methanol (building block N) instead of (3-(6-methoxypyridin-3-yl) -5-methylisoxazol-4-yl)methanol (building block M) was converted to the title compound (843 mg, 70%) which was obtained as a light yellow precipitate. MS (ESI): 369.2 ([M+H] ⁺ ).

b) 6-((3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with Example 137b, methyl 6-((3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-((3 -(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (563 mg, 74%) which was obtained as a white precipitate. MS (ESI): 355.0 ([M+H] ⁺ ).

c) (S)-6-((3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(1-hydroxypentan-2-yl)nicotinamide

By analogy with Example 137c, 6-((3-(6-(dimethylamino)-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((3- (6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (S)-2-aminopentan-1-ol instead of tetrahydropyran-4-amine was converted to the title compound (93 mg, 67%) which was obtained as a white precipitate. MS (ESI): 440.3 ([M+H] ⁺ ).

Example 142

4-methoxy-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)nicotinamide

a) methyl 4-methoxy-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 137a, (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) instead of (3-(6-methoxypyridin-3-yl)-5 -methylisoxazol-4-yl)methanol (building block M), using methyl 6-chloro-4-methoxy-pyridine-3-carboxylate instead of methyl 6-chloropyridine-3-carboxylate, was converted to the title compound (67 mg, 27%), which was obtained as a light yellow precipitate. MS (ESI): 370.1 ([M+H] ⁺ ).

b) 4-methoxy-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 137b, methyl 4-methoxy-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-(( 3-(6-Methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (70 mg, 99%) which was obtained as a light yellow precipitate . MS (ESI): 356.2 ([M+H] ⁺ ).

c) (S)-6-((3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(1-hydroxypentan-2-yl)nicotinamide

By analogy with Example 137c, 4-methoxy-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-((3 -(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid was converted to the title compound (29 mg, 46%) which was obtained as a white precipitate . MS (ESI): 439.2 ([M+H] ⁺ ).

Example 143

6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

a) methyl 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate

By analogy with the experiment of Example 137a, (3-(5-fluoro-6-methylpyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methanol (building block O) instead of (3-(6 -methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methanol (building block M), using methyl 6-fluoropyridine-3-carboxylate instead of methyl 6-chloropyridine-3-carboxylate, was converted to the title compound ( 118 mg, 62%) which was obtained as a light yellow precipitate. MS (ESI): 358.2 ([M+H] ⁺ ).

b) 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid

By analogy with the experiment of Example 137b, methyl 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylate instead of methyl 6-( (3-(6-Methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (120 mg, 99%) which was obtained as a light yellow draft. MS (ESI): 344.1 ([M+H] ⁺ ).

c) 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide

By analogy with the experiment of Example 137c, 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-(( 3-(6-Methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid was converted to the title compound (28 mg, 38%) which was obtained as white draft. MS (ESI): 427.3 ([M+H] ⁺ ).

Example 144

6((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-isopropyl-pyridine-3-carboxamide

By analogy with the experiment of Example 137c, 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-(( 3-(6-Methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using isopropylamine instead of tetrahydropyran-4-amine was converted to the title compound (20 mg , 59%), which was obtained as a yellow precipitate. MS (ESI): 385.2 ([M+H] ⁺ ).

Example 145

6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3 -carboxamide

By analogy with the experiment of Example 137c, 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid instead of 6-(( 3-(6-methoxy-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridine-3-carboxylic acid using (S)-2-aminopentan-1-ol instead of tetrahydropyran-4-amine, was converted to the title compound (27 mg, 54%) which was obtained as a grey-white precipitate. MS (ESI): 429.2 ([M+H] ⁺ ).

Example 146

N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-4-amino-1- methylcyclohexanol instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (107 mg, 91%) which was obtained as a grey-white foam. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 147

N-(1,3-dihydroxy-2-methylpropan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

To a stirred suspension of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide (Example 83 , 32.5 mg, 82.2 µmol) in water (100 ml), aqueous HCl (1.0 M, 82.2 µl, 82.2 µmol) was added at room temperature. 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 mixture was quenched by adding aqueous NaHCO ₃ (1.0 M, 9 ml), then diluted with EtOAc (10 ml). The layers were separated and the aqueous phase was subsequently extracted with EtOAc (2×10 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 50% EtOAc in heptane to 10% MeOH in EtOAc) gave the title compound (9 mg, 27%) as a light brown oil. MS (ESI): 414.3 ([M+H] ⁺ ).

Example 148

N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-4-amino-1- methylcyclohexanol 2,2,2-trifluoroacetate instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (64 mg, 64%) which was obtained as a white precipitate. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 149

N-((1R,3S)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide or enantiomer

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using cis-3-amino-1- (trifluoromethyl)cyclopentanol hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the racemic title compound (161 mg, 47%) which was obtained as a white precipitate. MS (ESI): 478.2 ([M+H] ⁺ ).

Separation of the enantiomers by chiral HPLC (column: Chiralpak AD) gave the title compound (65 mg) which was obtained as a white precipitate. MS (ESI): 478.4 ([M+H] ⁺ ).

Example 150

N-((1S,3R)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide or enantiomer

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using cis-3-amino-1- (trifluoromethyl)cyclopentanol hydrochloride instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the racemic title compound (161 mg, 47%) which was obtained as a white precipitate. MS (ESI): 478.2 ([M+H] ⁺ ).

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

Example 151

(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyridazin-3-yl)methanone

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1S,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (26 mg, 69%) which was obtained as a light brown foam. MS (ESI): 408.2 ([M+H] ⁺ ).

Example 152

N-((1RS,3RS)-3-hydroxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using racemic trans-(1RS,3RS) -3-aminocyclopentanol hydrochloride instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to 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)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-4-aminocyclohexanol instead of (1R ,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (23 mg, 59%) which was obtained as a light brown precipitate. MS (ESI): 424.2 ([M+H] ⁺ ).

Example 154

trans-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-4-methoxycyclohexanamine hydrochloride instead of ( 1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (22 mg, 55%) which was obtained as a light brown foam. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 155

(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3 -yl) methanone

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 6,6-difluoro-2- azaspiro[3.3]heptane 2,2,2-trifluoroacetate, instead of (1R,2S)-2-aminocyclohexanol hydrochloride, was converted to the title compound (12 mg, 30%) which was obtained as a white foam. MS (ESI): 442.2 ([M+H] ⁺ ).

Example 156

N-(3-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-aminocyclohexanol instead of (1R,2S )-2-aminocyclohexanol hydrochloride was converted to the title compound (16 mg, 41%) which was obtained as a grey-white foam. MS (ESI): 424.2 ([M+H] ⁺ ).

Example 157

3-oxa-6-azabicyclo[3.1.1]heptan-6-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl ) methanone

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 3-oxa-6-azabicyclo[ 3.1.1]heptane 2,2,2-trifluoroacetate instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (21 mg, 56%) which was obtained as a grey-white foam. MS (ESI): 408.2 ([M+H] ⁺ ).

Example 158

cis-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-4-methoxycyclohexanamine instead of (1R ,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (18 mg, 45%) which was obtained as a grey-white foam. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 159

6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol (building block F) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D) was converted to the title compound (32 mg, 33%) which was obtained as a white precipitate. MS (ESI): 430.2 ([M+H] ⁺ ).

Example 160

(S)-6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol (building block F) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D), using (S)-6-chloro-N-(tetrahydrofuran-3-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4 -yl)pyridazin-3-carboxamide was converted to the title compound (18 mg, 32%) which was obtained as a white precipitate. MS (ESI): 438.1 ([M+H] ⁺ ).

Example 161

6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol (building block F) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D), using 6-chloro-N-(3-methyloxetan-3-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4-yl )pyridazine-3-carboxamide was converted to the title compound (18 mg, 32%) which was obtained as a white precipitate. MS (ESI): 416.2 ([M+H] ⁺ ).

Example 162

6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-methyl-isoxazol-4-yl)methanol (building block F) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D), using 6-chloro-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran -4-yl)pyridazin-3-carboxamide was converted to the title compound (17 mg, 29%) which was obtained as a white precipitate. MS (ESI): 442.2 ([M+H] ⁺ ).

Example 163

trans-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) trans-tert-butyl N-(3-methoxycyclobutyl)carbamate

NaH (60% in mineral oil, 32 mg, 0.801 mmol) was added 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. After 30 min, iodomethane (43.4 μl, 0.694 mmol) was added and the reaction mixture was allowed to warm to room temperature over 2.5 hours. LC-MS analysis showed no starting compounds, only monomethylated and dimethylated products remained. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (1 ml), diluted with water (15 ml) and extracted with EtOAc (2×15 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 15% EtOAc in heptane) gave the title compound (32 mg, 30%) as white crystals. MS (ESI): 146.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate

TFA (130 µl, 1.69 mmol) was added to a stirred solution of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate (42 mg, 0.209 mmol) in CH ₂ Cl ₂ (2 ml) at 0°C and the resulting yellow solution was given warm up to room temperature. After 2 hours, all volatiles were removed by rotary evaporation under reduced pressure to give the title compound (60 mg, quantitatively) as a light yellow oil. MS (ESI): 102.2 ([M+H] ⁺ ).

c) trans-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

To a stirred solution of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate (45 mg, 0.209 mmol) in anhydrous DMF (0.8 ml) under argon yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid (45 mg, 0.138 mmol), N,N-diisopropylethylamine (200 µl, 1.15 mmol) and TBTU (66.4 mg, 0.207 mmol). The resulting yellow solution was stirred overnight at room temperature then immediately purified by preparative HPLC (column: C-18, eluent: H ₂ O and CH ₃ CN with 0.05% HCO ₂ H) to give the title compound (18.2 mg , 32.3%) as an orange powder. MS (ESI): 410.2 ([M+H] ⁺ ).

Example 164

cis-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) cis-tert-butyl N-(3-methoxycyclobutyl)carbamate

By analogy with Example 163a, cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate was converted to the title compound (59 mg, 55%), which received as white crystals. MS (ESI): 146.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) cis-3-methoxycyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, cis-tert-butyl N-(3-methoxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (62 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 102.2 ([M+H] ⁺ ).

c) cis-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-3-methoxycyclobutanamine 2,2 ,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to 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-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide

By analogy with the experiment of Example 183, (5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol (building block L) instead of (5-cyclopropyl-3-(6-methyl-3- pyridyl)isoxazol-4-yl)methanol (building block D) was converted to the title compound (10 mg, 19%) which was obtained as a gray-white precipitate. MS (ESI): 437.3 ([M+H] ⁺ ).

Example 166

trans-N-((1RS,3RS)-3-methoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

)

)

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using racemic trans-(1RS,3RS) -3-methoxycyclopentanamine bis-2,2,2-trifluoroacetate instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (33 mg, 51%) which was obtained as a white precipitate. MS (ESI): 424.2 ([M+H] ⁺ ).

Example 167

N-(6,6-difluorospiro[3.3]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with the experiment of Example 23d, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using 6,6-difluorospiro[3.3] heptan-2-amine instead of (1R,2S)-2-aminocyclohexanol hydrochloride was converted to the title compound (20 mg, 47%) which was obtained as a light brown amorphous substance. MS (ESI): 456.5 ([M+H] ⁺ ).

Example 168

6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

a) ethyl 6-((5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

By analogy with the experiment of Example 7a, (5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block C) instead of (5-methyl-3-(6-methylpyridine- 3-yl)isoxazol-4-yl)methanol (building block A) was converted to the title compound (120 mg, 19%) which was obtained as an orange oil. MS (ESI): 359.2 ([M+H] ⁺ ).

b) 6-((5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid

By analogy with the experiment of Example 23c, ethyl 6-((5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate instead of ethyl 6-((5- methyl 3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate was converted to the title compound (65 mg, 94%) which was obtained as a grey-white precipitate. MS (ESI): 345.2 ([M+H] ⁺ ).

c) 6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5-methyl -3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using tetrahydropyran-4-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title compound (81 mg, 50%) which was obtained as a grey-white precipitate. MS (ESI): 428.3 ([M+H] ⁺ ).

Example 169

cis-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) cis-tert-butyl N-(3-(2,2-difluoroethoxy)cyclobutyl)carbamate

By analogy with the experiment of Example 163a, cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate instead of iodomethane, was converted to the compound indicated in the title (109 mg, 81%) which was obtained as white crystals. MS (ESI): 196.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) cis-3-(2,2-difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, cis-tert-butyl N-(3-(2,2-difluoroethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in title (81 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 152.2 ([M+H] ⁺ ).

c) cis-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3- carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-3-(2,2 -difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (25 mg, 45%) which was obtained as a colorless amorphous substance. MS (ESI): 460.3 ([M+H] ⁺ ).

Example 170

trans-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) trans-tert-butyl N-(3-(2,2-difluoroethoxy)cyclobutyl)carbamate

In analogy to Example 163a, trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate in place of iodomethane, was converted to the title compound (95 mg, 71%), which was obtained as white crystals. MS (ESI): 196.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) trans-3-(2,2-difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, trans-tert-butyl N-(3-(2,2-difluoroethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in title (70 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 152.2 ([M+H] ⁺ ).

c) trans-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3- carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-3-(2,2 -difluoroethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to 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)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

a) cis-tert-butyl N-(3-ethoxycyclobutyl)carbamate

Similar to Example 163a, cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate using iodoethane instead of iodomethane was converted to the title compound (83 mg , 73%), which was obtained as a white precipitate. MS (ESI): 216.1 ([M+H] ⁺ ), 160.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) cis-3-ethoxycyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, cis-tert-butyl N-(3-ethoxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (90 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 116.1 ([M+H] ⁺ ).

c) cis-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-3-ethoxycyclobutanamine 2,2 ,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to 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)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) trans-tert-butyl N-(3-ethoxycyclobutyl)carbamate

In analogy to Example 163a, trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate, using iodoethane instead of iodomethane, was converted to the title compound (72 mg, 63%) which was obtained as a white precipitate. MS (ESI): 160.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) trans-3-ethoxycyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, trans-tert-butyl N-(3-ethoxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (88 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 116.1 ([M+H] ⁺ ).

c) trans-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-3-ethoxycyclobutanamine 2,2 ,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to 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)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) cis-tert-butyl N-(3-(difluoromethoxy)cyclobutyl)carbamate

CuI (20.3 mg, 0.107 mmol) was added to a stirred solution of cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate (100 mg, 0.534 mmol) in acetonitrile (2 mL) under argon. The reaction mixture was vigorously stirred and heated to 45°C for 30 min before a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (190 mg, 110 μl, 1.07 mmol) in acetonitrile (2.0 ml) was added drop by drop over a period of 40 min. The reaction mixture was stirred at 45° C. for 3 hours, then cooled to room temperature, adsorbed onto silica gel and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 10% EtOAc in heptane) gave the title compound (82.5 mg, 65.1%) as a white precipitate. MS (ESI): 182.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) cis-3-(difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, cis-tert-butyl N-(3-(difluoromethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (43 mg, quantitatively) which was obtained as a light yellow oil. MS (ESI): 138.1 ([M+H] ⁺ ).

c) cis-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-3-(difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (41 mg, 66%) which was obtained as a colorless amorphous substance. MS (ESI): 446.3 ([M+H] ⁺ ).

Example 174

trans-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) trans-tert-butyl N-(3-(difluoromethoxy)cyclobutyl)carbamate

By analogy with the experiment of Example 173a, trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate was converted to the title compound (97 mg, 77%), which received as a white precipitate. MS (ESI): 182.0 ([M-C ₄ H ₈ +H] ⁺ ).

b) trans-3-(difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, trans-tert-butyl N-(3-(difluoromethoxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (42 mg, quantitatively) which was obtained as a light yellow oil. MS (ESI): 138.1 ([M+H] ⁺ ).

c) trans-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-3-(difluoromethoxy)cyclobutanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (37 mg, 60%) which was obtained as a white precipitate. MS (ESI): 446.3 ([M+H] ⁺ ).

Example 175

trans-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

a) trans-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate

A round bottom flask was filled 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 minutes by bubbling argon through the reactor medium. The reaction mixture was heated to 80°C and stirred overnight before being cooled to room temperature, then immediately filtered through a pad of dicalite. The filter cake was washed with Et ₂ O and the filtrate was concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, gradient: 0% to 7% EtOAc in heptane) to give the title compound (113 mg, 66%) as a yellow crystalline solid. MS (ESI): 158.1 ([M-C ₄ H ₈ +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 CH ₂ Cl ₂ (1 ml) in an argon atmosphere at 0°C was added a solution of TFA (80 μl, 1.04 mmol) in anhydrous CH ₂ Cl ₂ (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 CH ₂ Cl ₂ (1 ml) was added dropwise to form a colorless solution, which was stirred for an additional 20 min. Finally, a solution of trans-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate (110.5 mg, 0.518 mmol) in anhydrous CH ₂ Cl ₂ (1.50 ml) was added dropwise and the resulting light red solution was stirred at 0° C for 1 hour, then allowed to warm to room temperature and stirred overnight. The reaction mixture was again cooled to 0°C, then extinguished by adding saturated aqueous Na ₂ CO ₃ (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 was extracted with EtOAc (3×20 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 9% EtOAc in heptane) gave the title compound (91 mg, 77%) as white needles. MS (ESI): 172.1 ([M-C ₄ H ₈ +H] ⁺ ).

c) trans-3-cyclopropoxycyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, trans-tert-butyl N-(3-cyclopropoxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (43 mg, quantitatively), which was obtained in the form of a gray-white substance. MS (ESI): 128.1 ([M+H] ⁺ ).

d) trans-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-3-cyclopropoxycyclobutanamine 2,2 ,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (42 mg, 70%) which was obtained as a colorless amorphous substance. MS (ESI): 436.3 ([M+H] ⁺ ).

Example 176

cis-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

a) cis-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate

By analogy with the experiment of Example 175a, cis-tert-butyl N-(3-hydroxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-hydroxycyclobutyl)carbamate was converted to the title compound (107 mg, 63%), which obtained as a yellow crystalline precipitate. MS (ESI): 158.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) cis-tert-butyl N-(3-cyclopropoxycyclobutyl)carbamate

By analogy with the experiment of Example 175b, cis-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate instead of trans-tert-butyl N-(3-(vinyloxy)cyclobutyl)carbamate was converted to the title compound (91 mg , 81%), which was obtained as white needles. MS (ESI): 172.1 ([M-C ₄ H ₈ +H] ⁺ ).

c) cis-3-cyclopropoxycyclobutanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, cis-tert-butyl N-(3-cyclopropoxycyclobutyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (44 mg, quantitatively), which was obtained in the form of a gray-white amorphous substance. MS (ESI): 128.1 ([M+H] ⁺ ).

d) cis-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using cis-3-cyclopropoxycyclobutanamine 2,2 ,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (43 mg, 71%) which was obtained as a white foam. MS (ESI): 436.3 ([M+H] ⁺ ).

Example 177

6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazin-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-cyclopropyl-isoxazol-4-yl)methanol (building block G) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D), using 6-chloro-N-(3-methyloxetan-3-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4-yl )pyridazine-3-carboxamide was converted to the title compound (8.5 mg, 16%) which was obtained as a white precipitate. MS (ESI): 442.2 ([M+H] ⁺ ).

Example 178

6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazin-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-cyclopropyl-isoxazol-4-yl)methanol (building block G) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D), using 6-chloro-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran -4-yl)pyridazin-3-carboxamide was converted to the title compound (13 mg, 23%) which was obtained as a pink precipitate. MS (ESI): 468.3 ([M+H] ⁺ ).

Example 179

(S)-6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide

By analogy with Example 183, (3-(6-chloro-3-pyridyl)-5-cyclopropyl-isoxazol-4-yl)methanol (building block G) instead of (5-cyclopropyl-3-(6-methyl-3 -pyridyl)isoxazol-4-yl)methanol (building block D), using (S)-6-chloro-N-(tetrahydrofuran-3-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4 -yl)pyridazin-3-carboxamide was converted to the title compound (14 mg, 27%) which was obtained as a white precipitate. MS (ESI): 442.2 ([M+H] ⁺ ).

Example 180

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide

By analogy with Example 183, (5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block D) using 6-chloro-N-(3-methyloxetan-3- yl)pyridazine-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide was converted to the title compound (27 mg, 49%) which was obtained as a white precipitate. MS (ESI): 422.3 ([M+H] ⁺ ).

Example 181

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide

By analogy with Example 183, (5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block D) using 6-chloro-N-(2-oxaspiro[3.3] heptan-6-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide was converted to the title compound (6.5 mg, 11%) which was obtained as white precipitate. MS (ESI): 448.3 ([M+H] ⁺ ).

Example 182

(S)-6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide

By analogy with the experiment of Example 183, (5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block D), using 6-chloro-N-((3S)-tetrahydrofuran- 3-yl)pyridazin-3-carboxamide instead of 6-chloro-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide was converted to the title compound (10 mg, 21%) which was obtained as a white precipitate . MS (ESI): 422.3 ([M+H] ⁺ ).

Example 183

6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

To a stirred solution of (5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol (building block D, 30 mg, 0.130 mmol) and 6-chloro-N-(tetrahydropyran-4-yl )pyridazine-3-carboxamide (35 mg, 0.130 mmol) in anhydrous N,N-dimethylacetamide (0.60 ml) was added Cs ₂ CO ₃ (46.7 mg, 0.143 mmol). The reaction mixture was stirred at room temperature for 15 hours, then filtered and immediately purified by preparative HPLC (column: C-18, eluent: H ₂ O and CH ₃ CN with 0.05% HCO ₂ H) to give the title compound , as a white precipitate (23 mg, 40%). MS (ESI): 436.3 ([M+H] ⁺ ).

Example 184

6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5-methyl -3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using 1-(trifluoromethyl)cyclopropanamine instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (10 mg, 51%), which was obtained as a colorless amorphous substance. MS (ESI): 452.3 ([M+H] ⁺ ).

Example 185

6-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

To a stirred solution of (5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methanol (structural block E, 56 mg, 0.217 mmol) and 6-chloro-N-(tetrahydropyran- 4-yl)pyridazin-3-carboxamide (62.9 mg, 260 μmol) in anhydrous N,N-dimethylacetamide (0.60 ml) was added Cs ₂ CO ₃ (141 mg, 0.434 mmol) at room temperature. After 17 hours, the reaction mixture was diluted with EtOAc (15 ml) and the organic layer was washed with aqueous Na ₂ CO ₃ (1.0 m, 10 ml), half-saturated saline (15 ml) and saline (15 ml). The aqueous layers were extracted with EtOAc (15 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 15% to 100% EtOAc in heptane) gave the title compound (32 mg, 32%) as a grey-white precipitate. MS (ESI): 464.2 ([M+H] ⁺ ).

Example 186

N-((2S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1R,2S,4S)- 7-oxabicyclo[2.2.1]heptan-2-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the title racemic compound (48 mg, 80%) which was obtained in the form of white foam. MS (ESI): 422.2 ([M+H] ⁺ ).

Example 187

(RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazin-3-carboxamide

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using racemic (RS)-oxepan-4 α-amine instead of (1,1-dioxytetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the racemic title compound (48 mg, 72%) which was obtained as a white foam. MS (ESI): 424.2 ([M+H] ⁺ ).

Example 188

6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1R,3S,4R)-7-oxabicyclo[2.2.1]heptan-3 -yl)pyridazine-3-carboxamide or enantiomer

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using racemic (1R*,3S*, 4R*)-7-oxabicyclo[2.2.1]heptan-2-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the racemic title compound (48 mg, 80%) which was obtained as a white precipitate. MS (ESI): 422.2 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Reprosil Chiral-NR) gave 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-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S,3R,4S)-7-oxabicyclo[2.2.1]heptan-3 -yl)pyridazine-3-carboxamide or enantiomer

By analogy with the experiment of Example 30, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using racemic (1S*,3R*, 4R*)-7-oxabicyclo[2.2.1]heptan-2-amine instead of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amine hydrochloride was converted to the racemic title compound (48 mg, 80%) which was obtained as a white precipitate. MS (ESI): 422.2 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Reprosil Chiral-NR) gave the enantiopure (-)-title compound (16 mg) which was obtained as a light brown gum. MS (ESI): 422.2 ([M+H] ⁺ ).

Example 190

N-((1R,3R)-3-ethoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

a) tert-butyl ((1R,3R)-3-ethoxycyclopentyl)carbamate

In analogy with Example 163a, tert-butyl ((1R,3R)-3-hydroxycyclopentyl)carbamate, using iodoethane instead of iodomethane, was converted to the title compound (35 mg, 31%) which was obtained as a colorless oil. MS (ESI): 174.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) (1R,3R)-3-ethoxycyclopentanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, tert-butyl ((1R,3R)-3-ethoxycyclopentyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in the title (33 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 130.1 ([M+H] ⁺ ).

c) N-((1R,3R)-3-ethoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1R,3R)-3- ethoxycyclopentanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (39 mg, 83%) which was obtained as a colorless amorphous substance. MS (ESI): 438.3 ([M+H] ⁺ ).

Example 191

N-((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide

a) tert-butyl ((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)carbamate

By analogy with the experiment of Example 163a, tert-butyl ((1R,3R)-3-hydroxycyclopentyl)carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate instead of iodomethane, was converted to the title compound (88 mg, 67%), which was obtained in the form of white crystals. MS (ESI): 210.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) (1R,3R)-3-(2,2-difluoroethoxy)cyclopentanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, tert-butyl ((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the title compound (38 mg, quantitatively) which was obtained as a light yellow oil. MS (ESI): 166.2 ([M+H] ⁺ ).

c) N-((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy) pyridazine-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using (1R,3R)-3- (2,2-difluoroethoxy)cyclopentanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (37 mg, 73%) which was obtained as a colorless amorphous substances: 474.3 ([M+H] ⁺ ).

Example 192

6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide

By analogy with Example 183, (5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol (building block P) instead of (5-cyclopropyl-3-(6-methyl- 3-pyridyl)isoxazol-4-yl)methanol (building block D) was converted to the title compound (15 mg, 31%) which was obtained as a white powder. MS (ESI): 429.2 ([M+H] ⁺ ).

Example 193

6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide

By analogy with the experiment of Example 183, (5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol (building block I) instead of (5-cyclopropyl-3-(6-methyl-3- pyridyl)isoxazol-4-yl)methanol (building block D) was converted to 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)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazine -3-carboxamide

a) trans-tert-butyl N-(4-(2,2-difluoroethoxy)cyclohexyl)carbamate

In analogy to Example 163a, trans-tert-butyl N-(4-hydroxycyclohexyl)carbamate, using 2,2-difluoroethyl trifluoromethanesulfonate in place of iodomethane, was converted to the title compound (69 mg, 53%) which was obtained as white crystals. MS (ESI): 224.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) trans-4-(2,2-difluoroethoxy)cyclohexanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, trans-tert-butyl N-(4-(2,2-difluoroethoxy)cyclohexyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the compound indicated in title (72 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 180.1 ([M+H] ⁺ ).

c) trans-N-4-((2,2-difluoroethoxy)cyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3- carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid using trans-4-(2,2 -difluoroethoxy)cyclohexanamine 2,2,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to the title compound (15 mg, 17%) which was obtained as a white powder. MS (ESI): 488.2 ([M+H] ⁺ ).

Example 195

N-(4-ethoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazin-3-carboxamide

a) trans-tert-butyl N-(4-ethoxycyclohexyl)carbamate

In analogy to Example 163a, trans-tert-butyl N-(4-hydroxycyclohexyl)carbamate, using iodoethane instead of iodomethane, was converted to the title compound (20 mg, 18%) which was obtained as a white precipitate. MS (ESI): 188.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) trans-4-ethoxycyclohexanamine 2,2,2-trifluoroacetate

By analogy with the experiment of Example 163b, trans-tert-butyl N-(4-ethoxycyclohexyl)carbamate instead of trans-tert-butyl N-(3-methoxycyclobutyl)carbamate was converted to the title compound (21 mg, quantitatively), which was obtained as a light yellow oil. MS (ESI): 144.1 ([M+H] ⁺ ).

c) trans-N-(4-ethoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide

By analogy with Example 163c, 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylic acid using trans-4-ethoxycyclohexanamine 2,2 ,2-trifluoroacetate instead of trans-3-methoxycyclobutanamine 2,2,2-trifluoroacetate was converted to 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-(3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridazin-3-carboxamide

a) (3Z)-N-hydroxypyridine-3-carboximidoyl chloride

To a stirred solution of (3E)-pyridine-3-carbaldehyde oxime (25.0 g, 205 mmol) in DMF (205 ml) at room temperature was added N-chlorosuccinimide (27.34 g, 205 mmol) in small portions (note: the reaction is exothermic). 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 by filtration on a Schott funnel, then washed with water (50 ml) and dried under high vacuum to give the title compound (16.53 g, 52%) as a light brown precipitate. MS (ESI): 157.0 ([M+H] ⁺ ).

b) ethyl 5-methyl-3-(3-pyridyl)isoxazole-4-carboxylate

To a stirred suspension of (3Z)-N-hydroxypyridine-3-carboximidoyl chloride (18.6 g, 119 mmol) in Et ₂ O (202 ml) at 0°C was added ethyl but-2-inoate (13.9 ml, 119 mmol) followed by Et ₃ N (19.9 ml, 143 mmol). After 30 min the mixture was allowed to warm to room temperature and the resulting suspension was stirred overnight. The reaction mixture was poured into a 1:1 mixture of brine and water (150 ml) and extracted with EtOAc (2×100 ml). The organic phase was filtered through a schott funnel to remove the insoluble brown precipitate, then the filtrate was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 20% to 80% EtOAc in heptane) gave the title compound (8.11 g, 29%) as a grey-white precipitate. MS (ESI): 233.1 ([M+H] ⁺ ).

c) (5-methyl-3-(3-pyridyl)isoxazol-4-yl)methanol

By analogy with the experiment for the structural block M c, ethyl 5-methyl-3-(3-pyridyl)isoxazole-4-carboxylate instead of ethyl 3-(6-methoxy-3-pyridyl)-5-methyl-isoxazole-4-carboxylate was converted to the title compound (4.32 mg, 66%) which was obtained as a light yellow precipitate. MS (ESI): 191.2 ([M+H] ⁺ ).

d) 4-((6-chloropyridazin-3-yl)oxymethyl)-5-methyl-3-(3-pyridyl)isoxazole

By analogy with the experiment of Example 23a, (5-methyl-3-(3-pyridyl)isoxazol-4-yl)methanol instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (building block A) was converted to the title compound (2.53 g, 81%) which was obtained as a light yellow precipitate. MS (ESI): 303.1 ([M+H] ⁺ ).

e) ethyl 6-((5-methyl-3-(3-pyridyl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

By analogy with the experiment of Example 23b, 4-((6-chloropyridazin-3-yl)oxymethyl)-5-methyl-3-(3-pyridyl)isoxazole instead of 4-((6-chloropyridazin-3-yloxy)methyl)- 5-methyl-3-(6-methylpyridin-3-yl)isoxazole was converted to the title compound (1.91 g, 69%) which was obtained as a light yellow precipitate. MS (ESI): 341.2 ([M+H] ⁺ ).

f) 6-((5-methyl-3-(3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridazin-3-carboxamide

By analogy with the experiment of Example 1b, ethyl 6-((5-methyl-3-(3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxylate instead of methyl 6-((5-methyl-3-(6 -methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxylate was converted to the title compound (122 mg, 77%) which was obtained as a grey-white precipitate. MS (ESI): 396.2 ([M+H] ⁺ ).

Reference Example RE-B

6-((3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridazin-3-carboxamide

a) (2E)-5-chloropyridine-2-carbaldehyde oxime

By analogy with the experiment for building block Ia, 5-chloropyridine-2-carbaldehyde was converted to the title compound (6.74 g, 89%), which was obtained as a light brown precipitate. MS (ESI): 157.0 ([M+H] ⁺ ).

b) ethyl 3-(5-chloro-2-pyridyl)-5-methyl-isoxazole-4-carboxylate

To a stirred suspension of (2E)-5-chloropyridine-2-carbaldehyde oxime (1.00 g, 6.40 mmol) in CHCl ₃ (20 ml) at room temperature was added a solution of N-chlorosuccinimide (853 mg, 6.40 mmol) in CHCl ₃ (20 ml ) followed by a catalytic amount of pyridine (51 mL, 0.64 mmol). After 30 minutes, the mixture was heated to 50° C. for 3 hours. The resulting brown suspension was allowed to warm to room temperature before adding a solution of (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (1.170 g, 6.40 mmol) in CHCl ₃ (0.8 ml). The reaction mixture was heated to 50°C followed by the addition of a solution of Et ₃ N (0.890 ml, 6.4 mmol) in CHCl ₃ (0.8 ml). The reaction mixture was stirred at 50° C. for 30 min before being poured into ice water (50 ml) and extracted with CH ₂ Cl ₂ (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient: 0% to 50% EtOAc in heptane) gave the title compound (1.35 g, 79%) as a light yellow oil. MS (ESI): 267.1 ([M+H] ⁺ ).

c) (3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methanol

By analogy with the experiment for the structural block M c, ethyl 3-(5-chloro-2-pyridyl)-5-methyl-isoxazole-4-carboxylate instead of ethyl 3-(6-methoxy-3-pyridyl)-5-methyl- isoxazole-4-carboxylate was converted to the title compound (773 mg, 73%) which was obtained as a grey-white precipitate. MS (ESI): 225.0 ([M+H] ⁺ ).

d) 4-((6-chloropyridazin-3-yl)oxymethyl)-3-(5-chloro-2-pyridyl)-5-methyl-isoxazole

By analogy with the experiment of Example 23a, (3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methanol instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol- 4-yl)methanol (building block A) was converted to the title compound (2.47 g, 83%) which was obtained as a light brown precipitate. MS (ESI): 337.0 ([M+H] ⁺ ).

f) ethyl 6-((3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridazine-3-carboxylate

By analogy with the experiment of Example 23b, 4-((6-chloropyridazin-3-yl)oxymethyl)-3-(5-chloro-2-pyridyl)-5-methyl-isoxazole instead of 4-((6-chloropyridazin-3- yloxy)methyl)-5-methyl-3-(6-methylpyridin-3-yl)isoxazole was converted to the title compound (1.89 g, 72%) which was obtained as a white precipitate. MS (ESI): 375.1 ([M+H] ⁺ ).

f) 6-((3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid

By analogy with the experiment of Example 23c, ethyl 6-((3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridazine-3-carboxylate instead of ethyl 6-((5-methyl -3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylate was converted to the title compound (1.57 g, 93%) which was obtained as a white precipitate. MS (ESI): 347.1 ([M+H] ⁺ ).

g) 6-((3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide

By analogy with the experiment of Example 23d, 6-((3-(5-chloro-2-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid instead of 6-((5-methyl- 3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxylic acid was converted to the title compound (69mg, 64%) which was obtained as a white precipitate. MS (ESI): 430.1 ([M+H] ⁺ ).

Claims (567)

1. Compounds of formula (I)

where X is selected from i) N and ii) CH; Y is selected from i) N and ii) CR ¹⁰ ; Z is selected from i) N and ii) CR ¹¹ ; R ¹ is selected from i) C _1-6 -alkyl, ii) halo-C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) halo-C _1-6 -alkoxy, v) hydroxy-C _1-6 -alkyl, vi) C _3-8 -cycloalkyl, vii) halogen and viii) amino substituted on the nitrogen atom with one or two substituents independently selected from (a) H, (b) C _1-6 -alkyl and (c) C _3-8 cycloalkyl; R ² is selected from i) H and ii) halogen; R ³ is selected from i) H, ii) C _1-6 -alkyl, iii) C _3-8 -cycloalkyl, iv) hydroxy-C _1-6 -alkyl and v) halo-C _1-6 -alkyl; R ⁴ selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _3-8 -cycloalkyl and v) halogen; R ⁵ is H; R ⁶ selected from i) H, ii) C _1-6 -alkyl, iii) C _3-8 cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ , v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl, vi) cyano-C _1-6 -alkyl, vii) hydroxy-C _1-6 -alkyl, viii) dihydroxy-C _1-6 -alkyl, ix) halo-C _1-6 -alkyl, x) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , wherein the heterocycloalkyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiolanyl, oxaspiro-[3.3]heptanyl, tetrahydrothiopyranyl, 7-oxabicyclo[2.2.1]heptanyl and oxepanyl, and xi) heterocycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where heterocycloalkyl represents oxetanyl; R ⁷ , R ⁸ and R ⁹ are independently selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _1-6 alkoxyalkyl, v) C _1-6 -alkoxycarbonyl, vi) cyano, vii) C _3-8 -cycloalkoxy, viii) C _3-8 -cycloalkyl, ix) halo-C _1-6 -alkoxy, x) halo-C _1-6 -alkyl, xi) halogen, xii) hydroxy, xiii) hydroxy-C _1-6 -alkyl and xiv) oxo; R ¹⁰ selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _3-8 -cycloalkyl and v) halogen; R ¹¹ selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _3-8 -cycloalkyl and v) halogen; or R ⁵ and R ¹⁰ together form -(CH ₂ ) _n -; or R ⁵ and R ¹¹ together form -(CH ₂ ) _n -; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxa-6-azaspiro[3.3]heptanyl , 2-thia-6-azaspiro[3.3]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, thiomorpholinyl or azaspiro[3.3]heptanyl; n is selected from 1 and 2; or pharmaceutically acceptable salts. 2. Connection according to claim 1, where X selected from i) N and ii) CH; Y is selected from i) N and ii) CR ¹⁰ ; Z is selected from i) N and ii) CR ¹¹ ; R ¹ is selected from i) C _1-6 -alkyl, ii) halo-C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _3-8 -cycloalkyl, v) halogen and vi) amino substituted on the nitrogen atom with two independently selected C _1-6 alkyls; R ² is selected from i) H, ii) halogen; R ³ is selected from i) H, ii) C _1-6 -alkyl, iii) C _3-8 -cycloalkyl and iv) halo-C _1-6 -alkyl; R ⁴ selected from i) H and ii) C _1-6 alkyl; R ⁵ is H; R ⁶ selected from i) H, ii) C _1-6 -alkyl, iii) C _3-8 -cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy, (d) C _1-6 alkoxyalkyl, (e) C _1-6 -alkoxycarbonyl, (f) cyano, (g) C _3-8 -cycloalkoxy, (h) halo-C _1-6 -alkoxy, (i) halo-C _1-6 -alkyl, (j) halogen, (k) hydroxy and (l) hydroxy-C _1-6 -alkyl; iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy, (d) C _1-6 alkoxyalkyl, (e) C _1-6 -alkoxycarbonyl, (f) cyano, (g) C _3-8 -cycloalkoxy, (h) halo-C _1-6 -alkoxy, (i) halo-C _1-6 -alkyl, (j) halogen, (k) hydroxy and (l) hydroxy-C _1-6 -alkyl; v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl, vi) cyano-C _1-6 -alkyl, vii) dihydroxy-C _1-6 -alkyl, viii) halo-C _1-6 -alkyl, ix) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) hydroxy and (d) oxo; and where heterocycloalkyl is selected from (a) oxetanil, (b) tetrahydrofuranyl, (c) tetrahydropyranyl, (d) oxepanil, (e) 7-oxabicyclo[2.2.1]heptanyl, (f) oxaspiro[3.3]heptanyl, (g) tetrahydrothiopyranil; and x) oxetanyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) hydroxy; R ¹⁰ selected from i) H and ii) halogen; R ¹¹ selected from i) H, ii) C _1-6 -alkyl and iii) C _1-6 alkoxy; or R ⁵ and R ¹⁰ together form -(CH ₂ ) _n -; or R ⁵ and R ¹¹ together form -(CH ₂ ) _n -; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy, (d) cyano, (e) halogen, (f) hydroxy and (g) oxo; and where heterocycloalkyl is selected from (a) azetidinyl, (b) pyrrolidinyl, (c) piperidinil, (d) morpholinyl, n is 1; or pharmaceutically acceptable salts. 3. Connection according to claim 1, where X selected from i) N and ii) CH; Y is selected from i) N and ii) CR ¹⁰ ; Z is selected from i) N and ii) CR ¹¹ ; R ¹ is selected from i) C _1-6 -alkyl, ii) halo-C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _3-8 -cycloalkyl, v) halogen and vi) amino substituted on the nitrogen atom with two independently selected C _1-6 alkyls; R ² is selected from i) H, ii) halogen; R ³ is selected from i) H, ii) C _1-6 -alkyl, iii) C _3-8 -cycloalkyl and iv) halo-C _1-6 -alkyl; R ⁴ selected from i) H and ii) C _1-6 alkyl; R ⁵ is H; R ⁶ selected from i) H, ii) C _1-6 -alkyl, iii) C _3-8 -cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy, (d) C _1-6 alkoxyalkyl, (e) C _1-6 -alkoxycarbonyl, (f) cyano, (g) C _3-8 -cycloalkoxy, (h) halo-C _1-6 -alkoxy, (i) halo-C _1-6 -alkyl, (j) halogen, (k) hydroxy and (l) hydroxy-C _1-6 -alkyl; iv) C _3-8 -cycloalkyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy, (d) C _1-6 alkoxyalkyl, (e) C _1-6 -alkoxycarbonyl, (f) cyano, (g) C _3-8 -cycloalkoxy, (h) halo-C _1-6 -alkoxy, (i) halo-C _1-6 -alkyl, (j) halogen, (k) hydroxy and (l) hydroxy-C _1-6 -alkyl; v) C _1-6 -alkylsulfonyl-C _1-6 -alkyl, vi) cyano-C _1-6 -alkyl, vii) dihydroxy-C _1-6 -alkyl, viii) halo-C _1-6 -alkyl, ix) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) hydroxy and (d) oxo; and where heterocycloalkyl is selected from (a) oxetanil, (b) tetrahydrofuranyl, (c) tetrahydropyranyl, (d) oxepanil, (e) 7-oxabicyclo[2.2.1]heptanyl, (f) oxaspiro[3.3]heptanyl, (g) tetrahydrothiopyranil; and x) oxetanyl-C _1-6 -alkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) hydroxy; R ¹⁰ selected from i) H and ii) halogen; R ¹¹ selected from i) H, ii) C _1-6 -alkyl and iii) C _1-6 alkoxy; or pharmaceutically acceptable salts. 4. Connection according to claim 1, where X selected from i) N and ii) CH; Y is selected from i) N and ii) CR ¹⁰ ; Z is CR ¹¹ ; R ¹ is C _1-6 alkyl; R ² is selected from i) H, ii) halogen; R ³ is selected from i) C _1-6 -alkyl, ii) C _3-8 -cycloalkyl and iii) halo-C _1-6 -alkyl; R ⁴ selected from i) H and ii) C _1-6 alkyl; R ⁵ is H; R ⁶ selected from i) C _1-6 -alkyl, ii) C _3-8 -cycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxyalkyl and (d) halo-C _1-6 -alkyl; iii) hydroxy-C _1-6 -alkyl, iv) halo-C _1-6 -alkyl, v) heterocycloalkyl substituted with R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ are independently selected from (a) H and (b) C _1-6 alkyl; and where heterocycloalkyl is selected from (a) oxetanil, (b) tetrahydrofuranyl, (c) tetrahydropyranyl, (d) oxepanil and (e) oxaspiro[3.3]heptanil; R ¹⁰ is H; R ¹¹ is H; or pharmaceutically acceptable salts. 5. Connection according to claim 1, where X is CH; Y is N; Z is CR ¹¹ ; R ¹ is C _1-6 alkyl; R ² is H; R ³ is C _1-6 alkyl; R ⁴ is H; R ⁵ is H; R ¹¹ is H; or pharmaceutically acceptable salts. 6. Connection according to claim 1, where X is CH; Y is N; Z is CR ¹¹ ; R ¹ is C _1-6 alkyl; R ² is H; R ³ is C _1-6 alkyl; R ⁴ is H; R ⁵ is H; R ⁶ is tetrahydropyranyl substituted with R ⁷ , R ⁸ and R ⁹ ; R ⁷ , R ⁸ and R ⁹ are H; R ¹¹ is H; or pharmaceutically acceptable salts. 7. Connection according to any one of paragraphs. 1-6 selected from 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide; N-ethyl-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide; N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide; 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide; 6-((5-cyclopropyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; (S)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide; 2-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one ; 2-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one ; N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; 2-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine-3( 2H) - she; (S)-2-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3, 4-c]pyridin-3(2H)-one; (S)-N-(1-hydroxypentan-2-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; 5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-((3S)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridine-3-carboxamide; N-((3R)-1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridine-3-carboxamide; N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridin-3- carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one; N-((1S,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-((1S,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-((1R,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-((1R,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-((3S,4R)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide ; N-(2-hydroxyethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(1,1-dioxothian-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyridazin-3- carboxamide; N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(cyclopropylmethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(2-cyanoethyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazin-3 -carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyridazin-3-carboxamide; (RS)-N-(1,1-dioxothiolan-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy) pyridazine-3-carboxamide; N-ethyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-isobutyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide; N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(3,3-difluorocyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide; N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (3,3-difluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; (3,3-difluoropyrrolidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3-methyloxetan-3-yl)methyl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-ylmethyl)pyridazine-3-carboxamide; N-((3-hydroxyoxetan-3-yl)methyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((3R,4R)-3-methyltetrahydropyran-4-yl)pyridazine-3-carboxamide ; (4,4-difluoropiperidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (3-methoxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; (3-hydroxy-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; azetidin-1-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; (RS)-N-(2,2-dimethyltetrahydropyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide ; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide; (6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(morpholino)methanone; (6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl ) methanone; 4-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; (6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl ) methanone; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridazin-3 -carboxamide; (3-fluoroazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; (3-hydroxyazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; (3-fluoro-3-methylazetidin-1-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl)methanone; ethyl 1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamido)cyclopropanecarboxylate; N-(1-cyanocyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; N-(1,1-dioxothian-4-yl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; N-(2-hydroxy-1,1-dimethyl-ethyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; N-cyclopropyl-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazin-3-carboxamide; 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(oxetan-3-yl)pyrazine-2-carboxamide; 5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide; N-(4-hydroxy-2-methylbutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)pyridazin-3- carboxamide; (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide; (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide; 1-(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carbonyl)azetidine-3-carbonitrile; N-(1-(hydroxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(4,4-difluorocyclohexyl)-5-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide; (S)-N-(1-cyanobutan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (R)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide; N-(2-hydroxyethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; 2-(1,1-dioxothian-4-yl)-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]-1H-pyrrolo [3,4-c]pyridin-3-one; (S)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyrazine-2-carboxamide; 2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy]-6-tetrahydropyran-4-yl-7H-pyrrolo[3,4-b]pyridin-5- she is; N-(1,1-dioxothiolan-3-yl)-5-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methoxy)pyrazin-2- carboxamide; N-(cyclopropylmethyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; 2-(4,4-difluorocyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-1H-pyrrolo[3,4-c]pyridine- 3(2H)-she; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide; (R)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-3-yl)pyrazine-2-carboxamide ; (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide; 5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyrazine-2-carboxamide; 5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-((cis)-4-(trifluoromethyl)cyclohexyl)pyrazine-2-carboxamide; (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide; N-((cis)-4-hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; N-((trans)-4-hydroxy-4-methylcyclohexyl)-5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)nicotinamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrrolo[3,4- c]pyridin-3(2H)-one; 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydrothiopyran-4-yl)pyridazine-3-carboxamide; N-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide; (2,2-dioxydo-2-thia-6-azaspiro[3.3]heptan-6-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyridazin-3-yl)methanone; (2,2-dioxydo-2-thia-6-azaspiro[3.3]heptan-6-yl)(5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyrazin-2-yl)methanone; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopentyl)pyridazin-3-carboxamide; 5-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4,4,4-trifluorobutyl)pyrazine-2-carboxamide; N-(1-isopropylazetidin-3-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-2-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3, 4-c]pyridin-3(2H)-one; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazin-3-carboxamide; 6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide; N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; 6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; 6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide; N-cyclopropyl-6-((5-ethyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (R)-N-(1-hydroxypentan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide; 6-((5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; N-((3R,4S)-3-hydroxytetrahydropyran-4-yl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide ; 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3-carboxamide; 6-((3-(6-cyclopropyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-(1,1-dioxothian-4-yl)pyridine-3-carboxamide; N-((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; N-((1R,2R)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide ; N-((1S,2S)-2-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; 2-fluoro-N-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)nicotinamide; 6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide; N-isopropyl-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)nicotinamide; (S)-N-(1-hydroxypentan-2-yl)-6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)nicotinamide; (1,1-dioxidothiomorpholino)(6-((3-(6-methoxypyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone; (S)-6-((3-(6-(dimethylamino)pyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(1-hydroxypentan-2-yl)nicotinamide; 4-methoxy-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide; 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-tetrahydropyran-4-yl-pyridine-3-carboxamide; 6((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-isopropyl-pyridine-3-carboxamide; 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3 -carboxamide; N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide ; N-(1,3-dihydroxy-2-methylpropan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide ; N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide ; N-((1R,3S)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide; N-((1S,3R)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide; (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy )pyridazin-3-yl)methanone; N-((1RS,3RS)-3-hydroxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; trans-N-(4-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; trans-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3 -yl) methanone; N-(3-hydroxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl(6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-yl ) methanone; cis-N-(4-methoxycyclohexyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide; (S)-6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide; 6-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide; trans-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; cis-N-(3-methoxycyclobutyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide; trans-N-((1RS,3RS)-3-methoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-(6,6-difluorospiro[3.3]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide ; 6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; cis-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; trans-N-3-((2,2-difluoroethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; cis-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; trans-N-(3-ethoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; cis-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; trans-N-(3-(difluoromethoxy)cyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; trans-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; cis-N-(3-cyclopropoxycyclobutyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazin-3-carboxamide; 6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide; (S)-6-((3-(6-chloropyridin-3-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide; 6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide; (S)-6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; 6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; N-((2S)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide; (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)-N-((1R,3S,4R)-7-oxabicyclo[2.2.1]heptan-3 -yl)pyridazine-3-carboxamide; N-((2R)-7-oxabicyclo[2.2.1]heptan-2-yl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine -3-carboxamide; N-((1R,3R)-3-ethoxycyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazine-3-carboxamide; N-((1R,3R)-3-(2,2-difluoroethoxy)cyclopentyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin- 3-carboxamide; 6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide; N-[4-(2,2-difluoroethoxy)cyclohexyl]-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridazin-3 -carboxamide; N-(4-ethoxycyclohexyl)-6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridazin-3-carboxamide; or pharmaceutically acceptable salts. 8. Connection according to any one of paragraphs. 1-7 selected from N-((1S)-1-(hydroxymethyl)butyl)-6-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methoxy)pyridine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide; N-cyclopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1,1,1-trifluoropropan-2-yl)pyridazin-3 -carboxamide; N-isopropyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-tert-butyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; N-(1-(methoxymethyl)cyclopropyl)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-(trifluoromethyl)cyclopropyl)pyridazine-3-carboxamide; 5-methyl-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclopropyl)pyridazin-3-carboxamide; (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide; (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyltetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide; (S)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydrofuran-3-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(4-methyltetrahydro-2H-pyran-4-yl)pyridazine-3-carboxamide; (R)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-3-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(2-oxaspiro[3.3]heptan-6-yl)pyridazine-3-carboxamide; 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(1-methylcyclobutyl)pyridazin-3-carboxamide; 6-((3-(5-fluoro-6-methyl-3-pyridyl)-5-methyl-isoxazol-4-yl)methoxy)-N-((1S)-1-(hydroxymethyl)butyl)pyridine-3 -carboxamide; 6-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide; 6-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; 6-((5-cyclopropyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(3-methyloxetan-3-yl)pyridazine-3-carboxamide; (RS)-6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(oxepan-4-yl)pyridazin-3-carboxamide; 6-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide; 6-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxamide; or pharmaceutically acceptable salts. 9. Connection according to any one of paragraphs. 1-8, where the compound is 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydro-2H-pyran-4-yl)pyridazine -3-carboxamide or pharmaceutically acceptable salts. 10. Connection according to any one of paragraphs. 1-9 for use as a therapeutically active substance to modulate GABA _A α5 receptor activity. 11. Pharmaceutical composition for modulating the activity of the GABA _A α5 receptor, containing an effective amount of the compound according to any one of paragraphs. 1-9 and a therapeutically inert carrier. 12. The use of a compound according to any one of paragraphs. 1-9 for the treatment or prevention of diseases associated with GABA _A receptors α5. 13. Connection according to any one of paragraphs. 1-9 for the treatment or prevention of diseases associated with GABA _A receptors α5. 14. The use of a compound according to any one of paragraphs. 1-9 for the preparation of a medicament for the treatment or prevention of diseases associated with GABA _A α5 receptors. 15. A method of treating or preventing diseases associated with GABA _A α5 receptors, which includes administering an effective amount of a compound according to any one of paragraphs. 1-9.