RU2800160C2 - New isoxazolil ether derivatives as pam gaba a alfa5 - Google Patents

Abstract

FIELD: organic compounds.

SUBSTANCE: invention relates to organic compounds useful for the treatment or prevention of diseases in mammals. The invention provides new compounds that have the general formula (I) or (II), where R², R³, R⁵, R⁹⁹, W, Y and Z are presented in the claims, and a pharmaceutical composition containing these compounds.

EFFECT: compounds have the activity of a positive allosteric modulator of GABA_A receptors α5 and can be used to treat or prevent Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, fragile X disorder.

14 cl, 2 tbl, 335 ex

Description

This invention relates to organic compounds useful for the treatment or prevention of mammals, and in particular to positive allosteric modulators (PAM) of GABA _A α5 receptors for the treatment or prevention of diseases associated with the GABA _A α5 receptor, and diseases or disorders that can be treated by modulating the activity of the GABA _A α5 receptor, such as 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 disorder.

The present invention provides a new compound of Formula (I) and (II)

W choose from

i) N and

ii) CR ⁴ ;

Y choose from

i) N and

ii) CH;

Z choose from

i) N and

ii) CH;

R ⁹⁹ choose from

i) C _1-6 -alkyl,

ii) C _1-6 -alkoxy,

iii) halo-C _1-6 -alkoxy,

iv) hydroxy-C _1-6 -alkyl,

v) C _3-8 -cycloalkyl,

vi) H and

vii) halogen;

R ² choose from

i) H,

ii) halogen,

iii) C _1-6 -alkyl,

iv) C _3-8 -cycloalkyl and

v) halo-C _1-6 -alkyl;

R ³ choose from

i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ ,

ii) amino substituted on the nitrogen atom with one or two substituents independently selected from R ⁹ and R ¹⁰ ,

iii) aryl substituted with R ¹¹ , R ¹² and R ¹³ and

iv) heteroaryl substituted with R ¹¹ , R ¹² and R ¹³ ;

R ⁴ choose from

1) H,

ii) C _1-6 -alkyl,

iii) halo-C _1-6 -alkyl,

iv) C _1-6 -alkoxy,

v) C _3-8 -cycloalkyl and

vi) halogen;

R ⁵ choose from

i) H,

ii) C _1-6 -alkyl,

iii) C _3-8 -cycloalkyl,

iv) halo-C _1-6 -alkyl and

v) halogen;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _1-6 -alkoxy-C _1-6 -alkyl,

v) C _1-6 -alkoxycarbonyl,

vi) cyano,

vii) amino substituted on the nitrogen atom with one or two substituents independently selected from R ²² and R ²³ ,

viii) C _3-8 -cycloalkyl, where C _3-8 -cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ ,

ix) C _3-8 -cycloalkoxy, where C _3-8 -cycloalkoxy is substituted with R ²⁴ , R ²⁵ and R ²⁶ ,

x) C _3-8 -cycloalkyl-C _1-6 -alkoxy, where C _3-8 -cycloalkyl-C _1-6 -alkoxy is substituted with R ²⁴ , R ²⁵ and R ²⁶ ,

xi) C _3-8 -cycloalkylaminocarbonyl, where C _3-8 -cycloalkylaminocarbonyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ ,

xii) C _3-8 -cycloalkylcarbonyl, where C _3-8 -cycloalkylcarbonyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ ,

xiii) C _3-8 -cycloalkyl-C _1-6 -alkoxycarbonyl, where C _3-8 -cycloalkyl-C _1-6 -alkoxycarbonyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ ,

xiv) aryloxy substituted with R ²⁷ , R ²⁸ and R ²⁹ ,

xv) aryl substituted with R ²⁷ , R ²⁸ and R ²⁹ ,

xvi) heteroaryl substituted with R ²⁷ , R ²⁸ and R ²⁹ ,

xvii) heteroaryloxy substituted with R ²⁷ , R ²⁸ and R ²⁹ ,

xviii) halo-C _1-6 -alkoxy,

xix) halo-C _1-6 -alkyl,

xx) halogen,

xxi) hydroxy,

xxii) hydroxy-C _1-6 -alkyl and

xxiii) oxo;

R ⁹ and R ¹⁰ are independently selected from

i) H,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkyl,

iv) heterocycloalkyl substituted with R ³⁰ , R ³¹ and R ³² ,

v) heterocycloalkyl-C _1-6 -alkyl substituted with R ³⁰ , R ³¹ and R ³² ,

vi) hydroxy-C _1-6 -alkyl,

vii) C _1-6 -alkoxy,

viii) C _3-8 -cycloalkyl and

ix) halogen;

R ¹¹ , R ¹² and R ¹³ are independently selected from

i) H,

ii) hydroxy,

iii) hydroxy-C _1-6 -alkyl,

iv) C _1-6 -alkoxy,

v) C _1-6 -alkyl,

vi) cyano,

vii) arila,

viii) C _3-8 -cycloalkyl,

ix) halo-C _1-6 -alkyl,

x) halogen-C _1-6 -alkoxy,

xi) heteroaryl,

xii) amino substituted on the nitrogen atom with one or two substituents independently selected from R ¹⁴ and R ¹⁵ ,

xiii) C _3-8 -cycloalkyl-C _1-6 -alkyl,

xiv) heterocycloalkyl substituted with R ¹⁶ , R ¹⁷ and R ¹⁸ ,

xv) heterocycloalkoxy substituted with R ¹⁶ , R ¹⁷ and R ¹⁸ ,

xvi) heterocycloalkyl-C _1-6 -alkyl substituted with R ¹⁶ , R ¹⁷ and R ¹⁸ ,

xvii) halogen;

R ¹⁴ and R ¹⁵ are independently selected from

i) H and

ii) C _1-6 alkyl;

R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from

i) H,

ii) halogen,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) C _1-6 alkyl;

R ²² and R ²³ are independently selected from

i) H,

ii) C _1-6 -alkyl and

iii) C _1-6 -alkylcarbonyl;

R ²⁴ , R ²⁵ and R ²⁶ are independently selected from

i) C _1-6 -alkyl,

ii) H,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) halo-C _1-6 -alkyl,

vi) halo-C _1-6 -alkoxy,

vii) halogen,

viii) hydroxy and

ix) oxo;

R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

i) H,

ii) C _1-6 -alkoxy,

iii) C _1-6 -alkyl,

iv) C _3-8 -cycloalkyl and

v) halogen;

R ³⁰ , R ³¹ and R ³² are independently selected from

1) H,

ii) halogen,

iii) C _1-6 -alkoxy,

vi) C _3-8 -cycloalkyl,

vii) C _1-6 alkyl;

or pharmaceutically acceptable salts.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), fall into two main classes: (1) GABA _A receptors, which are members of the ligand-gated ion channel superfamily, and (2) GABA _B receptors, which are members of the G-protein-coupled receptor family. The GABA _A receptor complex, which is a membrane-bound heteropentameric protein polymer, consists predominantly of α, β, and γ subunits. GABA _A 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 a pentamer, with the most common stoichiometry being two α, two β, and one γ subunit. Combinations of GABA _A subunits generate functional, chain, and behavioral specificity (Sieghart, 2006; Vithlani et al., 2011). GABA _A receptors containing the α5 subunit (GABA _A α5) are of particular interest due to their limited expression pattern and unique physiological and pharmacological properties (Sur et al., 1999; Mohler, 2011). Receptors containing GABA _A α5 subunits are predominantly localized in the hippocampus, prefrontal cortex, accumulative nucleus, and amygdala, which are key regions thought to be involved in the neuropathology and pathophysiology of various CNS disorders.

Hyperactivity of the hippocampus as a result of reduced expression of GABA _A α5 or GABA deficiency or other conditions is a common feature of various CNS disorders characterized by a decrease in cognitive functions (memory and executive function). For such a pathological condition, a positive allosteric modulator (PAM) of GABA _A α5, rather than a negative allosteric modulator (NAM), may be an effective treatment for cognitive impairment associated with such diseases.

Numerous data suggest that an imbalance between excitatory/inhibitory neurotransmission resulting from GABA dysfunction of the signal transduction system, the main system of inhibitory neurotransmission in the brain, should underlie 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 circuit balance (C/T) in these disorders. 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, Rett syndrome, Down syndrome; neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ABS), fragile X disorder, AIDS dementia, age-related memory impairment, psychotic disorders, psychotic substance use disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorder, acute stress disorder a, post-traumatic stress disorder (PTSD), addiction, movement disorder, Parkinson's disease, restless legs syndrome, mild cognitive impairment (MCI), cognitive impairment disorders, age-related cognitive decline, multi-infarction dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit/hyperactivity disorder, neuropathic pain, epilepsy, stroke, and attention disorders.

The most preferred indication according to the present invention is autism spectrum disorder (ASD). ASD is a complex, heterogeneous developmental disorder of the central nervous system characterized by worsening of three main symptoms: social interaction, repetitive behavior, and cognitive deficits. The estimated prevalence of ASD in the US is 1 in 68 children (CDC, 2014), and 1% of the world's population has ASD (WHO, 2013).

There is no single approved pharmacological treatment for the underlying social communication deficits and recurring deficits in Autism Spectrum Disorder (ASD), and the disorder continues to be an area of highly unmet medical need. To date, approved treatments for associated ASD symptoms are limited to antipsychotics (risperidone and aripiprazole) for the treatment of irritability associated with ASD symptoms. New evidence suggests that the GABA system, the brain's major inhibitory neurotransmitter system, 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 GABA signaling in ASD. [ ¹²³ I]-yomazenil PET has been reported to dramatically decrease GABA receptor binding in the superior and medial frontal cortex of ASD patients (Mori et al., 2012). In addition, a pilot PET study with [ ¹¹ C]-RO154513 revealed reduced binding of this indicator, suggesting a decrease in GABA _A receptor α5 in ASD (Mendez et al., 2012). The MRS study has found altered GABA levels in ASD (Gaetz et al., 2014; Rojas et al., 2014) and, in particular, some recent studies have shown decreased GABA and altered somatosensory function in children with ASD (Puts et al., 2016; Robertson et al., 2016). Consistent with these observations, a post-mortem decrease in the expression of GABA _A receptor subunits, including GAMR _B3 (DeLorey, 2005; Abrahams and Geschwind, 2008) and the GABA-synthesizing enzymes, glutamic acid decarboxylase (GCD) 65 and 67, was found in the parietal and cerebellar cortex of autistic patients (Fatemi et al., 20). 02). Importantly, it has been argued that a decrease in GABA inhibitory activity leads to the increased excitability that is seen in ASD, including a high frequency of seizures and auditory and tactile sensitivity (Rubenstein and Merzenich, 2003; Frye et al., 2016). Altered GABA function can lower the seizure threshold, as demonstrated by the high comorbidity of epilepsy in ASD, which occurs in about a third of affected individuals. Finally, enhancement of GABA _A receptor activity by non-selective BZDs has been shown to reduce behavioral deficits in mouse models of ASD, but very narrow therapeutic margins have been observed due to sedation mediated by the GABA _A α1 subtype (Han et al., 2012, 2014; Soto et al. 2013). These results support the notion that balancing GABA transmission through GABA _A α5 receptors can improve ASD symptoms without the side effects associated with non-selective benzodiazepines.

Objects of the present invention are compounds of Formula (I) or (II) and their pharmaceutically acceptable salts and esters, the preparation of the above compounds, drugs containing them and their manufacture, as well as the use of the above compounds for the treatment or prevention of diseases associated with the GABA _{A α5 receptor, and diseases or disorders that can be treated by modulating the activity of the GABA A α5} receptor, such as 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 disorder. The compounds of this invention are selective positive allosteric modulators (SAMs) of the GABA _A α5 receptor because they enhance the function of receptors that contain GABA _A α5 by increasing the GABA flux (chloride influx) at a given concentration of gamma-aminobutyric acid (GABA) EC ₂₀ . The compounds of this invention have a higher effect as PAM than compounds known in the art. In a preferred embodiment, the compounds of this invention bind selectively to α5 subunits over α1, α2 and α3 subunits. Compatible with the α5 subtype distributed in the brain, selective GABA _A α5 PAMs will restore GABA 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). In another preferred embodiment, the compounds of this invention have improved chemical stability, especially under low and high pH conditions.

The term "C _1-6 -alkyl" means a monovalent linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. Examples of C _1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and pentyl. Specific C _1-6 alkyl groups are methyl, ethyl, isopropyl, isobutyl and tert-butyl. A more specific example is methyl.

The term "C _1-6 -alkoxy" means a group of 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 t-butoxy, methoxy, ethoxy and isopropoxy. More specific examples are ethoxy, methoxy and tert-butoxy. A more specific example is tert-butoxy.

The terms "halogen" and "halo" in this document are used interchangeably and mean fluorine, chlorine, bromine or iodine. Specific halogens include fluorine and chlorine.

The term "halo-C _1-6 -alkoxy" means a C _1-6 -alkoxy group, where at least one of the hydrogen atoms of the C _1-6 -alkoxy group has been replaced by the same or different halogen atoms. The term "perhalo-C _1-6 alkoxy" means a C _1-6 alkoxy group wherein all hydrogen atoms of the C _1-6 alkoxy group have been replaced by the same or different halogen atoms. Examples of halo-C _1-6 -alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. Specific halo-C _1-6 alkoxy groups include trifluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoromethylethoxy, and trifluorodimethylethoxy. More specific examples are trifluoroethoxy, difluoroethoxy and difluoromethoxy.

The term "halo-C _1-6 -alkyl" means a C _1-6 -alkyl group, where at least one of the hydrogen atoms of the C _1-6 -alkyl group has been replaced by the same or different halogen atoms. The term "perhalo-C _1-6 -alkyl-C _1-6 -alkyl" means a C _1-6 -alkyl-C _1-6 -alkyl group, where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of halo-C _1-6 -alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Specific halo-C _1-6 -alkyl groups include difluoromethyl, trifluoromethyl, fluoromethyl, trifluoroethyl and difluoroethyl. More specific halo-C _1-6 -alkyl groups include trifluoromethyl and difluoromethyl.

The term "hydroxy" means a -OH group.

The term "oxo" means a =O group.

The term "hydroxy-C _1-6 -alkyl" means a C _1-6 -alkyl group, where at least one of the hydrogen atoms of the C _1-6 -alkyl group has been replaced by a hydroxyl group. Examples of hydroxy-C _1-6 -alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, hydroxymethylethyl and hydroxybutyl. Specific examples include hydroxymethylpropyl and hydroxymethylethyl.

The term "amino" means a -NH ₂ group.

The term "C _1-6 alkoxy-C _1-6 alkyl" means a C _1-6 alkyl group wherein at least one of the hydrogen atoms of the C _1-6 alkyl group has been replaced by a C _1-6 alkoxy group. Typical C _1-6 -alkoxy-C _1-6 -alkyl groups include methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl.

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

The term "C _1-6 -alkoxycarbonyl" means a group of Formula -C(O)-R', where R' represents a C _1-6 -alkoxy group. Examples of C _1-6 alkoxycarbonyl groups include those in which R' is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy. Specific examples of C _1-6 alkoxycarbonyl groups include those in which R' is ethoxy or t-butoxy.

The term "C _1-6 -alkylcarbonyl" means a group of Formula -C(O)-R', where R' represents a C _1-6 -alkyl group. Examples of C _1-6 -alkylcarbonyl groups include groups of Formula -C(O)-R', in which R' represents methyl or ethyl. Specific examples of C _1-6 -alkylcarbonyl groups include groups of Formula -C(O)-R', in which R' represents methyl.

The term "piano" means the -C≡N group.

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

The term "C _3-8 -cycloalkoxy" means a group of Formula -O-R', where R' represents a C _3-8 -cycloalkyl group. Examples of the cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. A specific example is cyclopropoxy.

The term "C _3-8 cycloalkyl-C _1-6 alkoxy" means a C _1-6 alkoxy group wherein at least one of the hydrogen atoms of the C _1-6 alkoxy group is replaced by a C _3-8 cycloalkyl group. Examples of C _3-8 -cycloalkyl-C _1-6 -alkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, cyclobutylethoxy, cyclopentylethoxy and cyclohexylethoxy. Specific examples include cyclopropylethoxy.

The term "C _3-8 -cycloalkyl-C _1-6 -alkyl" means a C _1-6 -alkyl group, where at least 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, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl and cyclohexylethyl. A specific example is cyclopropylethyl.

The term "C _3-8 -cycloalkylcarbonyl" means a group of the Formula -C(O)-R', where R' represents a C _3-8 -cycloalkyl group. Examples of C _3-8 cycloalkylcarbonyl groups include groups of Formula -C(O)-R', in which R' is cyclopropyl. Specific examples include groups in which R' is cyclopropyl.

The term "C _3-8 -cycloalkyl-C _1-6 -alkoxycarbonyl" means a group of Formula -C(O)-R', where R' represents a C _3-8 -cycloalkyl-C _1-6 -alkoxy group. Examples of C _3-8 -cycloalkyl-C _1-6 -alkoxycarbonyl groups include groups in which R' represents cyclopropylmethoxy, cyclopropylethoxy, cyclobutylpropoxy or cyclopropylbutoxy.

The term "C _3-8 cycloalkylaminocarbonyl" means a group of Formula -C(O)NR'R'', where R' is H and R'' is a C _3-8 cycloalkyl group. Examples of C _3-8 cycloalkylaminocarbonyl groups include those where R' is H and R'' is cyclopropyl or cyclobutyl. Specific examples include groups in which R' is H and R'' is cyclopropyl.

The term "C _1-6 -alkyl-C _3-8 -cycloalkyl-C _1-6 -alkyl" means a C _1-6 -alkyl group, where at least one of the hydrogen atoms of the C _1-6 -alkyl group is replaced by a C _1-6 -alkyl-C _3-8 -cycloalkyl group. Examples include methylcyclobutylmethyl, methylcyclopropylmethyl, methylcyclobutylethyl and methylcyclopropylethyl.

The term "C _1-6 -alkyl-C _3-8 -cycloalkylcarbonyl" means a group of Formula -C(O)-R', where R' represents a C _1-6 -alkyl-C _3-8 -cycloalkyl group. Examples of C _1-6 -alkyl-C _3-8 -cycloalkylcarbonyl include methylcyclopropylcarbonyl and methylcyclobutylcarbonyl. Specific examples include methylcyclopropylcarbonyl.

The term "aryl" means a monovalent aromatic carbocyclic mono - or bicyclic ring system containing from 6 to 10 ring-forming carbon atoms. Examples of the aryl group include phenyl and naphthyl. Specific aryl groups include phenyl.

The term "aryloxy" means a group of Formula -O-R', where R' is aryl. Specific aryloxy groups include phenoxy.

The term "heteroaryl" means a monovalent aromatic heterocyclic mono- or bicyclic ring system with 5-12 ring-forming atoms, which contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, and the remaining ring-forming atoms is carbon. Examples of the heteroaryl group include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Specific heteroaryl groups include pyridinyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, imidazo[1,2-a]pyridinyl, oxadiazolyl. More specific heteroaryl groups include pyrazolyl.

The term "heteroaryloxy" means a group of Formula -O-R', where R' is heteroaryl. Specific examples for R' include pyridinyl.

The term "heterocycloalkyl" means a monovalent saturated or partially unsaturated mono- or bicyclic ring system with 4-11 ring-forming atoms, which contains 1, 2 or 3 ring-forming heteroatoms selected from N, O and S, and the remaining ring-forming atoms is carbon. Bicyclic means consisting of two rings having one or two ring-forming carbon atoms in common. Examples of monocyclic saturated heterocycloalkyls are 4,5-dihydrooxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothio opipanil, piperazinil, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholin-4-yl, azepanil, diazepanil, homopiperazinil or oxazepanil. Examples of bicyclic saturated heterocycloalkyls are oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-azabicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 9-azabicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3. 3.1]nonyl or 3-thia-9-azabicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl and dihydropyranyl. Specific heterocycloalkyls are pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl, 3,5,6,7,8,8a-hexahydro-1H-oxazole[3,4-a]pyra zinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 1-oxa-7-azaspiro[3.5]nonanyl, 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl, 2,6-diazaspiro[3.3]heptanyl, 5-oxa-2-azaspiro[3.4]octanyl, 7-oxa-2-azaspiro[3.5]nonanil, 3-oxa-9-azaspiro[5.5]undecanil, 5-oxa-2-azaspiro[3.5]nonanil, 1-oxa-9-azaspiro[5.5]undecanil, 5-oxa-2-azaspiro[3.6]decanil, 2-azaspiro[3.3]heptane yl, 4,7-diazaspiro[2.5]octanyl, 2-azaspiro[3.5]nonanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1-oxa-8-azaspiro[4.5]decanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.1.1 ]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl and azetidinyl. More specific examples include morpholinyl, piperazinyl, azetidinyl, 5-oxa-2-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 5-oxa-2-azaspiro[3.4]octanyl, 2-azaspiro[3.3]heptanyl. Even more specific examples include morpholinyl, piperazinyl, azetidinyl, 5-oxa-2-azaspiro[3.5]nonanil. The most specific examples include azetidinyl, 5-oxa-2-azaspiro[3.5]nonanil.

The term "heterocycloalkyl-C _1-6 alkyl" means a C _1-6 alkyl group wherein one of the hydrogen atoms of the C _1-6 alkyl group has been replaced by a heterocycloalkyl group. Specific heterocycloalkyl-C _1-6 -alkyl is methyloxetanyl and methyltetrahydropyranyl.

The term "heterocycloalkoxy" means a group of Formula -O-R', where R' is a heterocycloalkyl group. A specific heterocycloalkyloxy is tetrahydrofuranyloxy.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of free bases or free acids and which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be obtained by adding an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins, etc. Specific pharmaceutically acceptable salts of the compounds of Formula (I) are hydrochloride salts, methanesulfonic acid salts and citric acid salts.

"Pharmaceutical esters" means that compounds of general Formula (I) or (II) can be derivatized at functional groups to give derivatives that are capable of being converted to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ethers, methylthiomethyl ethers and pivaloyloxymethyl ethers. In addition, any physiologically acceptable equivalents of compounds of general Formula (I) or (II), like metabolically labile esters, that are capable of producing the parent compounds of general Formula (I) or (II) in vivo are within the scope of this invention.

The term "protecting group" (PG) means a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can be carried out selectively at another unprotected reactive site in the sense traditionally associated with it in synthetic chemistry. The protecting groups may be removed at an appropriate time. Illustrative protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy protecting groups. Specific protecting groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluoroenylmethoxycarbonyl (Fmoc), and benzyl (Bn) groups. Additional specific protecting groups are tert-butoxycarbonyl (Boc) and fluoroenylmethoxycarbonyl (Fmoc) groups. A more specific protecting group is a tert-butoxycarbonyl (Boc) group.

The abbreviation µM stands for micromolar and is the equivalent of the symbol µM.

The abbreviation µl stands for microliter and is the equivalent of the symbol µl.

The abbreviation mcg stands for microgram and is the equivalent of the symbol μg.

The compounds of Formula (I) or (II) may contain several asymmetric centers and may be in the form of optically pure enantiomers, mixtures of enantiomers, namely, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

In accordance with the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can be in the "R" or "S" configuration.

Also, an embodiment of this invention is a compound of Formula (I) or (II) described herein, and its pharmaceutically acceptable salts or esters, in particular compounds of Formula (I) described in this document, and their pharmaceutically acceptable salts, more specifically compounds of Formula (I) described in this document.

In a particular embodiment, the present invention provides a compound of Formula (I) or (II) described herein, wherein

W choose from

i) N and

ii) CR ⁴ ;

Y choose from

i) N and

ii) CH;

Z choose from

i) N and

ii) CH;

R ⁹⁹ choose from

i) H and

ii) halogen;

R ² choose from

1) H,

ii) C _1-6 -alkyl,

iii) C _3-8 -cycloalkyl and

iv) halo-C _1-6 -alkyl;

R ³ choose from

i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from

a. pyrrolidinyl,

b. piperidinyl,

c. morpholinyl,

d. piperazinil,

e. 2-oxa-6-azaspiro[3.3]heptanyl,

f. 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl,

g. 3,5,6,7,8,8a-hexahydro-1H-oxazolo[3,4-a]pyrazinyl,

h. 2-oxa-7-azaspiro[3.5]nonanil,

i. 1-oxa-7-azaspiro[3.5]nonanil,

j. 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl,

k. 2,6-diazaspiro[3.3]heptanyl,

l. 5-oxa-2-azaspiro[3.4]octanyl,

m. 7-oxa-2-azaspiro[3.5]nonanil,

n. 3-oxa-9-azaspiro[5.5]undecanil,

O. 5-oxa-2-azaspiro[3.5]nonanil,

R. 1-oxa-9-azaspiro[5.5]undecanil,

q. 5-oxa-2-azaspiro[3.6]decanyl,

r. 2-azaspiro[3.3]heptanyl,

s. 4,7-diazaspiro[2.5]octanyl,

t. 2-azaspiro[3.5]nonanil,

u. 6-oxa-3-azabicyclo[3.1.1]heptanyl,

v. 1-oxa-8-azaspiro[4.5]decanyl,

w. 8-oxa-3-azabicyclo[3.2.1]octanyl,

X. 3-oxa-6-azabicyclo[3.1.1]heptanyl,

y. 3-oxa-8-azabicyclo[3.2.1]octanyl and

z. azetidinyl;

ii) amino substituted on the nitrogen atom with one or two substituents independently selected from R ⁹ and R ¹⁰ ,

iii) phenyl substituted with R ¹¹ , R ¹² and R ¹³ where R ¹¹ , R ¹² and R ¹³ are independently selected from

A. H,

b. C _1-6 -alkoxy,

c. halo-C _1-6 -alkyl,

d. halogen-C _1-6 -alkoxy and

e. halogen;

iv) heteroaryl substituted with R ¹¹ , R ¹² and R ¹³ , where R ¹¹ , R ¹² and R ¹³ are independently selected from

a. H,

b. C _1-6 -alkoxy,

c. C _1-6 -alkyl,

d. cyano,

e. C _3-8 -cycloalkyl,

f. halo-C _1-6 -alkyl,

g. halogen-C _1-6 -alkoxy,

h. amino substituted on the nitrogen atom with one or two substituents independently selected from R ¹⁴ and R ¹⁵ ,

i. C _3-8 -cycloalkyl-C _1-6 -alkyl,

j. heterocycloalkyl substituted with R ¹⁶ , R ¹⁷ and R ¹⁸ where R ¹⁶ , R ¹⁷ and R ¹⁸ are H and where heterocycloalkyl is piperazinyl,

k. heterocycloalkoxy, where heterocycloalkoxy is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ , where R ¹⁶ , R ¹⁷ and R ¹⁸ are H, and where heterocycloalkoxy is tetrahydrofuranyloxy,

l. heterocycloalkyl-C _1-6 -alkyl, where heterocycloalkyl-C _1-6 -alkyl is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ , where R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from

i. H and

ii. C _1-6 -alkyl;

and where heterocycloalkyl-C _1-6 -alkyl represents oxetanyl-C _1-6 -alkyl,

m. halogen;

and where heteroaryl is selected from pyridinyl, imidazo[1,2-a]pyridinyl and pyrazolyl;

R ⁴ choose from

i) H and

ii) halogen;

R ⁵ choose from

i) C _1-6 -alkyl,

ii) C _3-8 -cycloalkyl,

iii) halo-C _1-6 -alkyl and

iv) halogen;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _1-6 alkoxycarbonyl,

v) cyano,

vi) amino substituted on the nitrogen atom with one or two substituents independently selected from R ²² and R ²³ ,

vii) C _3-8 cycloalkyl-C _1-6 alkoxy, where C _3-8 cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyne;

viii) C _3-8 cycloalkylaminocarbonyl wherein C _3-8 cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are H;

ix) C _3-8 -cycloalkylcarbonyl, where C _3-8 -cycloalkyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyne;

x) C _3-8 cycloalkyl substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyl;

xi) C _3-8 -cycloalkoxy substituted with R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are H;

xii) aryloxy, where aryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H and

b. halogen;

and where aryl is phenyl;

xiii) aryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H and

b. alkoxy;

and where aryl is phenyl;

xiv) heteroaryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H and

b. C _1-6 -alkyl,

and where heteroaryl is selected from imidazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridinyl and oxadiazolyl;

xv) heteroaryloxy, where heteroaryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H,

b. C _1-6 -alkyl and

c. halogen;

and where heteroaryl is selected from

a. pyridinyl and

b. pyridazinyl;

xvi) halogen-C _1-6 -alkoxy,

xvii) halo-C _1-6 -alkyl,

xviii) halogen,

xix) oxo,

xx) hydroxy and

xxi) hydroxy-C _1-6 -alkyl;

R ⁹ and R ¹⁰ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) heterocycloalkyl substituted with R ³⁰ , R ³¹ and R ³² , where R ³⁰ , R ³¹ and R ³² are independently selected from

i) H and

ii) C _3-8 cycloalkyl;

and where heterocycloalkyl is selected from azetidinyl and oxetanyl,

iv) heterocycloalkyl-C _1-6 -alkyl, where heterocycloalkyl-C _1-6 -alkyl is substituted with R ³⁰ , R ³¹ and R ³² , where R ³⁰ , R ³¹ and R ³² represent H,

and where heterocycloalkyl-C _1-6 -alkyl is tetrahydropyranyl-C _1-6 -alkyl,

v) hydroxy-C _1-6 -alkyl and

vi) C _3-8 cycloalkyl;

R ¹⁴ and R ¹⁵ are independently selected from

i) H and

ii) C _1-6 alkyl;

R ²³ and R ²² are independently selected from

i) C _1-6 -alkyl and

ii) C _1-6 -alkylcarbonyl;

or pharmaceutically acceptable salts.

In a more specific embodiment, this invention provides a compound of Formula (I) described herein,

W is CR ⁴ ;

Y choose from

i) N and

ii) CH;

Z choose from

i) N and

ii) CH;

R ⁹⁹ choose from

i) H and

ii) halogen;

R ² choose from

i) H and

ii) C _1-6 alkyl;

5-oxa-2-azaspiro[3.5]nonanyl substituted with R ⁶ , R ⁷ and R ⁸ ;

R ³ choose from

i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ and

ii) heteroaryl substituted with R ¹¹ , R ¹² and R ¹³ ;

R ⁴ is H,

R ⁵ choose from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl and

iii) halogen;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) C _3-8 -cycloalkoxy,

vi) halo-C _1-6 -alkoxy,

vii) halo-C _1-6 -alkyl,

viii) halogen;

R ¹¹ , R ¹² and R ¹³ are independently selected from

i) C _1-6 -alkyl,

ii) H,

iii) C _3-8 -cycloalkyl and

iv) halo-C _1-6 -alkyl;

R ²⁴ , R ²⁵ and R ²⁶ are H;

or pharmaceutically acceptable salts.

In an even more specific embodiment of the present invention, a compound of Formula (I) described herein is provided,

W is CR ⁴ ;

Y choose from

i) N and

ii) CH;

Z choose from

i) N and

ii) CH;

R ⁹⁹ is selected from H or halogen;

R ² choose from

i) H and

ii) C _1-6 alkyl;

R ³ choose from

i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from piperazinyl, azetidinyl, 5-oxa-2-azaspiro[3.5]nonanyl, 5-oxa-2-azaspiro[3.4]octanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl and 2-azaspiro[3.3] heptanyl and

ii) pyrazolyl substituted with R ¹¹ , R ¹² and R ¹³ ;

R ⁴ is H,

R ⁵ choose from

i) C _1-6 -alkyl,

ii) halo-C _1-6 -alkyl and

iii) halogen;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) C _3-8 -cycloalkoxy,

vi) halo-C _1-6 -alkoxy,

vii) halo-C _1-6 -alkyl,

viii) halogen;

R ¹¹ , R ¹² and R ¹³ are independently selected from

i) C _1-6 -alkyl,

ii) H,

iii) C _3-8 -cycloalkyl and

iv) halo-C _1-6 -alkyl;

R ²⁴ , R ²⁵ and R ²⁶ are H;

or pharmaceutically acceptable salts.

In a further specific embodiment of the present invention, a compound of Formula (I) described herein is provided,

W is CR ⁴ ;

Y is N;

Z choose from

i) N and

ii) CH;

R ⁹⁹ is H;

R ² is C _1-6 alkyl;

R ³ is heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ ;

R ⁴ is H,

R ⁵ choose from

i) C _1-6 -alkyl and

ii) halogen;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) C _3-8 -cycloalkoxy,

vi) halogen;

R ²⁴ , R ²⁵ and R ²⁶ are H;

or pharmaceutically acceptable salts.

In the most specific embodiment of the present invention, a compound of Formula (I) described herein is provided,

W is CR ⁴ ;

Y is N;

Z choose from

i) N and

ii) CH;

R ⁹⁹ is H;

R ² is methyl;

R ³ is heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from piperazinyl, azetidinyl, 5-oxa-2-azaspiro[3.5]nonanil and morpholinyl;

R ⁴ is H,

R ⁵ choose from

i) methyl and

ii) chlorine;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) methyl,

iii) tert-butoxy,

iv) cyclopropyl,

v) C _3-8 -cycloalkoxy,

vi) fluorine;

R ²⁴ , R ²⁵ and R ²⁶ are H;

or pharmaceutically acceptable salts.

Even in the most specific embodiment of the present invention, a compound of Formula (I) described herein is provided,

W is CR ⁴ ;

Y is N;

Z choose from

i) N and

ii) CH;

R ⁹⁹ is H;

R ² is C _1-6 alkyl;

R ³ is heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ ;

R ⁴ is H,

R ⁵ choose from

i) C _1-6 -alkyl and

ii) halogen;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) C _1-6 -alkoxy,

ii) H,

iii) halogen;

or pharmaceutically acceptable salts.

Even in the most specific embodiment of the present invention, a compound of Formula (I) described herein is provided,

W is CR ⁴ ;

Y is N;

Z choose from

i) N and

ii) CH;

R ⁹⁹ is H;

R ² is methyl;

R ³ choose from

i) azetidinyl substituted with R ⁶ , R ⁷ and R ⁸ and

ii) 5-oxa-2-azaspiro[3.5]nonanyl substituted with R ⁶ , R ⁷ and R ⁸ ,

R ⁴ is H,

R ⁵ choose from

i) methyl and

ii) fluorine;

R ⁶ , R ⁷ and R ⁸ are independently selected from

i) tert-butoxy,

ii) H,

iii) fluorine;

or pharmaceutically acceptable salts.

In a specific embodiment, this invention provides a compound as described herein, wherein the compound is a compound of Formula (I).

In a particular embodiment, the present invention provides a compound as described herein, wherein W is CR ⁴ .

In a specific embodiment, this invention provides a compound described herein, wherein Y is N.

In a specific embodiment, this invention provides a compound as described herein, wherein R ⁹⁹ is selected from H or halogen.

In a specific embodiment, the present invention provides a compound as described herein, wherein ^R99 is H.

In a specific embodiment, this invention provides a compound as described herein, wherein R ² is selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, and halo-C _1-6 alkyl.

In a specific embodiment, this invention provides a compound as described herein, wherein R ² is C _1-6 alkyl.

In an additional specific embodiment of the present invention, a compound as described herein is provided, wherein R ² is methyl.

In a particular embodiment, the present invention provides a compound as described herein, wherein R ³ is selected from

i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ and

ii) heteroaryl substituted with R ⁶ , R ⁷ and R ⁸ .

In a more specific embodiment, this invention provides a compound described herein, wherein R ³ is selected from

i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from

a. pyrrolidinyl,

b. piperidinyl,

c. morpholinyl,

d. piperazinil,

e. 2-oxa-6-azaspiro[3.3]heptanyl,

f. 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl,

g. 3,5,6,7,8,8a-hexahydro-1H-oxazolo[3,4-a]pyrazinyl,

h. 2-oxa-7-azaspiro[3.5]nonanil,

i. 1-oxa-7-azaspiro[3.5]nonanil,

j. 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl,

k. 2,6-diazaspiro[3.3]heptanyl,

l. 5-oxa-2-azaspiro[3.4]octanyl,

m. 7-oxa-2-azaspiro[3.5]nonanil,

n. 3-oxa-9-azaspiro[5.5]undecanil,

O. 5-oxa-2-azaspiro[3.5]nonanil,

R. 1-oxa-9-azaspiro[5.5]undecanil,

q. 5-oxa-2-azaspiro[3.6]decanyl,

r. 2-azaspiro[3.3]heptanyl,

s. 4,7-diazaspiro[2.5]octanyl,

t. 2-azaspiro[3.5]nonanil,

u. 6-oxa-3-azabicyclo[3.1.1]heptanyl,

v. 1-oxa-8-azaspiro[4.5]decanyl,

w. 8-oxa-3-azabicyclo[3.2.1]octanyl,

X. 3-oxa-6-azabicyclo[3.1.1]heptanyl,

y. 3-Oxa-8-azabicyclo[3.2.1]octanyl and

z. azetidinyl and

ii) heteroaryl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heteroaryl is selected from

A. pyridinyl,

b. imidazo[1,2-а]pyridinyl and

c. pyrazolyl.

In an even more specific embodiment, this invention provides a compound as described herein, wherein R ³ is heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from

i) morpholinyl,

ii) piperazinil,

iii) azetidinyl and

iv) 5-oxa-2-azaspiro[3.5]nonanil.

In a further specific embodiment, this invention provides a compound as described herein, wherein R ³ is heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from

i) azetidinyl and

ii) 5-oxa-2-azaspiro[3.5]nonanil.

In a specific embodiment, this invention provides a compound as described herein, wherein R ⁴ is H or halogen.

In a specific embodiment, the present invention provides a compound as described herein, wherein ^R4 is H.

In a particular embodiment, this invention provides a compound of Formula (I) as described herein, wherein R ⁵ is selected from C _1-6 alkyl, C _3-8 cycloalkyl, halo-C _1-6 alkyl, and halogen.

In a more specific embodiment, this invention provides a compound as described herein, wherein R ⁵ is C _1-6 alkyl or halo.

In a further specific embodiment, this invention provides a compound as described herein, wherein R ⁵ is methyl or chlorine.

In a particular embodiment, this invention provides a compound as described herein, wherein R ⁶ , R ⁷ and R ⁸ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _1-6 alkoxycarbonyl,

v) cyano,

vi) amino substituted on the nitrogen atom with one or two substituents independently selected from R ²² and R ²³ ,

vii) C _3-8 cycloalkyl-C _1-6 alkoxy, where C _3-8 cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyl;

viii) C _3-8 cycloalkylaminocarbonyl wherein C _3-8 cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are H;

ix) C _3-8 -cycloalkylcarbonyl, where C _3-8 -cycloalkyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 -alkyl;

x) C _3-8 cycloalkyl substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyl;

xi) C _3-8 -cycloalkoxy substituted with R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are H;

xii) aryloxy, where aryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H and

b. halogen;

and where aryl is phenyl;

xiii) aryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H and

b. alkoxy;

and where aryl is phenyl;

xiv) heteroaryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H and

b. C _1-6 -alkyl,

and where heteroaryl is selected from imidazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridinyl and oxadiazolyl;

xv) heteroaryloxy, where heteroaryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

a. H,

b. C _1-6 -alkyl and

c. halogen;

and where heteroaryl is selected from

a. pyridinyl and

b. pyridazinyl;

xvi) halogen-C _1-6 -alkoxy,

xvii) halo-C _1-6 -alkyl,

xviii) halogen,

xix) oxo,

xx) hydroxy and

xxi) hydroxy-C _1-6 -alkyl.

In a more specific embodiment, this invention provides a compound described herein, wherein R ⁶ is selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) C _3-8 -cycloalkyl,

v) C _3-8 -cycloalkoxy and

vi) halogen.

In a further specific embodiment of the present invention, a compound as described herein is provided, wherein R ⁶ is selected from

i) C _1-6 -alkoxy and

ii) halogen.

In the most specific embodiment of the present invention, the compound described herein is provided, wherein R ⁶ is selected from

i) tert-butoxy and

ii) fluorine.

In a more specific embodiment, this invention provides a compound described herein, wherein R ⁷ is selected from

i) H,

ii) C _1-6 -alkyl and

iii) halogen.

In a further specific embodiment, the present invention provides a compound as described herein, wherein R ⁷ is H.

In a more specific embodiment, the present invention provides a compound as described herein, wherein ^R8 is H.

In a specific embodiment, this invention provides a compound described herein, wherein R ⁹ and R ¹⁰ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) heterocycloalkyl substituted with R ³⁰ , R ³¹ and R ³² , where R ³⁰ , R ³¹ and R ³² are independently selected from

i) H and

ii) C _3-8 cycloalkyl;

and where heterocycloalkyl is selected from azetidinyl and oxetanyl,

iv) heterocycloalkyl-C _1-6 -alkyl, where heterocycloalkyl-C _1-6 -alkyl is substituted by R ³⁰ , R ³¹ and R ³² , where R ³⁰ , R ³¹ and R ³² are H, and where heterocycloalkyl-C _1-6 -alkyl is tetrahydropyranyl-C _1-6 -alkyl,

v) hydroxy-C _1-6 -alkyl and

vi) C _3-8 cycloalkyl.

In a specific embodiment, this invention provides a compound as described herein, wherein R ¹⁴ and R ¹⁵ are independently selected from

i) H and

ii) C _1-6 alkyl.

In a specific embodiment, this invention provides a compound as described herein, wherein R ²² and R ²³ are independently selected from

i) C _1-6 -alkyl and

ii) C _1-6 -alkylcarbonyl.

In a particular embodiment, this invention provides a compound as described herein, wherein R ²⁴ , R ²⁵ , and R ²⁶ are independently selected from

i) H and

ii) C _1-6 alkyl.

In a specific embodiment, this invention provides a compound as described herein, wherein ^R24 , ^R25 and ^R26 are H.

In a specific embodiment, this invention provides a compound as described herein, wherein R ²⁷ , R ²⁸ and R ²⁹ are independently selected from

i) H,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy and

iv) halogen.

In a specific embodiment, this invention provides a compound as described herein, wherein R ³⁰ , R ³¹ and R ³² are independently selected from

i) H and

ii) C _3-8 cycloalkyl.

Specific examples of the compound of Formula (I) or (II) described herein are selected from

N-methyl-N-((3S)-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)pyrrolidin-3-yl)acetamide;

N-methyl-N-((3R)-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)pyrrolidin-3-yl)acetamide;

5-((3R)-3-hydroxypyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

5-((3S)-3-hydroxypyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

5-(4-hydroxypiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

5-(2,2-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

5-((2S,6R)-2,6-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

ethyl 1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)piperidine-4-carboxylate;

5-(4-(cyclopropanecarbonyl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)-5-morpholinopyridazin-3(2H)-one;

5-(cis-2,6-dimethylmorpholino)-2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(trifluoromethyl)pyridazin-3(2H)-one;

5-(t-butyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-isopropyl-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-ethyl-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

tert-butyl 4-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-morpholinopyridazin-3(2H)-one;

5-(3,6-dihydro-2H-pyran-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

N-cyclopropyl-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)piperidine-4-carboxamide;

5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((2S,6S)-2,6-dimethylmorpholino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((2R,6R)-2,6-dimethylmorpholino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(cis-2,6-dimethylmorpholino)-2-((3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)piperidine-4-carbonitrile;

5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-cyclopropylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-cyclopropyl-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

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

5-(cis-2,6-dimethylmorpholino)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(cis-2,6-dimethylmorpholino)-2-((3-(3-fluoropyridin-4-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(3-fluoropyridin-4-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

2-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;

7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one;

5-(dimethylamino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3(2H)-one;

(R)-7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

(S)-7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylpiperazin-1-yl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylpiperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(5-chloro-3-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

2-((3-(5-chloro-3-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)-2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-N-cyclopropyl-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-carboxamide;

(S)-N-cyclopropyl-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-carboxamide;

5-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(4-cyclopropyl-3-methylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(4-cyclopropyl-3-methylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-(2-methoxyphenyl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

5-(4-cyclopropylpiperazin-1-yl)-2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)pyridazin-3(2H)-one;

5-(cyclopropyl(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(methyl(oxetan-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-cyclopropylpiperazin-1-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-phenylpyridazin-3(2H)-one;

5-(4-fluorophenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-azaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one;

5-((2-hydroxy-2-methylpropyl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(2-fluorophenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one;

5-(cis-2,6-dimethylmorpholino)-2-((3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(2-methoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4,7-diazaspiro[2.5]octan-7-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one;

5-(4-methoxyphenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(methylamino)pyridazin-3(2H)-one;

5-(4-ethoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-fluoro-4-methoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one;

5-(5-methoxypyridin-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)azetidine-3-carbonitrile;

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one;

5-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one;

(R)-5-(3-(t-butoxy)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(2-methylmorpholino)-2-((3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(2-methylmorpholino)-2-((3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-phenoxyazetidin-1-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

5-((1-cyclopropylazetidin-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-hydroxy-3-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-(2-methoxypyridin-3-yl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(dimethylamino)-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one;

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(1-methylpyrazol-4-yl)pyridazin-3-one;

5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-hydroxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-methylpyridin-4-yl)pyridazin-3(2H)-one;

5-(2-methoxypyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyridin-4-yl)pyridazin-3(2H)-one;

5-(4-(2-ethyl-1H-imidazol-1-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-(2-methyl-1H-imidazol-1-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-(cyclopropylmethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-isopropoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3,4-dimethoxyphenyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)pyridazin-3-one;

5-(4-isopropoxyphenyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-[6-(dimethylamino)-3-pyridyl]-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-hydroxy-4-methylpiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((3S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

2-ethyl-7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((3aS,6aS)-tetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)pyridazin-3(2H)-one;

5-(3-(4-fluorophenoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridazin-3(2H)-one;

5-((3aR,6aS)-hexahydro-1H-furo[3,4-b]pyrrol-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(pyridin-3-yloxy)azetidin-1-yl)pyridazin-3(2H)-one;

5-(3-(3-fluorophenoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-(2-fluorophenoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(pyridin-4-yloxy)azetidin-1-yl)pyridazin-3(2H)-one;

5-(3-((5-chloropyridin-2-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(7-ethoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-cyclopropoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((1-cyclopropylazetidin-3-yl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-((6-chloropyridn-3-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-methoxypiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one;

5-(3-(cyclopropylmethoxy)azetidin-1-yl)-2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)pyridazin-3(2H)-one;

2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(cyclopropylmethoxy)azetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

5-(6-methoxy-2-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

5-(3-((2-chloropyridin-4-yl)oxy)azetidin-1-yld)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(5-chloro-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-(6-(difluoromethoxy)pyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(6-ethoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(1-ethyl-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(2-(dimethylamino)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)pyridazin-3(2H)-one;

5-(4-(4-methoxypyrimidin-5-yl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(piperazin-1-yl)pyridin-4-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;

5-(4-(3-methoxypyridazin-4-yl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(4-(1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-(difluoromethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

5-(1-isobutylpyrazol-4-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one;

5-(6-cyclopropyl-3-pyridyl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one;

5-(6-(methylamino)-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-(2-(difluoromethoxy)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylpyrrolidin-1-yl)pyridazin-3(2H)-one;

5-(5,6-dimethoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(6-ethoxy-5-methylpyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-fluoroazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-(difluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((2S,6R)-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

5-(5-fluoro-6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(4-isopropyl-3-methylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-(cyclopropylmethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-((6-methylpyridazin-3-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one;

5-(2-(azetidin-1-yl)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(5-chloro-6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(2-chloro-5-fluoro-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-(6-isopropoxy-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-(5-fluoro-2-methoxypyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(2,6-dimethylpyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((2R,3R)-3-methoxy-2-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-(2-ethyl-4-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-((2S,3S)-3-methoxy-2-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((2S,3S)-3-ethoxy-2-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(methylamino)pyridin-4-yl)pyridazin-3(2H)-one;

(R)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((2R,6S)-2,6-dimethylmorpholino)-2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one;

2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methoxyisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(1-propylpyrazol-4-yl)pyridazin-3-one;

6-(1-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-6-oxo-pyridazin-4-yl)pyridine-2-carbonitrile;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one;

5-(3-ethoxyazetidin-1-yl)-2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2RS,6SR)-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-cyclopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;

2-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-cyclopropoxyazetidin-1-yl)pyridazin-3(2H)-one;

(S)-7-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one;

5-(2-methoxypyridin-4-yl)-2-((5-methyl-3-(5-trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(5-trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

(R)-7-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-(3-((2-chloropyridin-4-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-cyclobutoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(3-cyclopropoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

(R)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-((2S,6R)-2,6-dimethylmorpholin-4-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

5-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(2,2-difluoroethoxy)azetidin-1-yl)pyridazin-3(2H)-one;

(S)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

5-(3-cyclopropoxyazetidin-1-yl)-2-((5-methyl-3-(5-trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(trifluoromethoxy)azetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-cyclobutoxyazetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(difluoromethoxy)azetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-oxa-8-azaspiro[4.5]decan-8-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3(2H)-one;

2-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-cyclopropylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

(R)-5-(3-(t-butoxy)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-methoxy-4-methylpiperidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(pyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one;

(S or R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one;

(R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3(2H)-one;

4-chloro-5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3(2H)-one;

5-(3-(t-butoxy)azetidin-1-yl)-2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

4-chloro-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3(2H)-one;

(S)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(pyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(pyridin-3-yl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(3-ethoxyazetidin-1-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-methyl-1,2,5-oxadiazol-3-yl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(5-chloro-6-methoxypyridin-3-yl)-2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-methylpyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(4-(3-chloropyridazin-4-yl)piperazin-1-yl)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(2-methylpyridin-3-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2S,3S) or (2R,3R)-3-methoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one;

(S)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2R,3R) or (2S,3S)-3-hydroxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methyl)-5-(4-(4-methoxypyrimidin-5-yl)piperazin-1-yl)pyridazin-3-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2S,3S) or (2R,3R)-3-ethoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-cyclopropylpyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one;

5-(4-(5-chloropyridazin-4-yl)piperazin-1-yl)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2R,3R) or (2S,3S)-3-ethoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one;

2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one;

(R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(S or R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(3-methylpyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-chloropyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(5-methylpyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(3-methoxypyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(3-(1-methylcyclopropoxy)azetidin-1-yl)pyridazin-3(2H)-one;

5-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(S)-5-(7-ethyl-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

5-(6,6-dimethyl-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-(6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.6]decan-2-yl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(8-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

2-((5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-2-((5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-((4S)-4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3-one;

5-((4R)-4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3-one;

2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

or pharmaceutically acceptable salts.

Additional specific examples of the compound of Formula (I) described herein are selected from

5-(2S,6R)-2,6-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one;

5-(4-cyclopropylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(S)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2RS,6SR)-2,6-dimethylmorpholino)pyridazin-3(2H)-one;

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-cyclopropoxyazetidin-1-yl)pyridazin-3(2H)-one;

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one;

(R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

(R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

or pharmaceutically acceptable salts.

Additional specific examples of the compound of Formula (I) described herein are selected from

(R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one;

5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one;

or pharmaceutically acceptable salts.

Methods for obtaining compounds of Formula (I) or (II) described in this document, is also the subject of the invention.

The preparation of compounds of Formula (I) or (II) according to this invention can be carried out in a sequential or convergent synthetic way. The syntheses of the invention are shown in the following general schemes. The skills required to carry out the reactions and purify the resulting products are known to those skilled in the art. Substituents and suffixes used in the following description of methods have the meanings given earlier in this document, unless otherwise indicated.

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

The preparation of compounds of Formula (I) or (II) according to this invention can be carried out in a sequential or convergent synthetic way. The synthesis of the compounds of the invention is shown in the following Schemes 1-6 and in the description of 298 specific examples. The skills required to carry out the reactions and purify the resulting products are known to those skilled in the art. Substituents and suffixes used in the following description of methods have the meanings given earlier in this document, unless otherwise indicated.

In more detail, the compounds of Formula (I) or (II) can be obtained by the methods below, the methods given in the examples, or similar methods. The appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the sequence shown in Schemes 1-6, however, depending on the starting materials and their respective reactivity, the sequence of the reaction steps can be freely changed. Starting materials are either commercially available, or they can be obtained by methods similar to the methods below, by the methods described in the references given in the description, or in the examples, or by methods known in the art.

These compounds of Formula (I) or (II) and their pharmaceutically acceptable salts can be obtained by the method described below (Scheme 1).

Scheme 1: synthesis of pyridazinones; where all definitions are as described above and in the claims

In Scheme 1, a compound of Formula (I) or (II) can be prepared by a simple N-alkylation reaction between alkyl chlorides (III) or (IV) and pyridazinone of Formula (V) in the presence of a base (eg K ₂ CO ₃ ).

The synthesis of alkyl chlorides (III) or (IV) is outlined in Scheme 2.

Scheme 2: Synthesis of alkyl chlorides (III) or (IV); where all definitions are as described above and in the claims

Commercially available aldehydes (1a) or (1b) are converted to the corresponding oximes (2) by treatment with hydroxylamine hydrochloride in the presence of a base (eg NaOH or Et ₃ N). After electrophilic chlorination with N-chlorosuccinimide (NXC), intermediate chlorooximes (3) in the presence of a base (Et ₃ N) are subjected to a 1,3-dipolar cycloaddition reaction with readily available enamines (4) or enols (5) to obtain isoxazoles of Formula (6). Their reduction to alcohols (8) can be carried out directly with LiAlH ₄ or DIBAL-G at controlled temperature or in two steps by hydrolysis to their respective carboxylic acids (7) followed by reduction (NaBH ₄ ) by treatment with ethyl chloroformate in the presence of a base (Et ₃ N). The final conversion to the target alkyl chlorides (III) or (IV) is carried out under the influence of thionyl chloride.

Scheme 3: synthesis of a structural element (A-Z)

For convenience, alkyl chlorides (III) or (IV) can be reacted in the presence of a base (K ₂ CO ₃ ) with commercially available 4-chloro-1H-pyridazin-6-one (9) to obtain sample-stable structural element (AZ) of 5-chloropyridazinones, as shown in Scheme 3.

Scheme 4: synthesis of pyridazinones (I) or (II) from the structural element (AZ); where R ³ represents amino, substituted at the nitrogen atom with one or two substituents, or substituted heterocycloalkyl; all other definitions are as described above and in the claims

In certain embodiments of the invention, in which R ³ is nitrogen, the pyridazinones of Formula (I) or (II) can be obtained using a nucleophilic aromatic substitution reaction between the structural element (AZ) and the primary (R ⁹ = H) or secondary amine HNR ⁹ R ¹⁰ , including a wide variety of heterocycloalkylamines (Scheme 4).

Scheme 5: synthesis of pyridazinones (I) or (II) from the structural element (AZ); where R ³ represents aryl or heteroaryl; all other definitions are as described above and in the claims

In additional embodiments where R ³ is heteroaryl or aryl, the pyridazinones of Formula (I) or (II) can be prepared by a palladium-mediated Suzuki coupling reaction between an aryl chloride building block (AZ) and commercially available boric acids or boranes (Scheme 5).

Scheme 6: alternative synthesis of pyridazinones (I); where R ³ represents aryl or heteroaryl; all other definitions are as described above and in the claims

Alternatively, illustrated in Scheme 6, the aryl chlorides can be converted to the corresponding boric acids by a palladium-mediated process and used in subsequent Suzuki coupling with commercially available aryl bromides to produce the pyridazinones of Formula (I).

Also, an embodiment of the present invention is a process for preparing a compound of Formula (I) or (II) as described above, comprising reacting a compound of Formula (III) or (IV) with a compound of Formula (V) in the presence of a base, in particular K ₂ CO ₃ .

where R ² , R ³ , R ⁵ , R ⁹⁹ , W, Y and Z are described in this document.

The subject of this invention is also a compound of Formula (I) or (II), more particularly compounds of Formula (I) described herein for use as a therapeutically active substance.

Similarly, the subject of this invention is a pharmaceutical composition containing a compound of Formula (I) or (II), more particularly compounds of Formula (I) described herein, and a therapeutically inert carrier.

A specific embodiment of this invention is a compound of Formula (I) or (II), more specifically the compounds of Formula (I) described herein, for the treatment or prevention, 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 disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Wheel syndrome epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile X disorder, more specifically for the treatment of autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, negative and/or cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD).

This invention also relates to the use of a compound of Formula (I) or (II), more specifically the compounds of Formula (I) described herein, for the treatment or prevention, 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 disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile X disorder, more specifically for the treatment of autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, negative and/or cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD).

The subject of the invention is also 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 disorder (ASD), Angelman's syndrome, Rett's syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral multiple sclerosis (ALS), fragile X disorder, more specifically the treatment of autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, negative and/or cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD), wherein the method comprises administering an effective amount of a compound of Formula (I) or (II), more specifically compounds of Formula (I) described herein.

An embodiment of this invention are also compounds of Formula (I) or (II), more specifically compounds of Formula (I) described herein, obtained by any of the methods described.

Analysis Methods

Membrane preparation and binding analysis

The affinity of the compounds to the GABA receptor subtypes was measured by competition of [3H]flumazenil (85 Ci/mmol; Roche) and the α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2 composition when bound to HEK293 cells that are expressed by rat (stably transfected) or human (transiently transfected) receptors.

Cell masses were suspended in Krebs-Tris buffer (4.8 mM KCl, 1.2 mM CaCl ₂ , 1.2 mM MgCl ₂ , 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized with a polytron for about 20 seconds on ice, and centrifuged for 60 min at 4°C ( 50000 g Sorvall, rotor: SM24=20000 rpm). The cell masses were resuspended in Krebs-Tris buffer and homogenized with a polytron for about 15 seconds on ice. The protein level was measured (Bradford method, Bio-Rad), 1 ml aliquots were prepared and stored at -80°C.

Radioligand binding assays were performed in a volume of 200 ml (96-well plates) containing 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 subunits, and test compound in the range of 10-10 ^-3 × 10 ^-6 M. Non-specific binding was determined using 1 0 ^-5 M diazepam and, as a rule, accounted for less than 5% of the total binding. Samples for analysis were incubated to equilibrium for 1 hour at 4° C., collected on GF/C universal filters (Packard) by filtration with a Packard combine, and washed with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, the radioactivity contained in the filter was detected by liquid scintillation counting. Ki values were calculated using Excel-Fit (Microsoft) and were the average of two determinations.

The Companion Example compounds were tested in the assay described and advantageous compounds were found to have a K value for displacing [ ³ H]-flumazenil from the human GABA _A receptor α5 subunits of 100 nM or less. Most preferred are compounds with a Ki (nM) < 35. In a preferred embodiment, the compounds of this invention bind selectively to α5 subunits over α1, α2 and α3 subunits. Representative test results obtained using the assay described above to measure the ability to bind to HEK293 cells that express human receptors (h) are shown in the Table below.

Functional expression of GABA _A receptors:

Preparation of Xenopus oocytes

Xenopus laevis oocytes at maturation stages V-VI were used to express cloned mRNA encoding GABA _A receptor subunits. Oocytes ready for RNA microinjection were purchased from Ecocyte, Castrop-Rauxel, Germany, and prior to the experiment were stored in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO ₃ 2.4, HEPES 10, MgSO ₄ 0.82, CaNO ₃ 0.33, CaCl ₂ 0.33, pH=7.5) at 20° S.

Microinjection of Xenopus oocytes

Oocytes were seeded in 96-well plates for use in an automated instrument (Robo-ocyte, MultiChannelSystems, Reutlingen, Germany) for recording microinjection and electrophysiological data. About 50 nl of an aqueous solution containing RNA transcripts for the target GABA _A receptor subunits was injected into each oocyte. RNA concentrations ranged from 0.3 to 16 ng/μl/subunit and were adjusted in pilot experiments to obtain GABA responses of appropriate magnitude and maximum effect of the reference modulator, beta-MCM (β-MCM), betacarboline negative allosteric modulator (NAM) at the binding site of benzodiazepine (BZD) to the GABA _A receptor, or midazolam, benzodiazepine positive allosteric modulator (AM) at the binding site of benzodiazepine (BZD) GABA _A receptor. The concentration of RNA encoding the γ2 subunits was typically 5 to 10 times higher than the concentration of RNA encoding the other subunits. Before the experiment, oocytes were stored 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.

electrophysiology

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

Each compound and concentration was tested on a minimum of 3 oocytes. Different oocytes were used for different concentrations of compounds. β-MCM, a negative allosteric modulator, or midazolam, a positive allosteric modulator, was tested on multiple (3-6) oocytes per 96-well plate for positive control at maximum efficiency. β-CMC suppressed GABA-induced current by about 50% (~0.5 fold increase), while midazolam potentiated GABA-induced current by about 150% (~2.5 fold increase).

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 time interval of administration of the test compound was calculated step by step. The extremum of the "trace ratio" obtained was taken as the potency ("fold increase") of the compound, expressed as "% GABA EC ₂₀ modulation" (100*(fold increase-1)). The results are shown in Table 1.

WO 2009/071476 discloses the reference compound RO-309 as Example 309.

WO 2009/071477 discloses reference compound RO-035 as Example 35, RO-036 as Example 36, RO-039 as Example 39 and RO-096 as Example 96.

Reference compounds were also tested for their affinity for the α5β3γ2 GABA receptor subtypes as well as their potency in oocytes that overexpress GABA α5β3γ2. The results are shown in Table 2.

The compounds of Formula (I) or (II) and their pharmaceutically acceptable salts can be used as drugs (eg in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered orally, in particular 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 topical to the eyes (for example, in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be carried out parenterally, namely intramuscularly, intravenously or intraocularly (for example, in the form of sterile injectable solutions).

The compounds of Formula (I) or (II) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees, hard gelatin capsules, injectable solutions or topical preparations. As such excipients for tablets, dragees and hard gelatin capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols, and the like.

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

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable suppository auxiliaries are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

Suitable excipients for topical eye preparations are, for example, cyclodextrins, lures, or a variety of other carriers and excipients known in the art.

Moreover, the pharmaceutical preparations may contain preservatives, solubilizers, viscosifiers, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, osmotic salts, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will generally be tailored to the individual requirements in each particular case. In general, in the case of oral administration, the daily dose is from about 0.1 mg to 20 mg per kg of body weight, preferably from about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), preferably divided into 1-3 individual doses, which may consist of, for example, equal amounts, if appropriate. In the case of topical administration, the preparation may contain from 0.001% to 15% by weight of the drug, and the required dose, which may be from 0.1 to 25 mg, can be administered either once a day or a week, or several times (2 to 4) a day, or with several doses per week. However, it will be understood that the upper or lower limit given in this document may be exceeded if indicated as an indication.

Preparation of pharmaceutical compositions containing the compounds of the invention:

Production technology

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 the appropriate grinding equipment.

4. Add ingredient 5 and mix for three minutes; compress on an appropriate press.

Production technology

1. Mix ingredients 1, 2 and 3 in an appropriate mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Fill into appropriate capsules.

The compound of Formula I, lactose and corn starch are first mixed in a mixer and then in a grinder. The mixture is returned to the mixer; talc is added there and mixed. Using a machine, the mixture is filled into appropriate capsules, for example hard gelatine capsules.

The invention is further illustrated by Examples, which are not restrictive.

If the prepared examples are obtained as a mixture of enantiomers, pure enantiomers can be obtained by the methods described herein, or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

Examples

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

To a solution of 6-methylnicotinaldehyde (9.86 g, 77.3 mmol) in methanol (35 ml) under nitrogen atmosphere was added hydroxylamine (50% wt. in water, 5.93 ml, 101 mmol).

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 an off-white solid. MS (ERI): 137.0 ([M+H] ⁺ ).

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

To a solution of (E)-6-methylnicotinaldehyde oxime (10.89 g, 80.0 mmol) in DMF (95 ml) at 6°C was added N-chlorosuccinimide (11.7 g, 88.0 mmol). 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 h, the mixture was heated to 50°C for 2 h. The resulting brown suspension was 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 Buchner funnel. The residue was washed with water, then dried under high vacuum to give the title compound (11.80 g, 60%) as a brown solid. MS (ERI): 247.1 ([M+H] ⁺ ).

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

To a solution of ethyl 5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-carboxylate (11.8 g, 47.9 mmol) in tetrahydrofuran (160 ml) at 2°C under nitrogen atmosphere was added lithium aluminum hydride (2.55 g, 67.1 mmol) over 20 min. After stirring at 4° C. for 1.5 h, water (2.61 ml) was added carefully and the mixture was stirred for an additional 50 min before quenching with aqueous NaOH (15 wt%, 2.61 ml). The reaction mixture was stirred for 30 minutes at room temperature, after which water (7.8 ml) was added. After stirring for 1 hour, the resulting suspension was filtered through a Buchner funnel and the residue was washed with tetrahydrofuran (20 ml) to give the title compound (9.08 g, 93%) as an orange solid. MS (ERI): 205.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole

To a stirred suspension of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol (360 mg, 1.76 mmol) in dichloromethane (3.2 ml) was added dropwise under nitrogen at 0°C thionyl chloride (257 dl, 3.53 mmol) over 15 minutes. The solution was then stirred at 0° C. for 30 minutes. The reaction mixture was made basic by dropwise addition of 1 M sodium hydrogen carbonate solution (20 ml). Then the organic layer was washed with water (30 ml) and the aqueous layers were extracted with dichloromethane (3×10 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the title compound (391 mg, 100%) as a white solid. MS (ERI): 223.1 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

To a mixture of 4-(chloromethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole (870 mg, 3.91 mmol), 5-chloropyridazin-3(2H)-one (663 mg, 5.08 mmol) and potassium carbonate (1.35 g, 9.77 mmol) was added acetone (15 ml). The reaction mixture was stirred at room temperature for 17 hours. Purification by flash chromatography (silica, gradient: 0% to 100% ethyl acetate in heptane) gave the title compound (1.17 g, 94%) as an off-white solid. MS (ERI): 317.1 ([M+H] ⁺ ).

a) ethyl 4-fluoro-3-oxobutanoate

To a stirred solution of ethyl acetate (9.59 g, 10.7 ml, 109 mmol) in anhydrous diethyl ether (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) over 30 min. The reaction mixture was stirred for 2 h at -78° C., then ethyl 2-fluoroacetate (10.5 g, 9.62 ml, 99 mmol) was added over 15 min. The CO ₂ -acetone bath was removed, 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 diethyl ether (3×50 ml). The combined organic extracts were washed with brine (30 ml), dried over sodium sulfate, filtered and evaporated at 35° C. under reduced pressure (650 mbar - 200 mbar). The resulting colorless liquid was purified by distillation under reduced pressure using a 30 cm Vigreux column. Fractions collected at 13 mbar and 71° C. (steam temperature) gave the title compound (12.67 g, 86%) as a colorless liquid. MS (ERI): 149.1 ([M+H] ⁺ ).

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

To a stirred solution of (E)-6-methylnicotinaldehyde oxime (1.00 g, 7.34 mmol) in anhydrous tetrahydrofuran (6.7 ml) at 6°C was added N-chlorosuccinimide (1.10 g, 8.08 mmol). After 30 minutes, the mixture was heated to 50°C for 1 hour, after which all the solvent was removed under reduced pressure. The resulting residue (chlorooxime) was dissolved in ethanol (6.7 ml) and stirred at room temperature for 30 minutes. In a separate flask, triethylamine (2.05 ml, 14.7 mmol) was added to a solution of ethyl 4-fluoro-3-oxobutanoate (1.65 g, 7.34 mmol) in tetrahydrofuran (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 ethanol was slowly added by cannula. The resulting yellow suspension was stirred for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate (100 ml) and the organic phase was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 50% ethyl acetate in heptane) gave the title compound (1.1 g, 57%) as a white solid. MS (ERI): 265.2 ([M+H] ⁺ ).

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

To a stirred suspension of ethyl 5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-carboxylate (404 mg, 1.53 mmol) in anhydrous toluene (4 ml) at -78° C. was added DIBAL-G (1.0 M in toluene, 1.84 ml, 1.84 mmol) dropwise. The reaction mixture was stirred at -78°C for 30 min, after which it was quenched by the addition of ethyl acetate (0.5 ml). After 15 min the reaction mixture was allowed to warm to 0° C. and saturated aqueous sodium bicarbonate solution (5 ml) was added. The reaction mixture was thoroughly stirred for 20 min, then diluted with ethyl acetate (30 ml) and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) gave the title compound (193 mg, 57%) as a white solid. MS (ERI): 223.2 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole

Similar to the A d building block experiment, (5-(fluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol was converted to the title compound (0.207 g, 99%) instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (0.207 g, 99%) which was obtained as a light yellow oily liquid. MS (ERI): 241.0 ([M+H] ⁺ ).

e) 5-chloro-2-[[5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

To a mixture of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole (218 mg, 0.906 mmol), 5-chloropyridazin-3(2H)-one (142 mg, 1.09 mmol) and potassium carbonate (0.376 g, 2.72 mmol) was added acetone (2.5 ml) and DMF (0.25 ml). The reaction mixture was heated to 50°C for 1 hour. The resulting suspension was filtered while still hot on a Buchner funnel and washed with acetone (10 ml) then ethyl acetate (10 ml). The filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 0% to 80% ethyl acetate in heptane) gave the title compound (165 mg, 54%) as a yellow crystal. MS (ERI): 335.1 ([M+H] ⁺ ).

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

Similar to the A a building block experiment, 6-(trifluoromethyl)pyridine-3-carboxaldehyde was converted from 6-methylnicotinaldehyde to the title compound (10.94 g, 96%) which was obtained as a light yellow solid. MS (ERI): 191.1 ([M+H] ⁺ ).

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

Similar to the experiment with building block A b, using (3E)-6-(trifluoromethyl)pyridine-3-carbaldehyde oxime in place of (E)-6-methylnicotinaldehyde oxime, (E)-ethyl-3-(pyrrolidin-1-yl)but-2-enoate was converted to the title compound (7.95 g, 96%) which was obtained as a yellow solid. MS (ERI): 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 tetrahydrofuran (21 ml), methanol (21 ml) and water (21 ml) at 0°C was added lithium hydroxide monohydrate (2.03 g, 48.4 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was re-cooled to 0°C, then acidified with aqueous citric acid (5 wt.%) to pH ~ 5 (a 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 Buchner funnel. The collected solid was washed with freezing water (50 mL) and dried under high vacuum to give the title compound (4.88 g, 91% yield) as a light yellow solid. MS (ERI): 273.1 ([M+H] ⁺ ).

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

Similar to the experiment with building block E with 5-methyl-3-(6-trifluoromethyl)-3-pyridyl)isoxazole-4-carboxylic acid instead of 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylic acid was converted to the title compound (3.87 g, 84%) which was obtained as a light yellow solid. MS (ERI): 259.1 ([M+H] ⁺ ).

f) 4-(chloromethyl)-5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazole

Similar to the A d building block experiment, (5-methyl-3-(6-(trifluoromethyl)-3-pyridyl)isoxazol-4-yl)methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (0.206 g, 96%) which was obtained as a brown solid. MS (ERI): 277.0 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl] pyride azin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazole was converted to the title compound (0.142 g, 71%) in place of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.142 g, 71%) which was obtained as an off-white solid. MS (ERI): 371.0 ([M+H] ⁺ ).

a) (E)-6-chloronicotinaldehyde oxime

To a solution of 6-chloronicotinaldehyde (100 mg, 0.706 mmol) in acetonitrile (1 ml) were added hydroxylamine hydrochloride (73.6 mg, 1.06 mmol) and tripotassium phosphate (75 mg, 0.353 mmol). The mixture was stirred at room temperature for 30 minutes before water (0.2 ml) was added. After 1 hour, the resulting suspension was diluted with water (5 ml) and the solid was collected by Buchner filtration, then dried in vacuo to give the title compound (57 mg, 51%) as a white solid. MS (ERI): 157.0 ([M+H] ⁺ ).

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

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

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

To a stirred solution of ethyl 3-(6-chloropyridin-3-yl)-5-methylisoxazole-4-carboxylate (77 mg, 0.289 mmol) in anhydrous tetrahydrofuran (2 ml) at 0°C was added DIBAL-G (1.0 M in hexane, 0.924 ml, 0.924 mmol) dropwise. The resulting light yellow solution was allowed to warm to room temperature and stirred for 4.5 h before re-cooling to 0° C. (ice bath) and quenching with aqueous Na/K tartrate (10 wt%, 7 ml). The mixture was stirred vigorously at room temperature (ice bath removed) for 30 min, then diluted with ethyl acetate (10 ml). After addition of aqueous ammonium chloride solution (20 wt%, 3 ml) and aqueous HCl (1.0 M, 1 ml), the aqueous layer was separated and extracted with ethyl acetate (2×15 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) gave the title compound (48 mg, 74%) as a white solid. MS (ERI): 225.0 ([M+H] ⁺ ).

d) 4-(chloromethyl)-3-(6-chloro-3-pyridyl)-5-methylisoxazole

Similar to the A d building block experiment, (3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methanol was converted from (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4yl)methanol to the title compound (44 mg, 88%) which was obtained as a white solid. MS (ERI): 243.0 ([M+H] ⁺ ).

e) 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl] pyride azin-3-one 4-(chloromethyl)-3-(6-chloropyridin-3-yl)-5-methylisoxazole (100 mg, 0.411 mmol), 5-chloropyridazin-3(2H)-one (78.5 mg, 0.60 1 mmol) and potassium carbonate (171 mg, 1.23 mmol) were suspended in N,N-dimethylacetamide (2 ml). The reaction mixture was stirred at 50°C for 35 min, cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 50% ethyl acetate in heptane) gave the title compound (108 mg, 78%) as a white solid. MS: 337.0; 339.1 [M+H] ⁺ ; 359.0 [M+Na] ⁺ .

Structural element E

5-chloro-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

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

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

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

Similar to the experiment with building block C with ethyl 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylate instead of ethyl 5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-carboxylate was converted to the title compound (1.48 g, 70%) which was obtained as an off-white solid. MS (ERI): 205.0 ([M+H] ⁺ ).

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

Triethylamine (1.1 ml, 7.9 mmol) was added to a stirred suspension of 3-(6-methyl-3-pyridyl)isoxazole-4-carboxylic acid (1.48 g, 7.25 mmol) in anhydrous tetrahydrofuran (24 ml). The resulting solution was cooled to -15°C (NaCl/ice bath) before a solution of ethyl chloroformate (0.73 ml, 7.6 mmol) in tetrahydrofuran (4 ml) was added dropwise. After 2 hours the resulting white precipitate was filtered through a Buchner funnel and the collected solid was washed with a minimum amount of tetrahydrofuran. The filtrate was re-cooled to -15° C. (NaCl/ice bath) and a solution of sodium borohydride (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 sodium borohydride (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 extracted with ethyl acetate (2×160 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) gave the title compound (606 mg, 44%) as an off-white solid. MS (ERI): 191.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-3-(6-methyl-3-pyridyl)isoxazole

Similar to the experiment with building block A d (3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol was converted to the title compound (329 mg, 95%) which was obtained as a brown oil. MS (ERI): 209.1 ([M+H] ⁺ ).

e) 5-chloro-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-(6-methyl-3-pyridyl)isoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.320 g, 66%) which was obtained as a yellow oily liquid. MS (ERI): 303.1 ([M+H] ⁺ ).

Structural element F

5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

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

To a stirred solution of 6-methylpyridazine-3-carbaldehyde (880 mg, 7.21 mmol) in ethanol (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 h, 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 an off-white solid. MS (ERI): 138.1 ([M+H] ⁺ ).

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

Similar to the A b building block experiment, (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 a brown oil. MS (ERI): 248.1 ([M+H] ⁺ ).

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

To a stirred suspension of calcium chloride (1.8 g, 16.2 mmol) in a mixture of anhydrous tetrahydrofuran (50 ml) and ethanol (33 ml) was added ethyl 5-methyl-3-(6-methylpyridazin-3 yl)isoxazole-4-carboxylate (1.0 g, 4.04 mmol) at 0°C, followed by sodium borohydride (1.22 g, 32.4 mmol, added in batches). The mixture was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature and stirred for another 1 hour. The reaction mixture was re-cooled to 0° C. and quenched by adding saturated aqueous ammonium chloride. The organic solvents were removed by rotary evaporation under reduced pressure, and the resulting aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 20% to 100% ethyl acetate in heptane) gave the title compound (407 mg, 49%) as a yellow solid. MS (ERI): 206.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-methyl-3-(6-methylpyridazin-3-yl)isoxazole

Similarly to the A d building block experiment, (5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol was converted to (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to give the title compound (320 mg, 98%) which was obtained as a light brown solid. MS (ERI): 224.1 ([M+H] ⁺ ).

e) 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block D e, 4-(chloromethyl)-5-methyl-3-(6-methylpyridazin-3-yl)isoxazole was converted instead of 4-(chloromethyl)-3-(6-chloropyridin-3-yl)-5-methylisoxazole to the title compound (0.455 g, 67%) which was obtained as a light brown solid. MS (ERI): 318.2 ([M+H] ⁺ ).

Structural element G

5-chloro-2-[[5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

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

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

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

Similarly, an experiment with a structural element A B, using ethyl (Z) -4.4-diaphor-3-pirrolidin-1-lino-2nd instead of (E) -til-3- (Pyrrolidin-1-Il) But-2-ONOATE, (3E) -6-methylpyridine-3-carbaldehydoxim was turned into a compound indicated in the headline (362 mg, 58 mg, 58 mg, 58 mg, 58 mg, 58 mg, 58 mg, 58 mg, 58 ), which was received in the form of orange oily liquid. MS (ERI): 283.2 ([M+H] ⁺ ).

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

To a stirred solution of ethyl 5-(difluoromethyl)-3-(6-methylpyridin-3-yl)isoxazole-4-carboxylate (0.490 g, 1.56 mmol) in anhydrous toluene (16 ml) at -78° C. was added DIBAL-G (1.0 M in toluene, 3.2 ml, 3.2 mmol) dropwise. The reaction mixture was stirred at -78°C for 3.5 h, after which was added an additional amount of DIBAL-G (1.0 M in toluene, 0.78 ml, 0.78 mmol). After 1.5 h, 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 h before extraction with ethyl acetate (2×40 ml). The combined organic extracts were washed with water (5 ml) and brine (5 ml), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 70% ethyl acetate in heptane) gave the title compound (165 mg, 44%) as a light yellow solid. MS (ERI): 241.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole

Similar to the A d experiment, (5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (300 mg, 97%) which was obtained as a light gray oily liquid. MS (ERI): 224.1 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole instead of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole was converted to the title compound (0.237 g, 58%) which was obtained as a yellow oily liquid. MS (ERI): 353.1 ([M+H] ⁺ ).

Structural element H

5-chloro-2-[[3-(6-cyclopropyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridtin-3-one

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

To a stirred solution of hydroxylamine hydrochloride (11.0 g, 161 mmol) in ethanol (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-bromopyridine-3-carbaldehyde (15.0 g, 80.6 mmol). The reaction mixture was heated at reflux for 1 hour, after which all volatiles 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 over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound (12.5 g, 77%) as a white solid. MS (ERI): 201.3 ([M+H] ⁺ ).

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

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

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

Ethyl 3-(6-bromo-3-pyridyl)-5-methylisoxazole-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 P d(OAc) ₂ (1.16 g, 5.14 mmol). The flask was degassed by alternative evacuation and back filling 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 h, then cooled to room temperature and immediately filtered through a pad of celite. The filter cake was washed with ethyl acetate and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound (5.5 g, 78%) as a yellow solid. MS (ERI): 272.7 ([M+H] ⁺ ).

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

To a stirred solution of ethyl 3-(6-cyclopropyl-3-pyridyl)-5-methylisoxazole-4-carboxylate (2.7 g, 11.4 mmol) in anhydrous tetrahydrofuran (20 ml) at -10°C was added lithium aluminum hydride (1.0 M in tetrahydrofuran, 13.7 ml, 13.7 mmol) dropwise. 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 immediately filtered through a pad of celite. The filter cake was washed with ethyl acetate and the filtrate was concentrated in vacuo to give the title compound (1.8 g, 81%) as an off-white solid. MS (ERI): 236.1 ([M+H] ⁺ ).

f) 4-(chloromethyl)-3-(6-cyclopropyl-3-pyridyl)-5-methylisoxazole

Similar to the A d building experiment, (5-(difluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (157 mg, 93%) which was obtained as a white solid. MS (ERI): 249.1 ([M+H] ⁺ ).

f) 5-chloro-2-[[3-(6-cyclopropyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-(6-cyclopropyl-3-pyridyl)-5-methylisoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.110 g, 69%) which was obtained as an off-white solid. MS (ERI): 343.0 ([M+H] ⁺ ).

Structural element I

5-chloro-2-[[5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

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

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

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

Similar to the experiment with building block C with ethyl 5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-carboxylate instead of ethyl 5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-carboxylate was converted to the title compound (260 mg, 95%) which was obtained as an orange solid. MS (ERI): 246.1 ([M+H] ⁺ ).

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

Similar to the E experiment with 5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-carboxylic acid instead of 3-(6-methyl-3-pyridyl)isoxazol-4-yl)carboxylic acid was converted to the title compound (85 mg, 47%) which was obtained as an orange solid. MS (ERI): 232.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazole

Similar to the A d building experiment, (5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (38 mg, 99%) which was obtained as a white solid. MS (ERI): 250.1 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-cyclopropyl-3-(b-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazole was converted instead of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (30 mg, 88%) which was obtained as an off-white solid. MS (ERI): 344.3 ([M+H] ⁺ ).

Structural element J

5-chloro-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

a) (3E)-5-fluoro-6-methylpyridine-3-carbaldehyde oxime

To a stirred suspension of 5-fluoro-6-methylpyridine-3-carbaldehyde (450 mg, 3.23 mmol) in ethanol (0.7 ml) under argon was added freezing water (4.3 ml) and hydroxylamine hydrochloride (247 mg, 3.56 mmol). After 10 min, aqueous NaOH (2.0 M, 4.12 ml, 8.25 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 h. The resulting clear solution was treated with acetic acid to pH ~ 5 (a white precipitate formed). After stirring for 15 minutes, the precipitate was collected by Buchner filtration, washed with water and dried under high vacuum to give the title compound (383 mg, 77%) as a white solid. MS (ERI): 155.1 ([M+H] ⁺ ).

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

To a stirred solution of (3E)-5-fluoro-6-methylpyridine-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 h after which (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 obtain a clear brown solution. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 30% ethyl acetate in heptane) gave the title compound (475 mg, 73%) as a light brown solid. MS (ERI): 265.2 ([M+H] ⁺ ).

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

To a stirred solution of ethyl 3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazole-4-carboxylate (470 mg, 1.78 mmol) in anhydrous tetrahydrofuran (10 ml) at 0° C., lithium aluminum hydride (94.5 mg, 2.49 mmol) was carefully added under argon. The reaction mixture was left to warm to room temperature for 2 h, then re-cooled to 0°C and carefully extinguished by adding water (0.1 ml). After gas evolution ceased, 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 minutes. The resulting light yellow suspension was filtered off and the precipitate was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, 0% to 5% MeOH in dichloromethane) to give the title compound (221 mg, 56%) as a yellow solid. MS (ERI): 223.2 ([M+H] ⁺ ).

d) 4-(chloromethyl)-3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazole

Similar to the A d experiment, (3-(5-fluoro-6-methylpyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methanol was converted to (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (193 mg, 81%), which was obtained as a white solid. MS (ERI): 241.1 ([M+H] ⁺ ).

f) 5-chloro-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (279 mg, 82%) which was obtained as an off-white solid. MS (ERI): 335.1 ([M+H] ⁺ ).

Structural element K

5-chloro-2-[[5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

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

To a stirred solution of ethyl 4-fluoro-3-oxobutanoate (1.0 g, 6.75 mmol) in cyclohexane (10 mL) was added dropwise (gently 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 bottom flask was equipped with a Dean-Stark trap and refluxed overnight. The reaction mixture was cooled to room temperature, after which all volatiles were removed by rotary evaporation under reduced pressure. The resulting crude residue (orange oily liquid) was immediately used in the next step without further purification.

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

To a stirred suspension of (E)-6-methylpyridazine-3-carbaldehyde oxime (350 mg, 2.55 mmol) in DMF (5 ml) at 6°C was added N-chlorosuccinimide (375 mg, 2.81 mmol). 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 h, the mixture was heated to 50°C for 2 h. The resulting brown suspension was recooled to 6°C, then a solution of ethyl (E)-4-fluoro-3-pyrrolidin-1-ylbut-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 extracted with ethyl acetate (3×40 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 50% ethyl acetate in heptane) gave the title compound (498 mg, 74%) as an orange oil. MS (ERI): 266.1 ([M+H] ⁺ ).

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

To a stirred suspension of ethyl 5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazole-4-carboxylate (498 mg, 1.88 mmol) in anhydrous toluene (16 ml) at -78° C. was added DIBAL-G (1.0 M in toluene, 5.63 ml, 5.63 mmol) dropwise. The reaction mixture was stirred at -78°C for 1 h, then left to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0° C., then quenched by addition of aqueous NaOH (1.0 M, 15 ml) followed by ethyl acetate (20 ml). The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3×40 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) gave the title compound (105 mg, 25%) as a light yellow powder. MS (ERI): 224.2 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazole

Similar to the A d building experiment, (5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (267 mg, 97%) which was obtained as a brown oil. MS (ERI): 242.1 ([M+H] ⁺ ).

e) 5-chloro-2-[[5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazole was converted to the title compound (75 mg, 20%) instead of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole, which was obtained as a yellow oily liquid. MS (ERI): 336.1 ([M+H] ⁺ ).

Structural element L

5-chloro-2-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

The preparation of [3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methanol is described in the following patents: US 20090143371, US 20090143385, WO 2010127975, WO 2013057123, WO 2013057124

a) 4-(chloromethyl)-3-(4-fluorophenyl)-5-methylisoxazole

Similar to the A d building block experiment, [3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methanol was converted instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (1.09 g, 95%) which was obtained as an off-white solid. MS (ERI): 226.1 ([M+H] ⁺ ).

b) 5-chloro-2-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-(4-fluorophenyl)-5-methylisoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.822 g, 76%) which was obtained as an off-white solid. MS (ERI): 320.1 ([M+H] ⁺ ).

Structural element M

5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

The preparation of [3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methanol is described in the following patents: US 20090143371, US 20090143385

a) 4-(chloromethyl)-3-(5-chloro-2-pyridyl)-5-methylisoxazole

Similar to the A d experiment, [3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4yl)methanol to the title compound (0.566 g, 95%) which was obtained as an off-white solid. MS (ERI): 243.1 ([M+H] ⁺ ).

b) 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-(5-chloro-2-pyridyl)-5-methylisoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.374 g, 76%) which was obtained as an off-white solid. MS (ERI): 337.0 ([M+H] ⁺ ).

Structural element N 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazol-4-yl]methyl]pyridazin-3-one

a) (2E)-5-chloropyridine-2-carbaldehyde oxime

Similar to the experiment with building block J a, 5-chloro-2-formylpyridine was converted instead of 5-fluoro-6-methylpyridine-3-carbaldehyde to the title compound (4.23 g, 96%) which was obtained as a white solid. MS (ERI): 157.0 ([M+H] ⁺ ).

b) ethyl 3-(5-chloro-2-pyridyl)-5-methylisoxazole-4-carboxylate

To a stirred solution of (2E)-5-chloropyridine-2-carbaldehyde oxime (1.8 g, 11.5 mmol) in DMF (24 ml) at room temperature was added N-chlorosuccinimide (1.71 g, 12.8 mmol) in three portions. The reaction mixture was stirred at room temperature for 3 h after which (E)-ethyl-3-(pyrrolidin-1-yl)but-2-enoate (2.63 g, 14.4 mmol) was added. The mixture was heated to 50°C overnight to obtain a clear brown solution. After cooling to room temperature, the reaction mixture was diluted with TBME (100 ml), washed with water (30 ml) and brine (30 ml), dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 15% ethyl acetate in heptane) gave the title compound (2.60 g, 85%) as a light yellow oil. MS (ERI): 267.1 ([M+H] ⁺ ).

c) [3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methanol

To a stirred solution of ethyl 3-(5-chloro-2-pyridyl)-5-methylisoxazole-4-carboxylate (800 mg, 3 mmol) in anhydrous tetrahydrofuran (16 ml) at 0° C., a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (1.5 ml, 1.5 mmol) was carefully added under argon. The reaction mixture was stirred at 0°C for 1 h, after which it was re-cooled to -15°C and carefully quenched by adding water (0.06 ml). After gas evolution ceased, aqueous NaOH (4.0 M, 0.06 ml) was added followed by water (0.17 ml) and the mixture was stirred at room temperature for 1.25 hours. After addition of sodium sulfate, the resulting suspension was filtered and the precipitate was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, 0% to 30% ethyl acetate in heptane) to give the title compound (545 mg, 81%) as a light yellow solid. MS (ERI): 225.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazole

Similar to the A d experiment, [3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methanol was converted from (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4yl)methanol to the title compound (0.554 g, 96%) which was obtained as a light yellow solid. MS (ERI): 269.1 ([M+H] ⁺ ).

f) 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.418 g, 79%) which was obtained as an off-white solid. MS (ERI): 363.1 ([M+H] ⁺ ).

Structural element O

5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

a) (5-methylisoxazol-3-yl)methanol

Sodium borohydride (2.94 g, 77.9 mmol) was added to a stirred solution of 5-methylisoxazole-3-carboxylic acid methyl ester (5 g, 35.4 mmol) in methanol (50 ml) at 0°C. Then the reaction mixture was left to stir at 25°C for 2 hours After adding water, the reaction mixture was extracted with ethyl acetate (2x100 ml). The organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by flash chromatography (silica, 0% to 30% ethyl acetate in heptane) gave the title compound (3.8 g, 76%) as a colorless oily liquid. MS (ERI): 114.0 ([M+H] ⁺ ).

b) 5-methylisoxazole-3-carbaldehyde

To a solution of (5-methylisoxazol-3-yl)methanol (2 g, 17.6 mmol) in dry dichloromethane (20 ml) at 0°C was added MnO ₂ (15.3 g, 176 mmol) and the reaction mixture was stirred at 25°C for 7 hours. The black solid was filtered through Celite and the filtrate was concentrated to give the title compound (1.5 g, 76%) as a brown oil. MS (ERI): 209.1 ([M+H] ⁺ ).

c) (3E)-5-methylisoxazole-3-carbaldehyde oxime

To a stirred solution of 5-methylisoxazole-3-carbaldehyde (250 mg, 2.25 mmol) in methanol (3 ml) at 0°C was added hydroxylamine (50% in water; 2.25 ml, 27.0 mmol) and the reaction mixture was stirred at 25°C for 2 h. The reaction mixture was then extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, then concentrated to give the title compound (200 mg, 70%) as a white solid. MS (ERI): 183.9 ([M+H] ⁺ ).

d) ethyl 5-methyl-3-(5-methylisoxazol-3-yl)isoxazole-4-carboxylate

К раствору (3Е)-5-метилизоксазол-3-карбальдегидоксима (1,1 г, 8,73 ммоль) в ДМФ (15 мл) в инертной атмосфере при 0°С порционно добавляли N-хлорсукцинимид (1,75 г, 13 1 ммоль), и реакционную смесь перемешивали при 25°С в течение 2 ч. К этому раствору при 25°С добавляли этил-(2Е)-3-(пирролидин-1-ил)бут-2-еноат (4 г, 21,8 ммоль) в ДМФ (5 мл), и реакционную смесь перемешивали при 25°С в течение 16 ч. Затем реакционную смесь концентрировали в темноте, и полученный остаток разбавляли этилацетатом (50 мл) и промывали Na ₂ CO ₃ (1 M в Н ₂ О), водой (100 мл) и рассолом. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 20% ethyl acetate in heptane) gave the title compound (1.5 g, 73%) as a white solid. MS (ERI): 237 ([M+H] ⁺ ).

e) [5-methyl-3-(5-methyl-1,2-oxazol-3-yl)-1,2-oxazol-4-yl]methanol

To the solution of ethyl-5-methyl-3- (5-metilizzasol-3-il) Izoxazole-4-carboxylate (2.7 g, 11.4 mmol) to tetrahydrofuran (20 ml) at -10 ° C, 1 m of alumidride of lithium in tetrahydrofurana (13.7 ml, 13.7 mmol), and the reactionary mixture) were added. They sewed at the same temperature for 30 minutes. The reaction mixture was quenched with sodium sulfate decahydrate at 0°C, and the reaction mass was filtered through a pad of celite. The filtrate was evaporated to give the title compound (1.8 g, 81%) as an off-white solid. MS (ERI): 195.1 ([M+H] ⁺ ).

f) 4-(chloromethyl)-5-methyl-3-(5-methylisoxazol-3-yl)isoxazole

Similar to the A d experiment, [5-methyl-3-(5-methyl-1,2-oxazol-3-yl)-1,2-oxazol-4-yl]methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (0.422 g, 92%) which was obtained as a light brown solid. MS (ERI): 213.1 ([M+H] ⁺ ).

g) 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-methyl-3-(5-methylisoxazol-3-yl)isoxazole was converted instead of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.495 g, 87%) which was obtained as an off-white solid. MS (ERI): 307.1 ([M+H] ⁺ ).

Structural element P

5-chloro-2-[[3-(6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

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

Similar to the A building block experiment, a 6-(trifluoromethyl)pyridine-3-carboxaldehyde was converted instead of 6-methylnicotinaldehyde to the title compound (5.28 g, 100%) which was obtained as a white solid. MS (ERI): 191.1 ([M+H] ⁺ ).

b) ethyl 3-[6-(trifluoromethyl)-3-pyridyl]isoxazole-4-carboxylate

Similar to the experiment with building block A b, using ethyl 3-(dimethylamino)acrylate in place of (E)-ethyl-3-(pyrrolidin-1-yl)but-2-enoate, (3E)-6-(trifluoromethyl)pyridine-3-carbaldehyde oxime in place of (E)-6-methylnicotinaldehyde oxime was converted to the title compound (1.70 g, 75%), which was obtained as an oily liquid of light yellow. MS (ERI): 287.2 ([M+H] ⁺ ).

c) 3-[6-(trifluoromethyl)-3-pyridyl1isoxazole-4-carboxylic acid

To a stirred solution of ethyl 3-[6-(trifluoromethyl)-3-pyridyl]isoxazole-4-carboxylate (1.43 g, 5.70 mmol) in tetrahydrofuran (6 ml) and methanol (6 ml) at 0°C was added lithium hydroxide monohydrate (586 mg, 13.9 mmol) followed by addition of water (6 ml). Then the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. After cooling to 0°C, the reaction mixture was acidified with a 5% citric acid solution to pH 5. The suspension was filtered and washed with water. The organic solvents of the filtrate were evaporated and the aqueous residue was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, dried over sodium sulfate, combined with the off-white solid mentioned above and concentrated to give the title compound (1.00 g, 66%) as a light yellow solid. MS (ERI): 259.1 ([M+H] ⁺ ).

d) [3-[6-(trifluoromethyl)-3-pyridyl1isoxazol-4-yl]methanol

A solution of ethyl chloroformate (0.38 ml, 3.96 mmol) in tetrahydrofuran (3 ml). After stirring at -15°C for 2 h, the suspension was filtered and washed with a minimum amount of tetrahydrofuran. The filtrate was then cooled to -15°C and a solution of sodium borohydride (355 mg, 9.39 mmol) in water (10 ml) was added dropwise at -15°C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was extracted with ethyl acetate (80 ml) and 2 M NaOH solution (15 ml). The aqueous layer was extracted from the extract with ethyl acetate (80 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (885 mg, 87%) as a yellow solid. MS (ERI): 245.1 ([M+H] ⁺ ).

e) 4-(chloromethyl)-3-[6-(trifluoromethyl)-3-pyridyl]isoxazole

Similar to the A d experiment, [3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methanol was converted instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (0.403 g, 94%) which was obtained as a yellow oil. MS (ERI): 263.0 ([M+H] ⁺ ).

f) 5-chloro-2-[[3-(6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-3-[6-(trifluoromethyl)-3-pyridyl]isoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (0.281 g, 58%) which was obtained as an off-white solid. MS (ERI): 357.0 ([M+H] ⁺ ).

Structural element Q

5-chloro-2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

The preparation of [3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methanol is described in the following patents: US 20090143371, WO 2013057123.

a) 4-(chloromethyl)-3-(4-chlorophenyl)-5-methylisoxazole

Similar to the A d building block experiment, [3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methanol was converted from (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (2.20 g, 91%) which was obtained as an off-white solid. MS (ERI): 242.0 ([M+H] ⁺ ).

b) 5-chloro-2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block A e, 4-(chloromethyl)-3-(4-chlorophenyl)-5-methylisoxazole was converted instead of 4-(chloromethyl)-5-methyl-3-(6-methyl-3-pyridyl)isoxazole to the title compound (1.62 g, 57%) which was obtained as an off-white solid. MS (ERI): 336.1 ([M+H] ⁺ ).

Structural element R

5-chloro-2-[[5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methyl]pyridazin-3-one

a) (2E)-5-(trifluoromethyl)pyrimidine-2-carbaldehyde oxime

Similar to the experiment with building block J a, 5-(trifluoromethyl)pyrimidine-2-carbaldehyde was converted instead of 5-fluoro-6-methylpyridine-3-carbaldehyde to the title compound (0.769 g, 79%) which was obtained as a brown solid. MS (ERI): 192.1 ([M+H] ⁺ ).

b) ethyl 5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl1isoxazole-4-carboxylate

Similar to the Jb building block experiment, (2E)-5-(trifluoromethyl)pyrimidine-2-carbaldehyde oxime was converted instead of (3E)-5-fluoro-6-methylpyridine-3-carbaldehyde oxime to the title compound (0.735 g, 61%) which was obtained as a yellow solid. MS (ERI): 302.1 ([M+H] ⁺ ).

c) 5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazole-4-carboxylic acid

Similar to the experiment with building block P with ethyl 5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazole-4-carboxylate instead of ethyl 3-[6-(trifluoromethyl)-3-pyridyl]isoxazole-4-carboxylate was converted to the title compound (0.720 g, 86%) which was obtained as a light yellow solid. MS (ERI): 274.1 ([M+H] ⁺ ).

d) [5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methanol

Similarly to the experiment with building block P d, 5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazole-4-carboxylic acid was converted from 3-[6-(trifluoromethyl)-3-pyridyl]isoxazole-4-carboxylic acid to the title compound (107 mg, 28%) which was obtained as a light yellow solid. MS (ERI): 260.0 ([M+H] ⁺ ).

f) 4-(chloromethyl)-5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazole

Similar to the A d building block experiment, [5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methanol was converted from (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (303 mg, 100%) which was obtained as a light brown solid. MS (ERI): 277.9 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazole was converted to the title compound (235 mg, 73%) instead of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole, which was obtained as an off-white solid. MS (ERI): 372.4 ([M+H] ⁺ ).

Structural element S

5-chloro-2-[[3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

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

Similar to the experiment with building block D a, 6-chloropyridazine-3-carbaldehyde was converted instead of 6-chloronicotinaldehyde to the title compound (1.028 g, 98%) which was obtained as a brown solid. MS (ERI): 158.0 ([M+H] ⁺ ).

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

Similar to the J b building block experiment, (3E)-6-chloropyridazine-3-carbaldehyde oxime was converted instead of (3E)-5-fluoro-6-methylpyridine-3-carbaldehyde oxime to the title compound (0.224 g, 66%) which was obtained as a yellow solid. MS (ERI): 306.1 ([M+H] ⁺ ).

c) [3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl] methanol

Similar to the experiment with building block D, ethyl 3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-carboxylate instead of ethyl 3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-carboxylate was converted to the title compound (81 mg, 32%) which was obtained as a light yellow solid. MS (ERI): 226.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-3-(6-chloropyridazin-3-yl)-5-methylisoxazole

Similar to the A d building block experiment, [3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl] methanol was converted instead of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4yl)methanol to the title compound (83 mg, 96%) which was obtained as a light yellow solid. MS (ERI): 244.1; 246.0 ([M+H] ⁺ ).

e) 5-chloro-2-[[3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

A mixture of 4-(chloromethyl)-3-(6-chloropyridazin-3-yl)-5-methylisoxazole (66 mg, 0.270 mmol), 5-chloropyridazin-3(2H)-one (38.8 mg, 0.297 mmol) and potassium carbonate (74.7 mg, 0.541 mmol) in N,N-dimethylacetamide (1.3 ml) was stirred at room temperature for 5 hours The mixture was diluted with water and was extracted with ethyl acetate (3x). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) to give the title compound (72 mg, 79%) as a white solid. MS (ERI): 338.0; 340.0 ([M+H] ⁺ ).

Structural element T

5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methyl]pyridazin-3-one

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

To a solution of 6-(trifluoromethyl)pyridazine-3-carbaldehyde (900 mg, 5.11 mmol) in a mixture of acetonitrile (8.1 ml) and water (0.900 ml) were added hydroxylamine hydrochloride (533 mg, 7.67 mmol) and tripotassium phosphate (542 mg, 2.56 mmol). The mixture was stirred at room temperature for 30 minutes. The resulting orange mixture was poured into an ice bath and diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (550 mg, 56%) as an orange solid. MS (ERI): 190.2 ([M+H] ⁺ ).

b) ethyl 5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazole-4-carboxylate

Similar to the Jb building block experiment, (3E)-6-chloropyridazine-3-carbaldehyde oxime was converted instead of (3E)-5-fluoro-6-methylpyridine-3-carbaldehyde oxime to the title compound (0.744 g, 86%) which was obtained as a yellow solid. MS (ERI): 302.4 ([M+H] ⁺ ).

c) [5-methyl-3-T6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methanol

A solution of ethyl 5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazole-4-carboxylate (100 mg, 0.332 mmol) in toluene (2.21 ml) was cooled to -68°C. After 10 minutes, a solution of DIBAL-G (1.0 M in toluene, 0.670 ml, 0.667 mmol) was added dropwise at -68°C over 3 minutes. After the addition was complete, the solution was stirred at -68° C. for 30 minutes. The reaction was quenched at -68°C by adding dropwise aqueous NaOH (1.0 M, 2.5 ml). The mixture was allowed to warm to room temperature before being partitioned between water (35 ml) and ethyl acetate (50 ml). The phases were separated. The aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (1×50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (78 mg, 91%) as a white solid. The compound was used without further purification. MS (ERI) m/z: 260.1 ([M+H] ⁺ ).

d) 4-(chloromethyl)-5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazole

Similar to the A d building block experiment, [5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (80 mg, 95%) which was obtained as a brown solid. MS (ERI): 277.8 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (60.2 mg, 59%) which was obtained as an off-white solid. MS (ERI): 371.9 ([M+H] ⁺ ).

Structural element U

5-chloro-2-[[5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

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

Similar to the experiment with building block A b, using (Z)-ethyl-3-(pyrrolidin-1-yl)pent-2-enoate in place of (E)-ethyl-3-(pyrrolidin-1-yl)but-2-enoate, (E)-6-methylpyridazin-3-carbaldehyde oxime in place of (3E)-5-fluoro-6-methylpyridine-3-carbaldehyde oxime was converted to the title compound (179 mg, 63%), which was obtained as a yellow oily liquid. MS (ERI): 262.2 ([M+H] ⁺ ).

b) [5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methanol

Similar to the experiment with building block K with ethyl 5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-carboxylate instead of ethyl 5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-carboxylate was converted to the title compound (80 mg, 41%), which was obtained as a white powder. MS (ERI): 220.1 ([M+H] ⁺ ).

c) 4-(chloromethyl)-5-ethyl-3-(b-methylpyridazin-3-yl)isoxazole

Similar to the A d building block experiment, [5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methanol was converted to (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to give the title compound (85 mg, 98%) which was obtained as a light brown solid. MS (ERI): 238.1; 240.0 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 4-(chloromethyl)-5-ethyl-3-(6-methylpyridazin-3-yl)isoxazole was converted to the title compound (84 mg, 71%) instead of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to give the title compound (84 mg, 71%), which was obtained as a light yellow oily liquid. MS (ERI): 332.0 ([M+H] ⁺ ).

Structural element V

5-chloro-2-[[3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

a) (2E)-5-chloro-3-fluoropyridine-2-carbaldehyde oxime

Similar to the experiment with building block J a, 5-chloro-3-fluoropyridine-2-carbaldehyde instead of 5-fluoro-6-methylpyridine-3-carbaldehyde was converted to the title compound (791 mg, 98%) which was obtained as a light yellow solid. MS (ERI): 185.0 ([M+H] ⁺ ).

b) ethyl 3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazole-4-carboxylate

To a stirred solution of (2E)-5-chloro-3-fluoropyridine-2-carbaldehyde oxime (0.785 g, 4.5 mmol) in DMF (16 ml) at room temperature was added N-chlorosuccinimide (0.661 g, 4.95 mmol) in four portions. The reaction mixture was stirred at room temperature for 2.5 h and at 50°C for 1 h, after which (E)-ethyl-3-(pyrrolidin-1-yl)but-2-enoate (0.989 g, 5.4 mmol) was added at room temperature. The mixture was heated to 50°C overnight to obtain a clear brown solution. After cooling to room temperature, the reaction mixture was diluted with TBME (100 ml), washed with water (30 ml) and brine (30 ml), dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 15% ethyl acetate in heptane) gave the title compound (1.19 g, 89%) as a light yellow solid. MS (ERI): 285.1 ([M+H] ⁺ ).

c) 3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazole-4-carboxylic acid

To a stirred solution of ethyl 3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazole-4-carboxylate (1.19 g, 8.91 mmol) in tetrahydrofuran (4.4 ml) and methanol (4.4 ml) at 0°C was added lithium hydroxide monohydrate (408 mg, 9.73 mmol) followed by addition of water (4.4 ml). Then the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. After cooling to 0°C, the reaction mixture was acidified with a 5% citric acid solution to pH 5. The suspension was filtered and washed with water. The organic solvents of the filtrate were evaporated and the aqueous residue was extracted with ethyl acetate (3×100 ml). The organic layers were combined, dried over sodium sulfate, combined with the off-white solid mentioned above and concentrated to give the title compound (769 mg, 76%) which was obtained as an off-white solid. MS (ERI): 257.0 ([M+H] ⁺ ).

d) [3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methanol

Ethyl chloroformate solution (0.30 ml, 3.1 2 mmol) in tetrahydrofuran (3 ml). The reaction mixture was stirred at -15°C for 3 hours Then the reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was cooled to -15°C and a solution of sodium borohydride (280 mg, 7.4 mmol) in water (8 ml) was added dropwise at -15°C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was extracted with ethyl acetate (80 ml) and 2 M NaOH solution (10 ml). The aqueous layer was extracted from the extract with ethyl acetate (80 ml). The organic layers were then combined, dried over sodium sulfate and purified by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) to give the title compound (513 mg, 71%) as an off-white solid. MS (ERI): 243.1 ([M+H] ⁺ ).

f) 3-(5-chloro-3-fluoro-2-pyridyl)-4-(chloromethyl)-5-methylisoxazole

Similar to the A d experiment, [3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methanol was converted in place of (5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methanol to the title compound (430 mg, 97%) which was obtained as a light brown solid. MS (ERI): 244.1; 261.0 ([M+H] ⁺ ).

f) 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment with building block B e, 3-(5-chloro-3-fluoro-2-pyridyl)-4-(chloromethyl)-5-methylisoxazole was converted from 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazole to the title compound (420 mg, 86%) which was obtained as an off-white solid. MS (ERI): 355.0 ([M+H] ⁺ ).

Structural element Z

[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]boric acid

A round bottom flask was charged with 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block A, 1.00 g, 3.16 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3 ,2-dioxaborolane (1.20 g, 4.74 mmol), dry potassium acetate (775 mg, 7.89 mmol), (19.0 g, 90 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (183 mg, 0.316 mmol) and tris(dibenzylideneacetone) dipalladium (0) (145 mg, 0.1 58 mmol). The flask was degassed by alternative evacuation and back filling with argon. Pre-degassed 1,4-dioxane (20 ml) was added and the resulting mixture was purged with argon for 15 minutes. The reaction mixture was stirred at 100°C for 16 h, then cooled to room temperature and immediately filtered through a pad of celite. The filter cake was washed with ethyl acetate and the filtrate was concentrated in vacuo. Purification by preparative HPLC (column: C-18, eluent: H ₂ O and CH ₃ CN with 0.05% HCO ₂ H) gave the title compound (506 mg, 46%) as a white powder. MS (ERI): 327.2 ([M+H] ⁺ ).

Preparation of amines and heterocyclic compounds

(2R,3R)-2-methylazetidin-3-ol hydrochloride

a) (2R,3R)-1-benzhydryl-2-methylazetidin-3-ol

To a solution of 2-(bromomethyl)-3-methyloxirane (7.2 g, 40.5 mmol) in methanol (24 ml) was added diphenylmethanamine (8.21 ml, 47.5 mmol). After stirring at room temperature for 2 days, the reaction mixture was stirred at 70° C. for 4 days. The mixture was then concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed twice with 1 M solution of K ₂ CO ₃ , water (50 ml) and brine (50 ml). The aqueous layers were extracted from the extract with ethyl acetate (50 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 20% to 100% ethyl acetate in heptane) and HPLC gave the title compound (1.19 g, 12%) as a white solid. MS (ERI): 254.2 ([M+H] ⁺ ). Purification by chiral HPLC gave the title compound (430 mg) as a white solid. MS (ERI): 254.2 ([M+H] ⁺ ).

b) (2R,3R)-2-methylazetidin-3-ol hydrochloride

To a solution of (2R,3R)-1-benzhydryl-2-methylazetidin-3-ol (443 mg, 1.75 mmol) in methanol (10 ml) under argon was added palladium on carbon 10% (184 mg, 0.173 mmol). The flask was gently evacuated, filled with hydrogen five times, and stirred vigorously at room temperature under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through Hyflo and washed thoroughly with methanol. The filtrate was concentrated in vacuo. After addition of acetonitrile (30 ml), the mixture was concentrated and dried under high vacuum to give the title crude compound (480 mg, <45% purity, 100%) as an off-white solid. MS (ERI): 88.1 ([M+H] ⁺ ).

(2S,3S)-2-methylazetidin-3-ol hydrochloride

a) (2S,3S)-1-benzhydryl-2-methylazetidin-3-ol

As with (2R,3R)-1-benzhydryl-2-methylazetidin-3-ol, 2-(bromomethyl)-3-methyloxirane was converted to the title compound (478 mg) which was obtained as a white solid. MS (ERI): 254.2 ([M+H] ⁺ ).

b) (2S,3S)-2-methylazetidin-3-ol hydrochloride

As with (2R,3R)-2-methylazetidin-3-ol hydrochloride, (2S,3S)-1-benzhydryl-2-methylazetidin-3-ol was converted to (2R,3R)-1-benzhydryl-2-methylazetidin-3-ol to give the title compound (260 mg, <88% purity, 100%) which was obtained as a white solid. MS (ERI): 88.1 ([M+H] ⁺ ).

6,6-dimethyl-5-oxa-2-azaspiro[3.4]octane hydrochloride

a) 1-benzhydryl-3-(3-hydroxy-3-methylbutyl)azetidin-3-ol

A solution of 4-chloro-2-methylbutan-2-ol (775 mg, 6.32 mmol) in tetrahydrofuran (3 ml) was cooled under nitrogen to -30°C. Methylmagnesium chloride 3 M in tetrahydrofuran (2.11 ml, 6.32 mmol) was then added dropwise at below -20°C. The reaction mixture was then allowed to warm to room temperature and magnesium powder (230 mg, 9.48 mmol) was added. Then 1,2-dibromoethane (5.5 μl, 0.063 mmol) was added and the reaction mixture was stirred at reflux for 3 hours. After one and two hours, 1,2-dibromoethane (5 μl, 0.063 mmol) was added. After cooling to room temperature, a solution of 1-benzhydrylazetidin-3-one (500 mg, 2.11 mmol) in tetrahydrofuran (3 ml) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours. After cooling to 0° C., a saturated aqueous ammonium chloride solution (20 ml) was carefully added. The reaction mixture was filtered and washed thoroughly with ethyl acetate (20 ml). The aqueous layer was extracted three times with ethyl acetate (10 ml). The combined organic extract was then dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica, 30% to 70% ethyl acetate in heptane) gave the title compound (250 mg, 37%) as a light yellow oil. MS (ERI): 326.3 ([M+H] ⁺ ).

b) 2-benzhydryl-6,6-dimethyl-5-oxa-2-azaspiro[3.4]octane

To a solution of 1-benzhydryl-3-(3-hydroxy-3-methylbutyl)azetidin-3-ol (240 mg, 0.737 mmol) in tetrahydrofuran (2.4 ml) at room temperature were added N,N-diisopropylethylamine (322 μl, 1.84 mmol), DMAP (9.01 mg, 0.074 mmol) and methanesulfonyl chloride (63.2 μl, 0.811 mmol). After stirring at room temperature for 15 minutes, the solution was stirred at 70° C. for 18 hours. After cooling to room temperature, N,N-diisopropylethylamine (322 μl, 1.84 mmol), DMAP (9.01 mg, 0.074 mmol) and methanesulfonyl chloride (63.2 μl, 0.811 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours. Then the reaction mixture was diluted with ethyl acetate (15 ml) and washed with sodium carbonate 1 M (15 ml). The aqueous layer was extracted with ethyl acetate (15 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 50% ethyl acetate in heptane) gave the title compound (60 mg, 27%) as a light yellow oily liquid. MS (ERI): 308.3 ([M+H] ⁺ ).

c) 6,6-dimethyl-5-oxa-2-azaspiro[3.4]octane hydrochloride

Under nitrogen atmosphere, 2-benzhydryl-6,6-dimethyl-5-oxa-2-azaspiro[3.4]octane (58 mg, 0.189 mmol) was dissolved in methanol (3 ml). Then 10% palladium on carbon (7 mg, 0.007 mmol) and 1 M aqueous hydrochloric acid solution (226 μl, 0.226 mmol) were added. The reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was then filtered through Hyflo and washed with methanol. The filtrate was concentrated and dried under high vacuum to give the crude title compound (55 mg, <61% purity, 100% yield) as an off-white solid. MS (ERI): 142.1 ([M+H] ⁺ ).

(1-methylcyclopropyl)piperazin-1-ylmethanone hydrochloride

a) tert-butyl-4-(1-methylcyclopropanecarbonyl)piperazine-1-carboxylate

To a solution of tert-butylpiperazine-1-carboxylate (1.56 g, 8.4 mmol) in DMF (12 ml) at 0°C under nitrogen atmosphere were added N,N-diisopropylethylamine (5.43 g, 7.34 ml, 42 mmol) and 1-methylcyclopropanecarboxylic acid (1.01 g, 10.1 mmol). Then TBTU (3.24 g, 10.1 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was then diluted with ethyl acetate (50 ml) and the organic phase was washed with 1 M sodium carbonate solution (50 ml), water (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was precipitated by adding cold heptane (30 ml) and then filtered. The collected product was washed with additional heptane, then dried under high vacuum to give the title compound (1.92 g, 85%) as a white solid. MS (ERI): 269.2 ([M+H] ⁺ ).

b) (1-methylcyclopropyl)piperazin-1-ylmethanone hydrochloride

To a stirred suspension of tert-butyl 4-(1-methylcyclopropanecarbonyl)piperazine-1-carboxylate (1.92 g, 7.15 mmol) in 1,4-dioxane (15 ml) at 0°C was added a 4.0 M solution of HCl in dioxane (8.94 ml, 35.8 mmol). Then the ice bath was removed and the suspension was stirred at room temperature for 2 hours and finally at 60°C for 4 hours, after which it was cooled to room temperature. The resulting suspension was filtered through a Buchner funnel. The collected hydrochloride salt was washed with additional 1,4-dioxane, then dried under high vacuum to give the title compound (1.63 g, 99%) as a white solid. MS (ERI): 169.1 ([M+H] ⁺ ).

2-cyclopropyl-2,6-diazaspiro[3.3]heptane-2,2,2-trifluoroacetic acid

a) tert-butyl-6-cyclopropyl-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a stirred solution of tert-butyl-2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (2.01 g, 4.13 mmol) in anhydrous tetrahydrofuran (5.2 ml) and methanol (5.2 ml) under argon atmosphere was added (1-ethoxycyclopropoxy)trimethylsilane (3.4 ml, 16.9 mmol), then sodium cyanoborohydride (779 mg, 12.4 mmol) and acetic acid (0.76 ml, 13.3 mmol). The reaction mixture was stirred at 50° C. overnight. After cooling to room temperature, water (4 ml) and 2 M NaOH (16 ml) were added and the mixture was stirred at room temperature. After 10 min the reaction mixture was diluted with dichloromethane (50 ml) and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 5% methanol in dichloromethane) gave the title compound (1.434 g, 73%) as a colorless oily liquid. MS (ERI): 239.1 ([M+H] ⁺ ).

b) 2-cyclopropyl-2,6-diazaspiro[3.3]heptane-bis(2,2,2-trifluoroacetate)

Trifluoroacetic acid (1.63 g, 1.1 ml) was added to a stirred solution of tert-butyl 6-cyclopropyl-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.480 g, 2.01 mmol) in dichloromethane (5.2 ml) at 0°C. The reaction mixture was stirred at 0° C. for 1 h, after which it was allowed to warm at room temperature for 1 h. The reaction mixture was concentrated to give the title compound (1.350 g, 50% purity, 92% yield) as a colorless oily liquid. MS (ERI): 139.1 ([M+H] ⁺ ).

(S)-5-oxa-2-azaspiro[3.4]octan-7-ol-2,2,2-trifluoroacetic acid

a) (7S)-5-oxa-2-azaspiro[3.4]octan-7-ol-2,2,2-trifluoroacetic acid

(S)-tert-butyl-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (0.210 g, 916 cmol) was dissolved in dichloromethane (2.4 ml) and the colorless solution was cooled to 0°C. At 0° C., trifluoroacetic acid (0.38 ml, 4.93 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound (342 mg, 92%) as a colorless oily liquid. MS (ERI): 130.1 ([M+H] ⁺ ).

(7R)-5-oxa-2-azaspiro[3.4]octan-7-ol-2,2,2-trifluoroacetic acid

a) (7R)-5-oxa-2-azaspiro[3.4]octan-7-ol-2,2,2-trifluoroacetic acid

(R)-tert-butyl-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (0.220 g, 960 μmol) was dissolved in dichloromethane (2.4 ml) and the colorless solution was cooled to 0°C. At 0° C., trifluoroacetic acid (0.38 ml, 4.93 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound (367 mg, 94%) as a colorless oily liquid. MS (ERI): 130.1 ([M+H] ⁺ ).

3-(cyclopropoxy)azetidine-2,2,2-trifluoroacetic acid

Trifluoroacetic acid (0.09 ml, 1.17 mmol) was added to a stirred solution of tert-butyl 3-cyclopropoxyazetidine-1-carboxylate (43 mg, 202 μmol) in dichloromethane (0.6 ml) at 0°C. The reaction mixture was stirred at 0° C. for 1 h, after which it was allowed to warm at room temperature for 2 h. The reaction mixture was concentrated to give the title compound as a colorless oily liquid, which was used in the next step without further purification. MS (ERI): 113.2 ([M+H] ⁺ ).

3-(2,2,2-trifluoroethoxy)azetidine-2,2,2-trifluoroacetic acid

Trifluoroacetic acid (0.13 ml, 1.69 mmol) was added to a stirred solution of tert-butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (80 mg, 313 μmol) in dichloromethane (0.6 ml) at 0°C. The reaction mixture was stirred at 0°C for 1 h, after which it was allowed to warm at room temperature for 2.5 h. The reaction mixture was concentrated to give the title compound as a colorless oily liquid, which was used in the next step without further purification. MS (ERI): 155.1 ([M+H] ⁺ ).

(7R)-7-fluoro-5-oxa-2-azoniaspiro[3.4]octane-2,2,2-trifluoroacetic acid

To a stirred solution of (R)-tert-butyl-7-fluoro-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (70 mg, 303 μmol) in dichloromethane (0.6 ml) at 0°C was added trifluoroacetic acid (130 μl, 1.69 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to give the title compound as a colorless oil, which was used in the next step without further purification. MS (ERI): 131.1 ([M+H] ⁺ ).

(7S)-7-fluoro-5-oxa-2-azoniaspiro[3.4]octane-2,2,2-trifluoroacetic acid

Trifluoroacetic acid (0.13 ml, 1.69 mmol) was added to a stirred solution of (S)-tert-butyl-7-fluoro-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (70 mg, 303 μmol) in dichloromethane (0.9 ml) at 0°C. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to give the title compound as a colorless oily liquid, which was used in the next step without further purification. MS (ERI): 131.1 ([M+H] ⁺ ).

(7R)-7-(difluoromethoxy)-5-oxa-2-azoniaspiro[3.4]octane-2,2,2-trifluoroacetic acid

Trifluoroacetic acid (0.17 ml, 2.21 mmol) was added to a stirred solution of (R)-tert-butyl-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (109 mg, 390 μmol) in dichloromethane (0.9 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound as a colorless oily liquid, which was used in the next step without further purification. MS (ERI): 179.3 ([M+H] ⁺ ).

(7S)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2,2,2-trifluoroacetic acid

Trifluoroacetic acid (0.16 ml, 2.08 mmol) was added to a stirred solution of (S)-tert-butyl-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (95 mg, 340 μmol) in dichloromethane (0.6 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound as a colorless oily liquid, which was used in the next step without further purification. MS (ERI): 179.3 ([M+H] ⁺ ).

3-(cyclopropoxy)azetidine

a) tert-butyl-3-vinyloxyazetidine-1-carboxylate

In a 100 ml round bottom flask, tert-butyl-3-hydroxyazetidine-1-carboxylate (1.50 g, 8.66 mmol), palladium (II) acetate (20 mg, 89.1 μmol) and 4,7-diphenyl-1,10-phenanthroline (29 mg, 87.2 (μmol)) were dissolved in butylvinyl ether (22 ml, 171 mmol) and triethylamine (1.0 ml, 7.17 mmol).The reaction mixture was stirred at 75°C over the weekend.The reaction mixture was cooled to room temperature, adsorbed onto Isolute HM-N and purified by flash chromatography (silica, 0% to 10% ethyl acetate in heptane) to give the title compound (1.139 g, 66%) as a yellow oil. MS (ESI): no result, mass not found.

¹ H-NMR (CHLOROFORM-d, 300 MHz): δ (ppm) 6.37 (dd, J=14.4, 7.0 Hz, 1H), 4.53-4.64 (m, 1H), 4.17 (dd, J=9.7, 6.5 Hz, 2H), 4.08 (dd, J=6.9, 2.4 Hz, 1H), 3.97 (dd, J=14.5, 2.4 Hz, 1H), 3.90 (dd, J=9.9, 4.2 Hz, 2H), 1.44 (s, 9H).

b) 3-(cyclopropoxy)azetidine

Diethylzinc (1.0 M solution in hexane, 4.0 ml, 4 mmol) was added to a 50 ml 3-neck round bottom flask with 4.0 ml dichloromethane and cooled to 0°C. A solution of trifluoroacetic acid (0.30 ml, 3.89 mmol) in dichloromethane (2.0 ml) was added very slowly via syringe. After stirring for 20 min at 0°C, a solution of diiodomethane (0.32 ml, 3.97 mmol) in dichloromethane (2.0 ml) was added. After an additional 20 min stirring at 0°C, a solution of tert-butyl 3-(vinyloxy)azetidine-1-carboxylate (0.395 g, 1.98 mmol) in dichloromethane (3 ml) was added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 ml) and extracted with dichloromethane (40 ml). The aqueous layer was extracted from the extract with dichloromethane (40 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give an orange oil, which is no product. The aqueous layer was basified with 5M NaOH to pH 10. The aqueous layer was then extracted four times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (270 mg, 48%) as a yellow oil. MS (ERI): 114.1 ([M+H] ⁺ ).

(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride

a) tert-butyl-(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

(R)-tert-Butyl-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 741 μmol) was dissolved in DMF (2 ml) and tetrahydrofuran (2 ml). Sodium hydride (60%, 47.4 mg, 1.19 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Then iodomethane (92.7 yl, 1.48 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, then extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water (3×10 ml) and brine (10 ml), dried over sodium sulfate, filtered and concentrated. The crude material was purified by ISCO flash chromatography (silica, 0% to 5% methanol in dichloromethane) to give the title compound as a colorless oily liquid (124 mg, 65%). MS: 188.1 ([M-C ₄ H ₈ +H] ⁺ ).

b) (R)-7-methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride

To a stirred solution of (R)-tert-butyl-7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (124 mg, 484 μmol) in 1,4-dioxane (2 ml) at 0°C was added a 4.0 M solution of HCl in dioxane (1.82 ml, 7.26 mmol). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered through a Buchner funnel, washed with additional 1,4-dioxane, then dried under high vacuum to give the title compound (95.8 mg, 99%) as a white solid. MS (ERI): 144.0 ([M+H] ⁺ -Cl).

7-methyl-5-oxa-2-azaspiro[3.4]octane-2,2,2-trifluoroacetic acid

Tert-butyl-7-methyl-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (70 mg, 308 centmol) was dissolved in dichloromethane (0.7 ml) and the colorless solution was cooled to 0°C. At 0° C., trifluoroacetic acid (0.14 ml, 1.82 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound (39.2 mg, 99%) as a colorless oily liquid. MS (ERI): 127.1 ([M+H] ⁺ ).

(7R)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane hydrochloride

To a stirred solution of (R)-tert-butyl-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (70 mg, 251 cmol) in dioxane (1 ml) was added a 4.0 M HCl solution in dioxane (940 μl, 3.76 mmol). The reaction mixture was stirred at room temperature overnight. The resulting suspension was filtered through a Buchner funnel and dried under high vacuum to give the title compound (51.3 mg, 95%) as a white solid. MS (ERI): 180.1 ([M+H] ⁺ ).

(7S)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2,2,2-trifluoroacetic acid

a) tert-butyl-7-benzoyloxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

In a 10 ml 2-neck round bottom flask, tert-butyl-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (0.200 g, 872 (xmol)) was dissolved in dichloromethane (3.4 ml) and the colorless solution was cooled to 0° C. Pyridine (0.22 ml, 2.72 mmol) was added followed by benzoyl chloride (0.20 ml, 1.72 mmol) When the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with dichloromethane (20 ml) and 1M HCl (5 ml). (silica, 0% to 30% ethyl acetate in heptane) gave the title compound (257 mg, 89%) as a white solid MS (ESI): 278.2 ([M-C₄H₈+H]⁺).

b) tert-butyl-(7S)-7-benzoyloxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate and tert-butyl-(7R-7-benzoyloxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

tert-Butyl 7-(benzoyloxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (1.160 g, 3.48 mmol) was separated by chiral preparative HPLC to give the title (-) enantiopure (S)-compound (470 mg, 41%) as a colorless oily liquid. MS (IER): no result; mass not found, titled (+) enantiopure (R)-compound (549 mg, 47%) as a colorless oily liquid. MS (IER): no result; weight not found.

c) (S)-tert-butyl-7-hydroxy-5-oxa-2-azaspiro [3.4]octane-2-carboxylate

Dissolve (S)-tert-butyl-7-(benzoyloxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (100 mg, 300 (μmol) in ammonia, 7N in methanol (1.71 ml, 12 mmol) in a sealed flask and stir at room temperature overnight. The reaction mixture was concentrated in vacuo.

Purification by flash chromatography (silica, 0% to 70% ethyl acetate in heptane) gave the title compound (68.4 mg, 85%) as a colorless oily liquid. MS (IER): no result; weight not found.

d) (S)-tert-butyl-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

(S)-tert-Butyl-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (300 mg, 1.31 mmol) was dissolved in acetonitrile (8.0 ml) and copper(I) iodide (49.8 mg, 262 (μmol) was added. The reaction mixture was heated to 45°C. a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (270 μl, 2.62 mmol) in acetonitrile (84.0 ml) was added The reaction mixture was stirred at 45°C for 3 hours The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate solution (30 ml) was added The product was extracted with ethyl acetate (2×30 ml) The combined organic phases were washed with water (3 ×20 ml) and brine (30 ml), then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 30% ethyl acetate in heptane) gave the title compound (193 mg, 57%) as a colorless oily liquid. MS (ESI): inconclusive; mass not found.

f) (7S)-7-(difluoromethoxy)-5-oxa-2-azaspiro [3.4]octane; 2,2,2-trifluoroacetic acid

To a stirred solution of (S)-tert-butyl-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (170 mg, 609 μmol) in dichloromethane (3.04 ml) was added TFA (469 μl, 6.09 mmol). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was dried under high vacuum to give the title compound (206.6 mg, 116%) as a light yellow oily liquid. MS (ERI): 180.1 ([M+H-114] ⁺ ).

3-(2,2,2-trifluoroethoxy)azetidine-bis-2,2,2-trifluoroacetic acid

a) tert-butyl-3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) dissolved in DMF (8.0 ml) was added sodium hydride, 60% dispersion in mineral oil (173 mg, 4.33 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C. 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.67 ml, 4.65 mmol) was added dropwise at 0°C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and then extracted with TBME (90 ml) and water (15 ml). The aqueous layer was extracted from the TBME extract (90 ml). The combined organic layers were washed with water (3×15 ml) and brine (15 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. Purification by flash chromatography (silica, 0% to 30% ethyl acetate in heptane) gave the title compound (428 mg, 58%) as a light yellow oil. MS (ERI): 256.3 ([M+H] ⁺ ).

b) 3-(2,2,2-trifluoroethoxy)azetidine-bis-2,2,2-trifluoroacetic acid

To a solution of tert-butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (340 mg, 1.33 mmol) in dichloromethane (3.5 ml) at 0° C. under nitrogen atmosphere was added trifluoroacetic acid (616 μl, 7.99 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give the title compound (463 mg, 91%) as a colorless oily liquid. MS (ERI): 156.1 ([M+H] ⁺ ).

3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine hydrochloride

a) (1-benzhydrylazetidin-3-yl)methanesulfonate

To a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.087 g, 4.54 mmol) in dichloromethane (6.0 ml) was added triethylamine (1.27 ml, 9.08 mmol) and the reaction mixture was cooled to 0°C. At this temperature, methanesulfonyl chloride (425 μl, 5.45 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. The reaction mixture was poured into water (5 ml) and extracted with dichloromethane (20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound (1.563 g, 100%) as a yellow oil which was used without further purification. MS (ERI): 318.2 ([M+H] ⁺ ).

b) 1-benzhydryl-3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine

To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (144 mg, 123 yl, 1.12 mmol) in DMF (1 ml) was added sodium hydride 60% (44.9 mg, 1.12 mmol). После перемешивания при комнатной температуре в течение 30 мин добавляли 1-бензгидрилазетидин-3-илметансульфонат (178 мг, 561 (μмоль). Суспензию перемешивали при 70°С в течение 18 ч, при 110°С в течение 2 ч и, наконец, при 130°С в течение 4 ч. После охлаждения до комнатной температуры реакционную смесь разбавляли этилацетатом (20 мл) и водой (10 мл). Водный слой экстрагировали из экстракта этилацетатом (20 мл). Органические слои промывали рассолом (20 мл). Органические слои объединяли, сушили над сульфатом натрия, фильтровали и концентрировали в вакууме. Очистка флэш-хроматографией (диоксид кремния, от 0% до 40% этилацетата в гептане) давала указанное в заголовке соединение (71 мг, 36%) в виде маслянистой жидкости коричневого цвета. МС (ЭРИ): 350,2 ([М+Н] ⁺ ).

c) 3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine hydrochloride

To a solution of 1-benzhydryl-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidine (71 mg, 203 cmol) in methanol (4 ml) was added hydrochloric acid 4M in dioxane (152 μl, 610 μmol). Palladium on charcoal (10%, 35 mg, 32.9 (μmol) was added under argon. The flask was then degassed by alternative evacuation and backfilling with hydrogen. The reaction mixture was heated to 50°C for 8 hours. The reaction mixture was then filtered through Hyflo and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (77.3 mg, 100%) as white wadded solid MS (ESI): 184.1 ([M+H] ⁺ ).

3-(2,2,2-trifluoro-1-methylethoxy)azetidine-2,2,2-trifluoroacetic acid

a) tert-butyl-3-(2,2,2-trifluoro-1-methylethoxy)azetidine-1-carboxylate

To a suspension of sodium hydride (60%, 166 mg, 4.16 mmol) in N,N-dimethylformamide (3 ml) was added dropwise a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (600 mg, 3.46 mmol) in N,N-dimethylformamide (3 ml) while cooling in an ice bath. After completion of the addition, the mixture was stirred at room temperature for 30 minutes. A solution of 1,1,1-trifluoropropan-2-yltrifluoromethanesulfonate (1.02 g, 4.16 mmol) in N,N-dimethylformamide (3 ml) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours, cooled in an ice bath and quenched with saturated aqueous sodium bicarbonate. The mixture was diluted with water and extracted with ethyl acetate (3x). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 50% EtOAC in heptane) gave the title compound (215 mg, 23%) as a colorless oily liquid. MS (ERI): 214.1 ([M+H-56] ⁺ ).

b) 2,2,2-trifluoroacetic acid; 3-(2,2.2-trifluoro-1-methylethoxy)azetidine

A solution of tert-butyl 3-((1,1,1-trifluoropropan-2-yl)oxy)azetidine-1-carboxylate (215 mg, 798 μmol) in dichloromethane (3.3 ml) was cooled in an ice bath. Trifluoroacetic acid (306 μl, 3.99 mmol) was added. The mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid (306 μl, 3.99 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the title compound (254 mg, 100%) as a light yellow oily liquid. MS (ERI): 170.0 ([M+H] ⁺ ).

(R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

a) 2-fluoroprop-2-en-1-ol

To a mixture of lithium aluminum hydride (131.2 g, 3.46 mol) in diethyl ether (3 L) was carefully added AlCl ₃ (63.0 ml, 1.15 mol) at -5°C. The mixture was stirred at -5°C for 30 min, then methyl 2-fluoroprop-2-enoate (240 g, 2.31 mol) was added dropwise at -5°C. The mixture was stirred at -5°C for 3.5 hours. Wet sodium sulfate was added at 0° C. and the mixture was filtered. The filtrate was isolated by atmospheric distillation at 50° C. to give the title compound (163.0 g, 46%) as a colorless liquid in ether. ¹ H-NMR (400 MHz, CDCl ₃ ): 4.63 (dd, J1 = 2.8 Hz, J2 = 17.2 Hz, 1H), 4.53 (dd, J1 = 2.8 Hz, J2 = 51.6 Hz, 1H), 4.08 (dd, J1 = 3.2 Hz, J2 = 10.8 Hz, 1H), 3.30 (m, 1H ).

b) 2-fluoroprop-2-enylmethanesulfonate

To a mixture of 2-fluoroprop-2-en-1-ol (160.0 g, 1.05 mol) and triethylamine (219 ml, 1.58 mol) in dichloromethane (400 ml) at -30°C was added MsCl (97.6 ml, 1.26 mol). The mixture was stirred at -30°C for 1 h. The mixture was diluted with dichloromethane (500 ml) and washed with water (3×700 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo to give the title compound (119.3 g, crude) as a yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ): 4.95 (dd, J1 = 3.6 Hz, J2 = 15.2 Hz, 1H), 4.86-4.70 (m, 3H), 3.08 (s, 3H).

c) tert-butyl-3-allyl-3-hydroxyazetidine-1-carboxylate

To a mixture of tert-butyl 3-oxoazetidine-1-carboxylate (150.0 g, 876 mmol) in tetrahydrofuran (1 L) at -78° C. was added allylmagnesium bromide (1 M, 876 ml). The mixture was stirred at -78°C for 1.5 h, then quenched with saturated aqueous ammonium chloride (10 L) and extracted with ethyl acetate (3×2 L). The combined organic phases were dried with sodium sulfate, filtered and concentrated in vacuo to give the title compound (192.5 g, crude) as an orange oil. MS (ESI): 158.1 ([M-C ₄ H ₈ +H] ⁺ ).

d) tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate

To a mixture of tert-butyl-3-allyl-3-hydroxyazetidine-1-carboxylate (150.0 g, 703 mmol) in DMF (750 ml) was added sodium hydride (60%, 42.2 g, 1.05 mol) at 0°C and stirred for 1 h. was added to the mixture at 0° C. and stirred for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride (1.5 L) and extracted with MTBE (3×800 ml). The combined organic phases were washed with water (3×500 ml), dried with sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, petroleum ether/ethyl acetate) gave the title compound (80 g, crude) as an orange oil. The product was immediately used in the next step. ¹ H-NMR (400 MHz, CDCl ₃ ): 5.86-5.76 (m, 1H), 5.25-5.20 (m, 2H), 4.77 (d, J1 = 16.4 Hz, 1H), 4.62 (d, J1 = 48.4 Hz, 1H), 3.99-3.92 (m, 4H), 3.80-3.7 3 (m, 2H), 2.58-2.54 (m, 2H), 1.47 (s, 9H).

e) tert-butyl-7-fluoro-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate

(1,3-Dimesitylimidazolidine-2-ylidene)-(2-isopropoxybenzylidene)ruthenium (VI) chloride (VI) 49 mg, 557 (μmol) The mixture was stirred at 100°C for 1.5 h then filtered through dicalite The filtrate was concentrated in vacuo Purification by flash chromatography (silica, ethyl acetate/heptane) gave the title compound (1.28 g, 95%) as a green oil MS (ESI): 188.1 ([MC ₄ H ₈ +H] ⁺ ).

f) tert-Butyl-7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

To a solution of tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate (1.26 g, 5.18 mmol) in methanol (51.8 ml) at room temperature was added Pd-C (10%, 276 mg, 259 μmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through a dicalite pad and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (1.18 g, 93%) as a green solid. MS (ESI): 190.1 ([M-C ₄ H ₈ +H] ⁺ ).

g) 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride

To a solution of tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate (1.18 g, 4.81 mmol) in dichloromethane (14.5 ml) at room temperature was added HCl in dioxane (4 M, 6.01 ml, 24.1 mmol). The mixture was stirred at room temperature for 24 h, concentrated in vacuo and dried to give the title compound (845 mg, 97%) as an off-white solid. MS (ERI): 146.1 ([M+H] ⁺ ).

h) (S)-benzyl-7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate and (R)-benzyl-7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Triethylamine (10.4 ml, 74.6 mmol) and benzyl chloroformate (7.13 ml, 49.9 mmol) were added to a suspension of 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride (4.43 g, 23.9 mmol) in dichloromethane (44.4 ml) at 0-5°C. The mixture was stirred at room temperature. After 2 h, triethylamine (2.5 ml, 17.9 mmol) and benzyl chloroformate (1.71 ml, 12.0 mmol) were added. After 3 hours of stirring at room temperature, the reaction mixture was diluted with 1 M HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The mixture was separated by chiral preparative HPLC (Chiralpak AD, 60:40 heptane/ethanol, 203 nm) to give the title (+) enantiopure (S)-compound or enantiomer (2.06 g, 31%) as an orange oil, MS (ESI): 280.2 ([M+H] ⁺ ). the title (-) enantiopure (R)-compound or enantiomer (2.07 g, 31%) as an orange oil, MS (ESI): 280.2 ([M+H] ⁺ ).

i) (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

To a solution of (R)-benzyl-7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate or enantiomer (2 g, 7.16 mmol) in methanol (71.6 ml) at room temperature was added Pd-C (10%, 762 mg, 716 (μmol) and aqueous HCl (4 H, 2.15 ml, 8.59 mmol). The mixture was stirred under hydrogen atmosphere at room temperature for 18 h. The reaction mixture was filtered through a dicalite pad and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (1.27 g, 97%) as an off-white solid. MS (ESI): 146.2 ([M+H]⁺), specific optical rotation: -41.488° (methanol, 0.667 g/100 ml).

(S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

To the solution (S)-Benzil-7-Fitor-5-Ox-Azaspiro [3.5] Nonanan-2-carboxylate or enantiomer (2 g, 7.16 mmol) in methanol (71.6 ml) at room temperature, PD-C (10%, 762 mg, 716 μmol) and 2.15 ml, 8.59 mmol) were added at room temperature. The mixture was stirred under a hydrogen atmosphere at room temperature for 19 hours. The reaction mixture was filtered through a dicalite pad and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (1.10 g, 85%) as an off-white solid. MS (ESI): 146.2 ([M+H] ⁺ ), specific optical rotation: +38.593° (methanol, 0.667 g/100 ml).

(R)-7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

a) tert-butyl-3-allyl-3-((2-methylallyl)oxy)azetidine-1-carboxylate

Similarly to the experimental procedure with tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate, 3-bromo-2-methylprop-1-ene was converted to the title compound (1.05 g, 84%) which was obtained as a light yellow oily liquid. MS (ESI): 265.5 ([M+H] ⁺ ).

b) tert-butyl-7-methyl-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate

To a solution of tert-butyl-3-allyl-3-((2-methylallyl)oxy)azetidine-1-carboxylate (1.02 g, 3.82 mmol) in dry degassed dichloromethane (636 ml) under argon at room temperature was added Grubbs II catalyst (324 mg, 382 μmol). The mixture was stirred at 40° C. for 19 hours. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica, ethyl acetate/heptane) gave the title compound (859 mg, 94%) as a brown oil. MS (ESI): 184.4 ([M-C ₄ H ₈ +H] ⁺ ).

c) tert-butyl-7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl-7-methyl-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate was converted to the title compound (807 mg, 100%) which was obtained as a colorless oily liquid. MS (ESI): 186.5 ([M-C ₄ H ₈ +H] ⁺ ).

d) 7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride

Similarly to the experimental procedure with 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, tert-butyl-7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was converted to the title compound (592 mg, 100%) which was obtained as a light gray solid. MS (ERI): 142.3 ([M+H] ⁺ ).

f) (S)-benzyl-7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate and (R)-benzyl-7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Similarly to the experimental procedure with (S)-benzyl-7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate and (R)-benzyl-7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, 7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride was converted into benzyl-7-methyl-5-ox a-2-azaspiro[3.5]nonane-2-carboxylate. The mixture was separated with chiral SFC (AD-H, 10% ethanol) to give the title (+) enantiopure (S)-compound or enantiomer (8.60 g, 42%) as a yellow oil, MS (ESI): 276.0 ([M+H] ^{+ ), specific optical rotation: +31.609° (methanol, 0.1 g/l) of the indicated title (-) enantiopure (11)-compound or enantiomer (9.01 g, 44%) as yellow oily liquid, MS (ESI): 276.1 ([M+H] + )} , specific optical rotation: -35.979° (methanol, 0.1 g/l).

f) (R)-7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

Similarly to the experimental procedure with (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer, (R)-benzyl-7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate or enantiomer was converted to the title compound (5.82 g, 100%) which was obtained as a white solid. MS (ERI): 142.3 ([M+H] ⁺ ).

7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride

a) tert-Butyl-3-allyl-3-((2-(trifluoromethyl)allyl)oxy)azetidine-1-carboxylate

Similarly to the experimental procedure with tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate, 2-(trifluoromethyl)prop-2-enyl-4-methylbenzenesulfonate (J. Org. Chem., 2006, 71, 7527-7532) was converted to the title compound (3.2 g, 54%) which was obtained as a liquid light brown. MS (ESI): 266.2 ([M-C ₄ H ₈ +H] ⁺ ).

b) tert-butyl-7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate, tert-butyl-3-allyl-3-((2-(trifluoromethyl)allyl)oxy)azetidine-1-carboxylate was converted to the title compound (146 mg, 70%) which was obtained as a yellow solid. MS (ESI): 238.1 ([M-C ₄ H ₈ +H] ⁺ ).

c) tert-butyl-7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl-7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate was converted to the title compound (147 mg, 91%) which was obtained as a light gray solid. MS (ESI): 240.2 ([M-C ₄ H ₈ +H] ⁺ ).

d) 7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride

Similarly to the experimental procedure with 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, tert-butyl-7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was converted to the title compound (111 mg, 97%) which was obtained as a gray solid. MS (ERI): 196.1 ([M+H] ⁺ ).

8-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride

a) tert-butyl-3-(2-fluoroallyl)-3-hydroxyazetidine-1-carboxylate

To a previously degassed solution of tetrahydrofuran (2.5 ml) and water (2.5 ml) at room temperature were added tert-butyl-3-oxoazetidine-1-carboxylate (250 mg, 1.46 mmol), indium (50.3 mg, 438 μmol) and 3-bromo-2-fluoroprop-1-ene (223 mg, 1.61 mmol). The mixture was stirred at 30°C for 3.5 h, then diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (silica, ethyl acetate/heptane) gave the title compound (130 mg, 39%) as a colorless oil. MS (ERI): 230.1 ([M+H] ⁺ ).

b) tert-butyl-3-(allyloxy)-3-(2-fluoroallyl)azetidine-1-carboxylate

Similarly to the experimental procedure with tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate, tert-butyl-3-(2-fluoroallyl)-3-hydroxyazetidine-1-carboxylate and 3-bromoprop-1-ene were converted to the title compound (130 mg, 85%) which was obtained as a colorless oily liquid. MS (ESI): 216.2 ([M-C ₄ H ₈ +H] ⁺ ).

c) tert-butyl-8-fluoro-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-methyl-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate, tert-butyl 3-(allyloxy)-3-(2-fluoroallyl)azetidine-1-carboxylate was converted to the title compound (40 mg, 37%) which was obtained as a brown oil. MS (ESI): 188.1 ([M-C ₄ H ₈ +H] ⁺ ).

d) tert-butyl-8-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl-8-fluoro-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate was converted to the title compound.

e) 8-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride

Similarly to the experimental procedure with 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, tert-butyl-8-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was converted to the title compound.

8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride

a) tert-butyl-3-hydroxy-3- (2- (trifluoromethyl) allyl) azetidine-1-carboxylate

In a similar manner to the experimental procedure with tert-butyl 3-(allyloxy)-3-(2-fluoroallyl)azetidine-1-carboxylate, tert-butyl-3-oxoazetidine-1-carboxylate and 2-(bromomethyl)-3,3,3-trifluoroprop-1-ene were converted to the title compound (1.17 g, 36%) which was obtained as a white solid. MS (ESI): 182.2 ([M-C ₄ H ₈ +H] ⁺ ).

b) tert-butyl-3-(allyloxy)-3-(2-(trifluoromethyl)allyl)azetidine-1-carboxylate

Similarly to the experimental procedure with tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate, tert-butyl-3-hydroxy-3-(2-(trifluoromethyl)allyl)azetidine-1-carboxylate and 3-bromoprop-1-ene were converted to the title compound (194 mg, 68%) which was obtained as a colorless oily liquid. MS (ESI): 266.2 ([M-C ₄ H ₈ +H] ⁺ ).

c) tert-butyl-8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate, tert-butyl-3-(allyloxy)-3-(2-(trifluoromethyl)allyl)azetidine-1-carboxylate was converted to the title compound (900 mg, 79%) which was obtained as a brown solid. MS (ERI): 294.2 ([M+H] ⁺ ).

d) tert-butyl-8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl-8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate was converted to the title compound (628 mg, 99%) which was obtained as a light gray solid. MS (ESI): 240.5 ([M-C ₄ H ₈ +H] ⁺ ).

d) 8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride

Similarly to the experimental procedure with 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, tert-butyl-8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was converted to the title compound (537 mg, 100%) which was obtained as a gray solid. MS (ERI): 196.4 ([M+H] ⁺ ).

8-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride

a) tert-butyl-3-hydroxy-3-(2-(trifluoromethyl)allyl)azetidine-1-carboxylate

Similarly to the experimental procedure with tert-butyl-3-(allyloxy)-3-(2-fluoroallyl)azetidine-1-carboxylate, tert-butyl-3-oxoazetidine-1-carboxylate and 3-bromo-2-methylprop-1-ene were converted to the title compound (789 mg, 30%) which was obtained as a colorless oily liquid. MS (ESI): 172.4 ([M-C ₄ H ₈ +H] ⁺ ).

b) tert-butyl-3-(allyloxy)-3-(2-(trifluoromethyl)allyl)azetidine-1-carboxylate

Similarly to the experimental procedure with tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate, tert-butyl-3-hydroxy-3-(2-methylallyl)azetidine-1-carboxylate and 3-bromoprop-1-ene were converted to the title compound (670 mg, 72%) which was obtained as a yellow oily liquid. MS (ESI): 212.5 ([M-C ₄ H ₈ +H] ⁺ ).

c) tert-butyl-8-methyl-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-en-2-carboxylate, tert-butyl-3-(allyloxy)-3-(2-methylallyl)azetidine-1-carboxylate was converted to the title compound (560 mg, 93%) which was obtained as a green oily liquid. MS (ERI): 183.9 ([M+H] ⁺ ).

d) tert-butyl-8-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

Similarly to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl-8-methyl-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate was converted to the title compound (423 mg, 75%) which was obtained as a light brown solid. MS (ESI): 186.1 ([M-C ₄ H ₈ +H] ⁺ ).

e) 8-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride

Similarly to the experimental procedure with 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, tert-butyl-8-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was converted to the title compound (312 mg, 100%) which was obtained as an orange solid. MS (ERI): 142.3 ([M+H] ⁺ ).

4-fluoro-1-oxa-9-azaspiro[5.5]undecane

a) 9-benzyl-1-oxa-9-azaspiro[5.5]undecan-4-ol

To a mixture of 1-benzyl-4-piperidone (4.9 ml, 26.42 mmol) and 3-buten-1-ol (1.91 g, 26.42 mmol) was slowly added sulfuric acid (70%, 10.0 ml, 26.42 mmol) at 0°C. The reaction mixture was vigorously stirred overnight, then diluted with water (100 ml) and the pH was adjusted to 7-8 with sodium bicarbonate. The organic layer was extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by chromatography (silica, functionalized with NH, ethyl acetate/hexane) gave the title compound (5 g, 65% yield) as a colorless liquid. MS (ERI): 262.5 ([M+H] ⁺ ).

b) 9-benzyl-4-fluoro-1-oxa-9-azaspiro[5.5]undecane

To a stirred solution of triethylamine trihydrofluoride (1.87 mL, 11.48 mmol) in dichloromethane (50 mL) at room temperature were added Xtalfluor-e (1.97 g, 8.61 mmol) and 9-benzyl-1-oxa-9-azaspiro[5.5]undecan-4-ol (1.5 g, 5.74 mmol) in succession at room temperature. After 24 hours, the reaction mixture was cooled to 0-5° C., quenched with 5% aqueous sodium bicarbonate, and the resulting mixture was extracted with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by HPLC gave the title compound (505 mg, 33%) as a colorless oily liquid. MS (ERI): 263.9 ([M+H] ⁺ ).

c) 4-fluoro-1-oxa-9-azaspiro[5.5]undecane

Similar to the experimental procedure with tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, 9-benzyl-4-fluoro-1-oxa-9-azaspiro[5.5]undecane was converted to the title compound (329 mg, 73%) which was obtained as an off-white solid. MS (ERI): 172.3 ([M+H] ⁺ ).

Example 1

N-methyl-N-[(3S)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyride azin-4-yl]pyrrolidin-3-yl]acetamide

To a solution of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (structural element A, 88.5 mg, 0.279 mmol) in DMSO (1 ml) in an argon atmosphere was added N-methyl-N-(pyrrolidin-3-yl)acetamide (55.7 μl, 0.419 mmol) and potassium carbonate (116 mg, 0.838 mmol). The vial was capped and heated to 80°C for 18 hours. The reaction mixture was diluted with EtOAc (20 ml) and washed with water (15 ml) and brine (15 ml). The aqueous layers were extracted twice with EtOAc (20 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title racemic compound (107 mg, 90%) as an off-white foam. MS (ERI): 423.3 ([M+H] ⁺ ).

Separation of the enantiomers by chiral HPLC (column: Chiralpak AD) gave the title (+)-compound which was obtained as an off-white foam.

Example 2

N-methyl-N-[(3R)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyride azin-4-yl]pyrrolidin-3-yl]acetamide

Similar to the experiment of Example 1, resolution of the enantiomers by chiral HPLC (column: Chiralcel OD) gave the title (-)-compound (39 mg) which was obtained as an off-white foam. MS (ERI): 423.2 ([M+H] ⁺ ).

Example 3

5-[(3R)-3-hydroxypyrrolidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

To a stirred suspension of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block A, 300 mg, 0.947 mmol) and (R)-3-hydroxypyrrolidine (0.14 ml, 1.73 mmol) in DMSO (0.5 ml) and acetonitrile (3 ml) was added potassium carbonate (393 mg, 2.84 mmol). Then the reaction mixture was stirred at 70°C for 18 hours After cooling to room temperature, the reaction mixture was diluted with EtOAc (80 ml), washed three times with water (10 ml) and brine (10 ml). The aqueous layers were extracted twice from the extract with EtOAc (80 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (341 mg, 93%) as an off-white foam. MS (ERI): 368.2 ([M+H] ⁺ ).

Example 4

5-[(3S)-3-hydroxypyrrolidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using (S)-3-hydroxypyrrolidine instead of (R)-3-hydroxypyrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (378 mg, 82%) which was obtained as a white solid. MS (ERI): 368.2 ([M+H] ⁺ ).

Example 5

5-(4-hydroxy-1-piperidyl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Potassium carbonate (67 mg, 0.49 mmol) and piperidin-4-ol (24.5 mg, 0.162 mmol) in acetonitrile (1 mL) and piperidin-4-ol (24.5 mg, 0.242 mmol). The vial was capped and heated to 80°C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAC (20 ml) and washed with water (15 ml) and brine (15 ml). The aqueous layers were extracted twice with EtOAc (20 ml). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (341 mg, 93%) as an off-white foam. MS (ERI): 382.3 ([M+H] ⁺ ).

Example 6

5-(2,2-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one

Similar to the experiment in Example 5, using 2,2-dimethylmorpholine instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (40.6 mg, 64%) which was obtained as an off-white foam. MS (ERI): 396.3 ([M+H] ⁺ ).

Example 7

5-(cis-2,6-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one

Similar to the experiment in Example 3, using cis-2,6-dimethylmorpholine in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one was converted to the title compound (205 mg, 71%) which was obtained as a white solid. MS (ERI): 396.2 ([M+H] ⁺ ).

Example 8

ethyl 1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)piperidine-4-carboxylate

Similar to Example 5, using ethylpiperidine-4-carboxylate instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (181 mg, 71%) which was obtained as an off-white solid. MS (ERI): 438.3 ([M+H] ⁺ ).

Example 9

5-(4-(cyclopropanecarbonyl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 5, using cyclopropyl(piperazin-1-yl)methanone instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one was converted to the title compound (142 mg, 64%) which was obtained as a white solid. MS (ERI): 435.4 ([M+H] ⁺ ).

Example 10

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 5, using (1-methylcyclopropyl)(piperazin-1-yl)methanone hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (36.7 mg, 59%) which was obtained as a white solid. MS (ERI): 449.3 ([M+H] ⁺ ).

Example 11

2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)-5-morpholinopyridazin-3(2H)-one

Similar to Example 3, using morpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block L) was converted to the title compound (36 mg, 41%) which was obtained as a light yellow solid. MS (ERI): 371.2 ([M+H] ⁺ ).

Example 12

5-(cis-2,6-dimethylmorpholino)-2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 3, using cis-2,6-dimethylmorpholine in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block L) was converted to the title compound (64 mg, 52%) which was obtained as a light yellow solid. MS (ERI): 399.3 ([M+H] ⁺ ).

Example 13

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one

Similar to Example 3, using cis-2,6-dimethylmorpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block M) was converted to the title compound (66 mg, 68%) which was obtained as a light yellow solid. MS (ERI): 416.2 ([M+H] ⁺ ).

Example 14

2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one

Similar to Example 3, using cis-2,6-dimethylmorpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazol-4-yl]methyl]pyridazin-3-one (building block N) was converted to the title compound (19 mg, 19%) which was obtained as a light yellow foam. MS (ERI): 442.3 ([M+H] ⁺ ).

Example 15

2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one

Similar to Example 3, using (1-methylcyclopropyl)piperazin-1-yl-methanone hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block L) was converted to the title compound (210 mg, 52%) which was obtained as a light yellow solid. MS (ERI): 452.3 ([M+H] ⁺ ).

Example 16

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one

Similarly, an experiment from example 3, using (1-methylcyclopropil) pipeperin-1-almetanon hydrochloride instead of (r) -3-hydroxypyrrolidine, 5-chlorin-2-[[3- (5-chlor-2-piridil) -5-metilizzasol-4-il] methyl (structural element m) turned into a compounded compounded in the heading of the heading (33 mg, 33%), which was received in the form of a whitish solid. MS (ERI): 469.3 ([M+H] ⁺ ).

Example 22

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-morpholinopyridazin-3-one

Similar to Example 5, using morpholine instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (61 mg, 88%) which was obtained as a light yellow solid. MS (ERI): 368.2 ([M+H] ⁺ ).

Example 24

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[4-(trifluoromethyl)-1-piperidyl]pyridazin-3-one

Similar to the experiment in Example 5, using 4-(trifluoromethyl)piperidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (70 mg, 85%) which was obtained as an off-white solid. MS (ERI): 434.2 ([M+H] ⁺ ).

Example 25

2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one

Similar to Example 3, using cyclopropyl(piperazin-1-yl)methanone instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazol-4-yl]methyl]pyridazin-3-one (building block N) was converted to the title compound (49 mg, 62%) which was obtained as an off-white solid. MS (ERI): 481.3 ([M+H] ⁺ ).

Example 26

2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 3, using (1-methylcyclopropyl)(piperazin-1-yl)methanone hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-cyclopropylisoxazol-4-yl]methyl]pyridazin-3-one (building block N) was converted to the title compound (48 mg, 58%) which was obtained as an off-white foam s. MS (ERI): 495.2 ([M+H] ⁺ ).

Example 27

N-cyclopropyl-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carboxamide

a) ethyl 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carboxylate

Similar to Example 5, using ethylpiperidine-4-carboxylate instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (40.6 mg, 64%) which was obtained as an off-white solid. MS (ERI): 438.3 ([M+H] ⁺ ).

b) 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carboxylic acid

To a solution of ethyl 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carboxylate (170 mg, 0.389 mmol) in THF (0.9 ml) and methanol (0.9 ml) was added lithium hydroxide monohydrate (50 mg, 1.19 mmol), then water (0.9 ml). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then acidified with 5% citric acid solution and then extracted with EtOAc. The aqueous layer was extracted from the extract with EtOAc. The organic layers were washed with water and brine. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (145 mg, 91%) as a light yellow foam. MS (ERI): 410.2 ([M+H] ⁺ ).

c) N-cyclopropyl-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carboxamide

To a solution of 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carboxylic acid (50 mg, 0.11 mmol) in EtOAc (2 ml) was added cyclopropylamine (16 μl, 0.23 mmol), triethylamine (100 μl, 0.23 mmol). 72 mmol) and a solution of propylphosphonic acid anhydride >50% wt. in EtOAc (0.14 ml, 0.24 mmol) and the reaction mixture was stirred at room temperature overnight. After adding cyclopropylamine (16 μl, 0.23 mmol) and a solution of anhydride propylphosphonic acid >50% wt. in EtOAc (70 μl, 0.12 mmol) the reaction mixture was stirred at 50°C for 4 hours After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 ml) and saturated NaHCO ₃ solution (5 ml). The aqueous layer was extracted from the extract with EtOAc (30 ml). The organic layers were washed with water (5 ml) and brine (5 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (43 mg, 87%) as an off-white solid. MS (ERI): 449.3 ([M+H] ⁺ ).

Example 28

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl]pyridazin-3-one

As in Example 3, using (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (76 mg, 87%) which was obtained as white cottony solid. MS (ERI): 394.2 ([M+H] ⁺ ).

Example 29

5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one or enantiomer

Similar to Example 5, using trans-2,6-dimethylmorpholine in place of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title racemic compound (109 mg, 87%) which was obtained as a yellow foam. MS (ESI): 396.3 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Reprosil Chiral-NR) gave the title (+)-compound (33 mg) which was obtained as a light yellow foam. MS (ERI): 396.2 ([M+H] ⁺ ).

Example 30

5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one or enantiomer

As in Example 29, resolution of the enantiomers by chiral HPLC (column: Reprosil Chiral-NR) gave the title (-)-compound (37 mg) which was obtained as a light yellow foam. MS (ERI): 396.2 ([M+H] ⁺ ).

Example 31

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridazin-3-one

Similar to the experiment in Example 3, using 1-(2,2,2-trifluoroethyl)piperazine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (81 mg, 82%) which was obtained as an off-white solid. MS (ERI): 449.2 ([M+H] ⁺ ).

Example 32

5-(cis-2,6-dimethylmorpholin-4-yl)-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using cis-2,6-dimethylmorpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block E) was converted to the title compound (436 mg, 77%) which was obtained as an off-white foam. MS (ERI): 382.2 ([M+H] ⁺ ).

Example 33

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyridazin-3-one

Similar to the experiment in Example 3, using 3-oxa-6-azabicyclo[3.1.1]heptan-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (51 mg, 77%), which was obtained in light yellow foam. MS (ERI): 380.2 ([M+H] ⁺ ).

Example 34

1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperidine-4-carbonitrile

Similar to Example 3, using piperidine-4-carbonitrile instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (38 mg, 69%) which was obtained as a light yellow foam. MS (ERI): 391.2 ([M+H] ⁺ ).

Example 35

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-one

Similarly, an experiment from example 3, using 3-ox-8-Azabyclic [3.2.1] octane hydrochloride instead of (r) -3-hydroxypyrrolidine, 5-chlor-2-[[5-methyl-3-piridil) Izoxazol-4-il] Mesy-3-he turned into a compound indicated in the heading (29 mg, 52%, 52% ), which was received in the form of foam light yellow. MS (ERI): 394.2 ([M+H] ⁺ ).

Example 36

5-(4-cyclopropylpiperazin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 1-cyclopropylpiperazine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (65 mg, 84%) which was obtained as an off-white solid. MS (ERI): 407.2 ([M+H] ⁺ ).

Example 38

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazin-3-one

Similar to the experiment in Example 3, using 2-oxa-6-azaspiro[3.3]heptane oxalate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (55 mg, 66%) which was obtained as an off-white solid. MS (ERI): 380.1 ([M+H] ⁺ ).

Example 39

5-(cis-2,6-dimethylmorpholin-4-yl)-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using cis-2,6-dimethylmorpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one (building block C) was converted to the title compound (72 mg, 91%) which was obtained as an off-white foam. MS (ERI): 450.2 ([M+H] ⁺ ).

Example 40

5-[4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (1-methylcyclopropyl)(piperazin-1-yl)methanone hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one (building block C) was converted to the title compound (49 mg, 56%), which was obtained as white cotton wool. MS (ERI): 503.2 ([M+H] ⁺ ).

Example 43

2-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

Similar to Example 3, using hexahydropyrrololo[1,2-a]pyrazin-6(2H)-one instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (20 mg, 15%) which was obtained as a yellow solid . MS (ERI): 421.21 ([M+H] ⁺ ).

Example 44

7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one

Similar to the experiment in Example 3, using tetrahydro-1H-oxazol[3,4-a]pyrazin-3(5H)-one hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (46 mg, 37%) which was obtained as a solid yellow. MS (ERI): 423.2 ([M+H] ⁺ ).

Example 45

5-(dimethylamino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

As in Example 64, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted using dimethylamine in place of N-methylcyclopropanamine oxalate to the title compound (19 mg, 19%) which was obtained as a light yellow solid. MS (ERI): 326.1 ([M+H] ⁺ ).

Example 46

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3-one

Similar to Example 3, using 2-oxa-7-azaspiro[3.5]nonane-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (60 mg, 78%) which was obtained as white cotton wool. MS (ERI): 408.2 ([M+H] ⁺ ).

Example 49

5-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-2-[[5-methyl-3-(6-methyl)-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (3aR,6aS)-3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride instead of (R)-3-hydroxypyrrolidine, 5 chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (59 mg, 68%) which was obtained as an off-white foam. MS (ERI): 394.2 ([M+H] ⁺ ).

Example 50

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3R)-3-methylpiperazin-1-yl]pyridazin-3-one

a) tert-butyl-(2R)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate

Similarly, an experiment from example 3, using trit-butyl- (2R) -2-methylpipipipipipipipipipipipipipipipipipipipipipipipipipipipiperic carboxylate instead of (r) -3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-piridil) Izoxazole-4-il] methyl] was turned into a compound indicated in the headline (123 mg, 74, 74, 74 %), which was received in the form of whitish foam. MS (ERI): 481.3 ([M+H] ⁺ ).

b) 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(-3-methylpiperazin-1-yl]pyridazin-3-one

To a solution of tert-butyl-(2R)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate (120 mg, 0.250 mmol) in dioxane (1.2 ml) at room temperature was added a 4 M solution of hydrochloric acid in dioxane (0. 35 ml, 1.4 mmol). The reaction mixture was stirred at 60°C for 1 h Then the reaction mixture was concentrated and the residue was extracted with dichloromethane (30 ml) and saturated NaHCO ₃ solution (5 ml). The aqueous layer was extracted twice from the extract with dichloromethane (30 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (85 mg, 90%) as a light brown oily liquid. MS (ERI): 381.2 ([M+H] ⁺ ).

Example 51

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-one

a) tert-Butyl-(2S)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate

Similarly, an experiment from example 3, using third-butyl- (2s) -2-methylpiperin-carboxylate instead of (r) -3-hydroxypyrrolidine, 5-chlor-2-[[5-methyl-3-piridil) Izoxazole-4-il] piridazine-3-he was turned into a compound indicated in the headline (123 mg, 74 mg, 74 mg, 74 mg, 74 mg, 74 mg, 74 mg, 74 %), which was received in the form of whitish foam. MS (ERI): 481.3 ([M+H] ⁺ ).

b) 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-one

Similar to Example 50b tert-butyl-(2S)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazine-1-carboxylate instead of tert-butyl-(2R)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl )isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazine-1-carboxylate was converted to the title compound (84 mg, 88%) which was obtained as a light yellow oily liquid. MS (ERI): 381.3 ([M+H] ⁺ ).

Example 52

2-[[3-(5-Chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-(cis-2,6-dimethylmorpholin-4-yl)pyridazin-3-one

Similar to the experiment in Example 3, using cis-2,6-dimethylmorpholine in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block V) was converted to the title compound (57 mg, 78%) which was obtained as an off-white solid. MS (ERI): 434.2 ([M+H] ⁺ ).

Example 53

2-[[3-(5-Chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-[4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]pyridazin-3-one

As in Example 3, using (1-methylcyclopropyl)(piperazin-1-yl)methanone hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-3-fluoro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block V) was converted to the title compound (53 mg, 60%) which was obtained as white cottony solid. MS (ERI): 487.2 ([M+H] ⁺ ).

Example 54

5-[4-(3,5-dimethyl-1,2,4-triazol-4-yl)-1-piperidyl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 4-(3,5-dimethyl-1,2,4-triazol-4-yl)piperidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (56 mg, 62%) which was obtained as whitish oh foam. MS (ERI): 461.3 ([M+H] ⁺ ).

Example 55

5-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)-2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 3, using 4-(3,5-dimethyl-1,2,4-triazol-4-yl)piperidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block L) was converted to the title compound (68 mg, 78%) which was obtained as a solid th white substance. MS (ERI): 464.3 ([M+H] ⁺ ).

Example 56

(3R)-N-cyclopropyl-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidine-3-carboxamide

a) ethyl-(3R)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidine-3-carboxylate

Аналогично эксперименту из Примера 3, используя этил-(3R)-пирролидин-3-карбоксилата гидрохлорид вместо (R)-3-гидроксипирролидина, 5-хлор-2-[[5-метил-3-(6-метил-3-пиридил)изоксазол-4-ил]метил]пиридазин-3-он превращали в указанное в заголовке соединение (147 мг, 88%), которое получали в виде бесцветной маслянистой жидкости. MS (ERI): 424.2 ([M+H] ⁺ ).

b) (3R)-1-[1[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxylic acid

As in Example 27b, ethyl 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxylate instead of ethyl 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyride zin-4-yl]piperidine-4-carboxylate was converted to the title compound (82 mg, 74%) which was obtained as an off-white foam. MS (ERI): 396.2 ([M+H] ⁺ ).

c) (3R)-N-cyclopropyl-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxamide

To a solution of (3R)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxylic acid (11.4 mg, 0.200 mmol) in DMF (0.6 ml) was added N,N-diisopropylethylamine (70 μl, 0.401 mmol) followed by adding TBTU (34 mg, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (30 ml) and water (3 ml). The aqueous layer was extracted from the extract with EtOAc (30 ml). The organic layers were washed with water (3 ml) and brine (3 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (23 mg, 55%) as an off-white solid. MS (ERI): 435.2 ([M+H] ⁺ ).

Example 57

(3S)-N-cyclopropyl-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidine-3-carboxamide

a) ethyl-(3S)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl1pyrrolidin-3-carboxylate

Similarly, an experiment from example 3, using ethyl- (3s)-pyrroline-3-carboxylate hydrochloride instead of (r) -3-hydroxypyrrolidine, 5-chlorin-2-[[5-methyl-3-piridil) Izoxazole-4-il] pyridazin-3-° Talled into a compound (146 mg, 8 mg, 8, 8, 8, 8, 8 mg, 8, 8, 8, 8, 8, 8, 8, 8, 8 mg, 8 8%), which was received in the form of a colorless oily liquid. MS (ERI): 424.2 ([M+H] ⁺ ).

b) (3S)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxylic acid

As in Example 27b, ethyl 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxylate instead of ethyl 1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyride zin-4-yl]piperidine 4-carboxylate was converted to the title compound (75 mg, 68%) which was obtained as an off-white solid. MS (ERI): 396.2 ([M+H] ⁺ ).

c) (3S)-N-cyclopropyl-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxamide

As in Example 56c, (3S)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]pyrrolidin-3-carboxylic acid instead of (3R)-1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyride zin-4-yl]pyrrolidine-3-carboxylic acid was converted to the title compound (30 mg, 59%) which was obtained as an off-white solid. MS (ERI): 435.3 ([M+H] ⁺ ).

Example 58

5-(2-cyclopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 3, using 2-cyclopropyl-2,6-diazaspiro[3.3]heptan-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (393 mg, 83%), which was obtained in the form of whitish foam. MS (ERI): 419.2 ([M+H] ⁺ ).

Example 59

5-[(3R)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

(1-Ethoxycyclopropoxy)trimethylsilane (85 yl, 0.4 2 mmol), sodium cyanoborohydride (20 mg, 0.32 mmol) and acetic acid (20 yl, 0.35 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was then cooled to room temperature, quenched with 2M NaOH solution (3 ml) and then extracted with dichloromethane (30 ml). The aqueous layers were extracted from the extract with dichloromethane (30 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (silica, gradient: 0% to 5% MeOH in CH ₂ Cl ₂ ) gave the title compound (61 mg, 72%) as an off-white foam. MS (ERI): 421.3 ([M+H] ⁺ ).

Example 60

5-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 59 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-one instead of 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3R)-3-methylpiperazin-1-yl] pyridazin-3-one was converted to the title compound (266 mg, 68%) which was obtained as a light yellow foam. MS (ERI): 421.2 ([M+H] ⁺ ).

Example 61

5-[4-(2-methoxyphenyl)-1-piperidyl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 4-(2-methoxyphenyl)piperidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (34 mg, 23%) which was obtained as an off-white solid. MS (ERI): 472.3 ([M+H] ⁺ ).

Example 62

5-(cis-2,6-dimethylmorpholin-4-yl)-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using cis-2,6-dimethylmorpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4yl]methyl]pyridazin-3-one (building block O) was converted to the title compound (67 mg, 88%) which was obtained as an off-white solid. MS (ERI): 386.2 ([M+H] ⁺ ).

Example 63

5-(4-cyclopropylpiperazin-1-yl)-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 1-cyclopropylpiperazine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block O) was converted to the title compound (70 mg, 91%) which was obtained as an off-white solid. MS (ERI): 397.2 ([M+H] ⁺ ).

Example 64

5-(cyclopropyl(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Triethylamine (0.219 ml, 1.58 mmol) and N-methylcyclopropanamine oxalate (254 mg, 1.58 mmol). The vial was capped and heated to 110°C for 17 hours. The reaction mixture was diluted with EtOAc (20 ml) and washed with water (15 ml) and brine (15 ml). The aqueous layers were extracted twice with EtOAc (20 ml). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (40 mg, 68%) as a light brown gum. MS (ERI): 352.2 ([M+H] ⁺ ).

Example 65

5-(methyl(oxetan-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 64, using N-methyloxetan-3-amine instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (12 mg, 20%) which was obtained as a light brown waxy solid. MS (ERI): 368.2 ([M+H] ⁺ ).

Example 66

5-(4-cyclopropylpiperazin-1-yl)-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 1-cyclopropylpiperazine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyride azin-3-one (building block C) was converted to the title compound (70 mg, 87%) which was obtained as an off-white solid substances. MS (ERI): 461.2 ([M+H] ⁺ ).

Example 67

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-phenylpyridazin-3(2H)-one

A round bottom flask was charged with 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block A, 60 mg, 0.189 mmol), phenylboronic acid (46.2 mg, 0.379 mmol), sodium carbonate aqueous solution (2.0 M, 0.21 ml, 0.420 mmol) and 1,1-bis (diphenylphosphino) ferrocenedichloropalladium (II) (4.25 mg, 0.0581 mmol). The flask was degassed by alternative evacuation and back filling with argon. Pre-degassed 1,4-dioxane (3.0 ml) was added and the resulting mixture was purged with argon for 10 minutes. The reaction mixture was stirred at 100°C for 16 h, then cooled to room temperature and immediately filtered through a pad of celite. The filter cake was washed with EtOAc and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 5% MeOH in CH ₂ Cl ₂ ) gave the title compound (64 g, 94%) as a white solid. MS (ERI): 359.1 ([M+H] ⁺ ).

Example 68

5-(4-fluorophenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 67, using (4-fluorophenyl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (51 mg, 86%) which was obtained as an off-white solid. MS (ERI): 377.1 ([M+H] ⁺ ).

Example 69

5-(2-azaspiro[3.3]heptan-2-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 2-azaspiro[3.3]heptane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (67 mg, 94%) which was obtained as an off-white solid. MS (ERI): 378.1 ([M+H] ⁺ ).

Example 70

5-((2-hydroxy-2-methylpropyl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 64, using 2-methyl-1-(methylamino)propan-2-ol instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (21 mg, 33%) which was obtained as an off-white rubbery substance. MS (ERI): 384.2 ([M+H] ⁺ ).

Example 72

5-(cis-2,6-dimethylmorpholin-4-yl)-2-[[3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-l]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using cis-2,6-dimethylmorpholine in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one (building block P) was converted to the title compound (60 mg, 82%) which was obtained as an off-white solid. MS (ERI): 436.1 ([M+H] ⁺ ).

Example 74

5-(4,7-diazaspiro[2.5]octan-7-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

a) tert-butyl-7-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate

Similar to the experiment of Example 3, using tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (146 mg, 85%) which was obtained as whitish solid. MS (ERI): 493.3 ([M+H] ⁺ ).

b) 5-(4,7-diazaspiro[2.5]octan-7-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Trifluoroacetic acid (0 .14 ml, 1.8 mmol). After stirring for 2.5 hours at room temperature, the reaction mixture was concentrated. The residue was then extracted with dichloromethane (30 ml) and saturated NaHCO ₃ solution (5 ml). The aqueous layer was extracted from the extract with dichloromethane (30 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (63 mg, 75%) as an off-white solid. MS (ERI): 393.1 ([M+H] ⁺ ).

Example 75

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-piperazin-1-ylpyridazin-3-one

a) tert-butyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl1-6-oxopyridazin-4-yl]piperazin-1-carboxylate

Similar to Example 3, using t-butylpiperazine-1-carboxylate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one was converted to the title compound (337 mg, 76%) which was obtained as a light yellow solid. MS (ERI): 467.3 ([M+H] ⁺ ).

b) 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl1-5-piperazin-1-ylpyridazin-3-one

Similar to Example 74b, tert-butyl 4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate instead of tert-butyl 7-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyride zin-4-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate was converted to the title compound (247 mg, 94%) which was obtained as a light yellow foam. MS (ERI): 367.2 ([M+H] ⁺ ).

Example 76

5-(4-methoxyphenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 67, using (4-methoxyphenyl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (17 mg, 28%) which was obtained as a light brown solid. MS (ERI): 389.1 ([M+H] ⁺ ).

Example 77

5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

a) tert-butyl-6-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl1-6-oxopyridazin-4-yl1-2,6-diazaspiro[3.3]heptan-2-carboxylate

As in Example 3, using tert-butyl 2,6-diazaspiro[3.3]heptan-2-carboxylate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (131 mg, 91%) which was obtained as white cotton wool. MS (ERI): 479.3 ([M+H] ⁺ ).

b) 5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyride azin-3-one

Similar to Example 74b, tert-butyl 6-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate instead of tert-butyl-7-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazole -4-yl]methyl]-6-oxopyridazin-4-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate was converted to the title compound (34 mg, 43%) which was obtained as an off-white foam. MS (ERI): 379.2 ([M+H] ⁺ ).

Example 78

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(methylamino)pyridazin-3(2H)-one

Similar to Example 64, using methylamine (33% solution in ethanol) instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one was converted to the title compound (95 mg, 88%) which was obtained as a light brown solid. MS (ERI): 312.2 ([M+H] ⁺ ).

Example 79

5-(4-ethoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using (4-ethoxyphenyl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (59 mg, 93%) which was obtained as a light brown solid. MS (ERI): 403.2 ([M+H] ⁺ ).

Example 80

5-(3-fluoro-4-methoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using (3-fluoro-4-methoxyphenyl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (60 mg, 94%) which was obtained as an off-white solid. MS (ERI): 407.1 ([M+H] ⁺ ).

Example 81

5-(6-Methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in place of phenylboronic acid, 5-chloro-2-[[5methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (26 mg, 42%), which was obtained as a light yellow solid. MS (ERI): 390.1 ([M+H] ⁺ ).

Example 82

5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 2-methyl-2,6-diazaspiro[3.3]heptane instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (29 mg, 38%) which was obtained as an off-white solid. MS (ERI): 393.2 ([M+H] ⁺ ).

Example 83

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one

Similar to Example 67, using (4-(trifluoromethyl)phenyl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (38 mg, 57%) which was obtained as a light brown solid. MS (ERI): 427.2 ([M+H] ⁺ ).

Example 84

5-(5-Methoxypyridin-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in place of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (8.2 mg, 11%) which was obtained as a brown solid. MS (ERI): 390.1 ([M+H] ⁺ ).

Example 85

1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]azetidine-3-carbonitrile

Similar to the experiment in Example 3, using azetidin-3-carbonitrile hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (45 mg, 56%) which was obtained as an off-white foam. MS (ERI): 363.2 ([M+H] ⁺ ).

Example 86

2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-(2-cyclopropyl-2,6-diazaspiro[3.3]heptan-6-yl)pyridazin-3-one

Similar to the experiment in Example 3, using 2-cyclopropyl-2,6-diazaspiro[3.3]heptane-bis(2,2,2-trifluoroacetate) instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block M) was converted to the title compound (74 mg, 81%) which was obtained as a white solid. MS (ERI): 439.2 ([M+H] ⁺ ).

Example 87

5-(2-cyclopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 2-cyclopropyl-2,6-diazaspiro[3.3]heptan-2,2,2-trifluoroacetic acid instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block O) was converted to the title compound ( 63 mg, 79%) which was obtained as an off-white solid. MS (ERI): 409.2 ([M+H] ⁺ ).

Example 88

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridazin-3(2H)-one

Similar to the experiment in Example 64, using (tetrahydro-2H-pyran-4-yl)methanamine instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (80 mg, 85%) which was obtained as an off-white solid. MS (ERI): 396.2 ([M+H] ⁺ ).

Example 89

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-one

Similar to the experiment in Example 3, using (2S)-2-methylmorpholine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (65 mg, 89%) which was obtained as an off-white foam. MS (ERI): 382.2 ([M+H] ⁺ ).

Example 90

5-[(3R)-3-tert-butoxypyrrolidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (3R)-3-tert-butoxypyrrolidine oxalate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (74 mg, 92%) which was obtained as an off-white foam. MS (ERI): 424.3 ([M+H] ⁺ ).

Example 91

5-[(2S)-2-methylmorpholin-4-yl]-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (S)-2-methylmorpholine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block E) was converted to the title compound (54 mg, 74%) which was obtained as an off-white foam. MS (ERI): 368.2 ([M+H] ⁺ ).

Example 92

5-[(2R)-2-methylmorpholin-4-yl]-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (R)-2-methylmorpholine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block E) was converted to the title compound (54 mg, 74%) which was obtained as an off-white foam. MS (ERI): 368.2 ([M+H] ⁺ ).

Example 93

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

a) tert-Butyl-cis-2,6-dimethyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate

As in Example 3, using t-butyl cis-2,6-dimethylpiperazine-1-carboxylate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl 3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (546 mg, 71%) which was obtained as an orange solid. ew color. MS (ERI): 495.5 ([M+H] ⁺ ).

b) 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

As in Example 74b, t-butyl cis-2,6-dimethyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate instead of t-butyl-7-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl ]methyl]-6-oxopyridazin-4-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate was converted to the title compound (234 mg, 87%) which was obtained as an orange oil. MS (ERI): 395.3 ([M+H] ⁺ ).

Example 94

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(3-phenoxyazetidin-1-yl)pyridazin-3-one

Similar to Example 3, using 3-phenoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (73 mg, 90%) which was obtained as an off-white foam. MS (ERI): 430.3 ([M+H] ⁺ ).

Example 95

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one

Similar to the experiment in Example 3, using 5-oxa-2-azaspiro[3.4]octane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (68 mg, 91%) which was obtained as an off-white foam. MS (ERI): 394.2 ([M+H] ⁺ ).

Example 96

5-((1-cyclopropylazetidin-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

a) tert-butyl-3-[[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]amino]azetidine-1-carboxylate

Similar to Example 64, using t-butyl-3-aminoazetidine-1-carboxylate instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (292 mg, 87%) which was obtained as a viscous oily light yellow liquid. MS (ERI): 453.2 ([M+H] ⁺ ).

b) 5-(azetidin-3-ylamino)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 50b, tert-butyl 3-[[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]amino]azetidine-1-carboxylate instead of tert-butyl-(2R)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isox zol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate was converted to the title compound (55 mg, 38%) which was obtained as a white foam. MS (ERI): 353.1 ([M+H] ⁺ ).

c) 5-((1-cyclopropylazetidin-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 59 5-(azetidin-3-ylamino)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one instead of 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3R)-3-methylpiperazin-1-yl]pyridazin-3 -one was converted to the title compound (24 mg, 46%) which was obtained as a white foam. MS (ERI): 393.3 ([M+H] ⁺ ).

Example 97

5-(azetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 5, using azetidine instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (331 mg, 91%) which was obtained as a white solid. MS (ERI): 338.2 ([M+H] ⁺ ).

Example 98

5-(3-hydroxy-3-methylazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using 3-methylazetidin-3-ol hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (260 mg, 93%) which was obtained as a white foam. MS (ERI): 368.3 ([M+H] ⁺ ).

Example 99

5-(3-ethoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-ethoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (449 mg, 83%) which was obtained as an off-white powder. MS (ERI): 382.2 ([M+H] ⁺ ).

Example 100

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyridazin-3-one

Similar to Example 3, using 6-oxa-3-azabicyclo[3.1.1]heptane oxalate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (43 mg, 72%) which was obtained as an off-white solid . MS (ERI): 380.3 ([M+H] ⁺ ).

Example 101

5-[4-(2-Methoxy-3-pyridyl)piperazin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

To a solution of 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-piperazin-1-ylpyridazin-3-one (70 mg, 0.19 mmol) in toluene (1 ml) was added 3-bromo-2-methoxypyridine (35 dl, 0.23 mmol) and sodium tert-butoxide (46 mg, 0.48 mmol). The flask was evacuated and refilled with argon. After adding the adduct of chloroform and tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.017 mmol) and racemic BINAF (24 mg, 0.039 mmol), the reaction mixture was heated to 100°C for 18 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 ml) and water (3 ml). The aqueous layer was extracted twice from the extract with EtOAc (30 ml). The organic layers were washed twice with water (3 ml) and brine (3 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (35 mg, 39%) as a light yellow foam. MS (ERI): 474.3 ([M+H] ⁺ ).

Example 102

5-(dimethylamino)-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

To a stirred solution of 4-(dimethylamino)-1H-pyridazin-6-one (80 mg, 0.57 mmol) in dimethylformamide (2.5 ml) under nitrogen at room temperature were added Cs ₂ CO ₃ (654 mg, 2.01 mmol) and 4-(chloromethyl)-3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazole (207 mg, 0.86 mmol). The sealed tube was stoppered and heated to 60°C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Buchner funnel and washed with a minimum amount of dimethylformamide (~1.0 ml). The filtrate was immediately purified by preparative HPLC (column: YMC Triart C-18, eluent: CH ₃ CN and 10 mM NH ₄ OAC in water) to give the title compound (74 mg, 37%) as an off-white solid. MS (ERI): 344.0 ([M+H] ⁺ ).

Example 103

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(1-methylpyrazol-4-yl)pyridazin-3-one

Similar to Example 67, using (1-methyl-1H-pyrazol-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (299 mg, 52%) which was obtained as an off-white solid. MS (ERI): 363.2 ([M+H] ⁺ ).

Example 104

5-(3-Methoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-methoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (31 mg, 53%) which was obtained as an off-white solid. MS (ERI): 368.3 ([M+H] ⁺ ).

Example 105

5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-hydroxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (108 mg, 97%) which was obtained as an off-white solid. MS (ERI): 354.2 ([M+H] ⁺ ).

Example 106

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-methylpyridin-4-yl)pyridazin-3(2H)-one

Similar to Example 67, using (2-methylpyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (58 mg, 98%) which was obtained as a light brown solid. MS (ERI): 374.1 ([M+H] ⁺ ).

Example 107

5-(2-methoxypyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using (2-methoxypyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (289 mg, 78%) which was obtained as a white solid. MS (ERI): 390.2 ([M+H] ⁺ ).

Example 108

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyridin-4-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 67, using (2-(trifluoromethyl)pyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (32 mg, 48%) which was obtained as a light gray solid. MS (ERI): 428.2 ([M+H] ⁺ ).

Example 109

5-[4-(2-ethylimidazol-1-yl)-1-piperidyl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

As in Example 3, using 4-(2-ethylimidazol-1-yl)piperidin-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (72 mg, 76%) which was obtained as an off-white oh foam. MS (ERI): 460.3 ([M+H] ⁺ ).

Example 110

5-[4-(2-methylimidazol-1-yl)-1-piperidyl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 3, using 4-(2-methylimidazol-1-yl)piperidin-2,2,2-trifioroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (66 mg, 78%), which was obtained as whitish solid. MS (ERI): 446.3 ([M+H] ⁺ ).

Example 111

5-[3-(cyclopropylmethoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using 3-(cyclopropylmethoxy)azetidine-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (67 mg, 87%) which was obtained as a colorless oily liquid . MS (ERI): 408.3 ([M+H] ⁺ ).

Example 112

5-(3-isopropoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-isopropoxyazetidin-2-2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (52 mg, 93%) which was obtained as a colorless oily liquid. MS (ERI): 396.3 ([M+H] ⁺ ).

Example 113

5-(3,4-dimethoxyphenyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 145, using (3,4-dimethoxyphenyl)boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (52 mg, 39%) which was obtained as an off-white solid. MS (ERI): 419.0 ([M+H] ⁺ ).

Example 114

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)pyridazin-3-one

Similar to Example 145, using [4-(trifluoromethoxy)phenyl]boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (54 mg, 38%) which was obtained as an off-white solid. MS (ERI): 442.9 ([M+H] ⁺⁾ .

Example 115

5-(4-isopropoxyphenyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 145, using (4-isopropoxyphenyl)boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (54 mg, 41%) which was obtained as an off-white solid. MS (ERI): 417.0 ([M+H] ⁺ ).

Example 116

5-[6-(dimethylamino)-3-pyridyl]-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

In a similar manner to Example 145, using [6-(dimethylamino)-3-pyridyl]boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (29 mg, 23%) which was obtained as a yellow solid. color. MS (ERI): 403.1 ([M+H] ⁺ ).

Example 117

5-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 64, using 3-(trifluoromethyl)azetidin-3-ol hydrochloride in place of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (45 mg, 68%) which was obtained as a light brown solid. MS (ERI): 422.1 ([M+H] ⁺ ).

Example 118

5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 64, using 3-methylpyrrolidin-3-ol in place of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (34 mg, 57%) which was obtained as a colorless viscous oily liquid. MS (ERI): 382.2 ([M+H] ⁺ ).

Example 119

5-(4-hydroxy-4-methylpiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 64, using 4-methylpiperidin-4-ol in place of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (60 mg, 96%) which was obtained as a colorless viscous oily liquid. MS (ERI): 396.2 ([M+H] ⁺ ).

Example 120

5-((3S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 64, using (S)-2-(pyrrolidin-3-yl)propan-2-ol instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl 3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (60 mg, 93%) which was obtained as a white solid. MS (ERI): 410.4 ([M+H] ⁺ ).

Example 123

5-[3-(4-fluorophenoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-(4-fluorophenoxy)azetidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (49 mg, 58%) which was obtained as an off-white foam. MS (ERI): 448.3 ([M+H] ⁺ ).

Example 124

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[3-(2-pyridyloxy)azetidin-1-yl]pyridazin-3-one

Similar to the experiment in Example 3, using 2-(azetidin-3-yloxy)pyridine-bis(2,2,2-trifluoroacetate) instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (93 mg, 98%) which was obtained as whitish foam. MS (ERI): 431.3 ([M+H] ⁺ ).

Example 126

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[3-(3-pyridyloxy)azetidin-1-yl]pyridazin-3-one

In a similar manner to Example 3, using 3-(azetidin-3-yloxy)pyridine-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (46 mg, 48%) which was obtained as an off-white solid th substance. MS (ERI): 431.4 ([M+H] ⁺ ).

Example 127

5-[3-(3-fluorophenoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using 3-(3-fluorophenoxy)azetidine-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (67 mg, 79%) which was obtained as a white foam. MS (ERI): 448.4 ([M+H] ⁺ ).

Example 128

5-[3-(2-fluorophenoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 3, using 3-(2-fluorophenoxy)azetidine-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (65 mg, 77%) which was obtained as a white foam. MS (ERI): 448.4 ([M+H] ⁺ ).

Example 129

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[3-(4-pyridyloxy)azetidin-1-yl]pyridazin-3-one

Similar to the experiment of Example 3, using 4-(azetidin-3-yloxy)pyridine-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (32 mg, 34%) which was obtained as an off-white solid th substance. MS (ERI): 431.4 ([M+H] ⁺ ).

Example 130

5-[3-[(5-Chloro-2-pyridyl)oxy]azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 2-(azetidin-3-yloxy)-5-chloropyridin-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (52 mg, 59%) which was obtained as white solid. MS (ERI): 465.1 ([M+H] ⁺ ).

Example 131

5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (7SR)-5-oxa-2-azaspiro[3.4]octan-7-ol-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (218 mg, 8 9%) which was obtained as a white solid. MS (ERI): 410.3 ([M+H] ⁺ ).

Example 132

5-[(7R)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (7R)-5-oxa-2-azaspiro[3.4]octan-7-ol-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (240 mg, 9 1%), which was obtained as an off-white solid. MS (ERI): 410.3 ([M+H] ⁺ ).

Example 133

5-[(7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Sodium hydride (60% dispersion in mineral oil) (16 mg, 0, 40 mmol). After stirring at room temperature for 30 minutes, methyl iodide (31 μl, 0.50 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and then extracted with EtOAc (40 ml) and water (5 ml). The aqueous layer was extracted from the extract with EtOAc (40 ml). The organic layers were washed three times with water (5 ml) and brine (5 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (silica, gradient: 0% to 5% MeOH in CH ₂ Cl ₂ ) gave the title compound (67 mg, 64%) as an off-white foam. MS (ERI): 424.3 ([M+H] ⁺ ).

Example 134

5-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133 5-[(7R)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl ]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (80 mg, 77%) which was obtained as an off-white foam. MS (ERI): 424.3 ([M+H] ⁺ ).

Example 135

5-[(7R)-7-ethoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133 5-[(7R)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one instead of 5-[(7R)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl ]-2-[[5-Methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one using ethyl iodide instead of methyl iodide was converted to the title compound (82 mg, 77%) which was obtained as an off-white foam. MS (ERI): 438.3 ([M+H] ⁺ ).

Example 136

5-[3-(cyclopropoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-cyclopropoxyazetidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (191 mg, 57%) which was obtained as an off-white solid. MS (ERI): 394.2 ([M+H] ⁺ ).

Example 137

5-((1-cyclopropylazetidin-3-yl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

a) tert-Butyl-3-[methyl-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]amino]azetidine-1-carboxylate

Similar to Example 64, using tert-butyl 3-(methylamino)azetidine-1-carboxylate instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (196 mg, 67%) which was obtained as a foam of light brown. MS (ERI): 467.2 ([M+H] ⁺ ).

b) 5-[azetidin-3-yl(methyl)amino]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 50b, tert-butyl 3-[methyl[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]amino]azetidine-1-carboxylate instead of tert-butyl-(2R)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isox zol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazin-1-carboxylate was converted to the title compound (80 mg, 68%) which was obtained as a white foam. MS (ERI): 367.1 ([M+H] ⁺ ).

c) 5-((1-Cyclopropylazetidin-3-yl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 59 5-[azetidin-3-yl(methyl)amino]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one instead of 2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3R)-3-methylpiperazin-1-yl]pyride zin-3-one was converted to the title compound (10 mg, 30%) which was obtained as a white viscous oily liquid. MS (ERI): 407.2 ([M+H] ⁺ ).

Example 138

5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

To a suspension of 5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (100 mg, 0.283 mmol) in THF (2 ml) 7 mmol). After cooling to 0°C, diisopropyl azodicarboxylate (72 μl, 0.37 mmol) dissolved in THF (0.5 ml) was added dropwise at 0°C. The reaction mixture was then stirred at room temperature for 18 h and at 50° C. for 24 h. The reaction mixture was cooled to room temperature and then extracted with EtOAc (20 ml) and saturated NaHCO ₃ solution (5 ml). The aqueous layer was extracted from the extract with EtOAc (20 ml). The organic layers were washed with water (5 ml) and brine (5 ml). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH ₂ Cl ₂ ) gave the title compound (38 mg, 29%) as a white foam. MS (ERI): 465.3 ([M+H] ⁺ ).

Example 139

5-(4-methoxy-1-piperidyl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 4-methoxypiperidine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (58 mg, 93%) which was obtained as an off-white foam. MS (ERI): 396.3 ([M+H] ⁺ ).

Example 140

5-(3-Methoxyazetidin-1-yl)-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-methoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block O) was converted to the title compound (57 mg, 98%) which was obtained as an off-white solid. MS (ERI): 358.2 ([M+H] ⁺ ).

Example 141

5-[3-(cyclopropylmethoxy)azetidin-1-yl]-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 3, using 3-(cyclopropylmethoxy)azetidine-2,2,2-trifluoroacetic acid instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block O) was converted to the title compound (62 mg, 96%), which was obtained as an off-white solid. MS (ERI): 398.3 ([M+H] ⁺ ).

Example 142

2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one

Similar to the experiment in Example 3, using 5-oxa-2-azaspiro[3.4]octane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(5-methylisoxazol-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block O) was converted to the title compound (59 mg, 94%) which was obtained as an off-white foam. MS (ERI): 384.2 ([M+H] ⁺ ).

Example 143

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(cyclopropylmethoxy)azetidin-1-yl)pyridazin-3(2H)-one

As in Example 3, using 3-(cyclopropylmethoxy)azetidin-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block M) was converted to the title compound (74 mg, 81%) which was obtained as an off-white th solid. MS (ERI): 428.3 ([M+H] ⁺ ).

Example 144

2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to Example 3, using 5-oxa-2-azaspiro[3.4]octane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(5-chloro-2-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block M) was converted to the title compound (58 mg, 94%) which was obtained as an off-white solid th substance. MS (ERI): 414.2 ([M+H] ⁺ ).

Example 145

5-(6-methoxy-2-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

(6-Methoxypyridin-2-yl)boric acid (148 mg , 0.63 mmol) followed by Na ₂ CO ₃ (100 mg, 1.94 mmol). This solution was purged with argon at 25° C. for 20 minutes. Pd(PPh ₃ ) ₄ (11 mg, 0.009 mmol) was added at 25°C and purged again with argon at 25°C for 5 min. The reaction mixture was stirred at 100°C for 16 hours. After cooling to 25° C., the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 ml). The filtrate was concentrated under reduced pressure and the crude residue was purified by preparative HPLC (column: YMC Triart C-18, eluent: CH ₃ CN and 10 mM NH ₄ OAC in water) to give the title compound (73 mg, 59%) as a white solid. MS (ERI): 390.1 ([M+H] ⁺ ).

Example 147

5-[3-[(2-Chloro-4-pyridyl)oxy]azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 138, using 2-chloro-4-hydroxypyridine instead of 2-chloro-5-hydroxypyridine, 5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl 3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (68 mg, 52%) which was obtained as an off-white solid . MS (ERI): 465.1 ([M+H] ⁺ ).

Example 148

5-(5-chloro-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 145, using (5-chloropyridin-3-yl)boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (52 mg, 42%) which was obtained as an off-white solid. MS (ERI): 394.1 ([M+H] ⁺ ).

Example 149

5-(6-(difluoromethoxy)pyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (76 mg, 71%), which was obtained in the form of a light brown rubbery substance. MS (ERI): 426.2 ([M+H] ⁺ ).

Example 150

5-(3-tert-Butoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-(tert-butoxy)azetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (378 mg, 82%) which was obtained as an off-white foam. MS (ERI): 410.3 ([M+H] ⁺ ).

Example 151

5-(6-ethoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in place of phenylboronic acid, 5-chloro-2-[[5methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (95 mg, 75%), which was obtained as an off-white solid. MS (ERI): 404.3 ([M+H] ⁺ ).

Example 152

5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (50 mg, 8 2%) which was obtained as a brown solid. MS (ERI): 389.4 ([M+H] ⁺ ).

Example 153

5-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (55 mg, 85%) which was obtained as a white solid. MS (ERI): 413.2 ([M+H] ⁺ ).

Example 154

5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (52 mg , 83%), which was obtained as a white solid. MS (ERI): 399.2 ([M+H] ⁺ ).

Example 155

5-(1-ethyl-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

In a similar manner to Example 67, using (1-ethyl-1H-pyrazol-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (56 mg, 83%) which was obtained as a light brown solid. MS (ERI): 377.2 ([M+H] ⁺ ).

Example 156

5-(2-(dimethylamino)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using (2-(dimethylamino)pyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (43 mg, 45%) which was obtained as a brown solid. MS (ERI): 403.2 ([M+H] ⁺ ).

Example 157

5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 67, using 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (11, 5 mg, 18%) which was obtained as an off-white solid. MS (ERI): 403.2 ([M+H] ⁺ ).

Example 158

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one

Similar to Example 146, using t-butyl-3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate instead of t-butyl-7-methyl-5-oxa-2-azaspiro[3.4]octane-2-carboxylate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3- it was converted to the title compound (78 mg, 95%) which was obtained as an off-white foam. MS (ERI): 436.3 ([M+H] ⁺ ).

Example 160

2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]-5-(3-methoxyazetidin-1-yl)pyridazin-3-one

Similar to Example 5, using 3-methoxyazetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block Q) was converted to the title compound (49 mg, 86%) which was obtained as a white solid. MS (ERI): 387.3 ([M+H] ⁺ ).

Example 161

2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one

Similar to Example 5, using 3-ethoxyazetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block Q) was converted to the title compound (51 mg, 86%) which was obtained as a white solid. MS (ERI): 401.2 ([M+H] ⁺ ).

Example 162

2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one

Similar to the experiment in Example 5, using 3-ethoxyazetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[3-(4-chlorophenyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block Q) was converted to the title compound (57 mg, 93%) which was obtained as a colorless oily liquid. MS (ERI): 413.2 ([M+H] ⁺ ).

Example 163

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(piperazin-1-yl)pyridin-4-yl)pyridazin-3(2H)-one

a) tert-Butyl-4-[4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]-2-pyridyl]piperazine-1-carboxylate

Similar to the experiment in Example 67, using tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-carboxylate instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (108 mg, 84%) which was obtained as a white foam. MS (ERI): 544.3 ([M+H] ⁺ ).

b) 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(piperazin-1-yl)pyridin-4-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 50 b tert-butyl 4-[4-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4 yl]-2-pyridyl]piperazine-1-carboxylate instead of tert-butyl-(2R)-2-methyl-4-[1-[[5-methyl-3-(6-methyl-3-pyri dil)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]piperazine-1-carboxylate was converted to the title compound (61 mg, 75%) which was obtained as a yellow foam. MS (ERI): 444.3 ([M+H] ⁺ ).

Example 166

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[4-(2-methylpyrazol-3-yl)-1-piperidyl]pyridazin-3-one

Similar to the experiment in Example 5, using 4-(1-methyl-1H-pyrazol-5-yl)piperidine instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (68 mg, 97%) which was obtained as an off-white foam. MS (ERI): 446.3 ([M+H] ⁺ ).

Example 167

5-[4-(2-ethylpyrazol-3-yl)-1-piperidyl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 5, using 4-(1-ethyl-1H-pyrazol-5-yl)piperidine instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (69 mg, 95%) which was obtained as an off-white foam. MS (ERI): 460.4 ([M+H] ⁺ ).

Example 168

5-[3-(difluoromethoxy)azetidin-1-yl]2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

As in Example 146, using t-butyl 3-(difluoromethoxy)azetidine-1-carboxylate instead of t-butyl-7-methyl-5-oxa-2-azaspiro[3.4]octane-2-carboxylate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the indicated the title compound (73 mg, 96%) which was obtained as an off-white foam. MS (ERI): 404.2 ([M+H] ⁺ ).

Example 169

5-(3-Methoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 5, using 3-methoxyazetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (30 mg, 51%) which was obtained as a white crystalline solid. MS (ERI): 369.2 ([M+H] ⁺ ).

Example 170

5-(3-ethoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 5, using 3-ethoxyazetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (54 mg, 90%) which was obtained as a white crystalline solid. MS (ERI): 383.3 ([M+H] ⁺ ).

Example 171

2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one

Similarly, the experiment from example 5, using 5-Octo-2-Azaspiro [3.4] octane of hydrochloride instead of pyperdin-4-ola, 5-chlor-2-[[5-methyl-3- (6-methylpyridasin-3-il) Izoxazole-4-il] methyl] pyridasin-3-О (structural element f) was turned into a compound indicated in the headline (46 mg, 74%, 74% ), which was received in the form of a crystalline substance of white color. MS (ERI): 395.3 ([M+H] ⁺ ).

Example 172

5-(1-isobutylpyrazol-4-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 145, using 1-(2-methylpropyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (83 mg, 65%) which was obtained as a white solid. MS (ERI): 405.1 ([M+H] ⁺ ).

Example 173

5-(6-cyclopropyl-3-pyridyl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Аналогично эксперименту из Примера 145, используя (6-циклопропилпиридин)-3-ил)борную кислоту вместо (6-метоксипиридин-2-ил)борной кислоты, 5-хлор-2-[[5-метил-3-(6-метил-3-пиридил)изоксазол-4-ил]метил]пиридазин-3-он превращали в указанное в заголовке соединение (87 мг, 68%), которое получали в виде твердого вещества белого цвета. MS (ERI): 400.1 ([M+H] ⁺ ).

Example 174

5-(6-(methylamino)-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 145, using N-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (41 mg, 33%) which was obtained as a white solid. MS (ERI): 389.1 ([M+H] ⁺ ).

Example 175

5-(2-(difluoromethoxy)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similarly, an experiment from example 67, using 4-brom-2- (diphormometoxi) pyridin instead of phenylboric acid, [1-[5-methyl-3- (6-methyl-3-piridil) Izoxazole-4-il] -6-oxopyridazin-4-il] boronic acid (structural element Z) was turned into a compound indicated in the headline (57 mg, 67 mg, 67 mg, 67 mg, 67 ), which was received in the form of a whitish solid. MS (ERI): 426.3 ([M+H] ⁺ ).

Example 176

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)pyridazin-3(2H)-one

As in Example 67, using 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole instead of phenylboronic acid, [1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl)boric acid (building block Z) was converted to the title compound (25 mg, 38%) which was obtained as a light brown solid. MS (ERI): 433.3 ([M+H] ⁺ ).

Example 177

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)pyridazin-3(2H)-one

Similar to Example 67, using 2-((tetrahydrofuran-3-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title ke compound (85 mg, 81%), which was obtained as an off-white foam. MS (ERI): 446.3 ([M+H] ⁺ ).

Example 178

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[(3R)-3-methylpyrrolidin-1-yl]pyridazin-3-one

Similar to the experiment in Example 5, using (R)-hydroxypyrrolidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (44.2 mg, 77%) which was obtained as a light yellow oily liquid. MS (ERI): 366.3 ([M+H] ⁺ ).

Example 179

5-(5,6-dimethoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 67, using (5,6-dimethoxypyridin-3-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (59 mg, 59%) which was obtained as an off-white foam. MS (ERI): 420.2 ([M+H] ⁺ ).

Example 180

5-(6-ethoxy-5-methylpyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using 5-bromo-2-ethoxy-3-methylpyridine instead of phenylboronic acid, [1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]boric acid (building block Z) was converted to the title compound (37 mg, 57%) which was obtained as a light brown solid colors. MS (ERI): 418.3 ([M+H] ⁺ ).

Example 181

5-(3-fluoroazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 3-fluoroazetidine hydrochloride in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (65 mg, 96%) which was obtained as an off-white solid. MS (ERI): 356.2 ([M+H] ⁺ ).

Example 182

2-((5-(difluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((2S,6R)-2,6-dimethylmorpholino)pyridazin-3(2H)-one

Similarly, an experiment from example 3, using cis-2.6-dimethylmorpholine instead of (r) -3-hydroxypyrrolidine, 5-chlor-2-[[5- (5- Diformethyl) -3- (6-methyl-3-pyrhydil) Izoxazole-4-4] methyl] pyridasin-3-О (structural element G) turned into a compound indicated in the headline (76 mg, 86%, 86% ), which was received in the form of foam light yellow. MS (ERI): 432.3 ([M+H] ⁺ ).

Example 183

5-(5-fluoro-6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 67, using (5-fluoro-6-methoxypyridin-3-yl)boric acid in place of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (69 mg, 72%) which was obtained as an off-white solid. MS (ERI): 408.2 ([M+H] ⁺ ).

Example 184

5-[(3S)-4-isopropyl-3-methylpiperazin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Acetone (67 μl, 0.91 mmol), sodium triacetoxyborohydride (59 mg, 0.27 mmol) and acetic acid (10.4 μ L, 0.18 mmol). The reaction mixture was stirred at room temperature for 22 h, after which it was concentrated and suspended in dichloroethane (15 ml). The organic layer was washed with an aqueous solution of Na ₂ CO ₃ (20 ml) and water/brine (1:1) (20 ml). The aqueous layers were extracted from the extract with dichloroethane (15 ml). The organic layers were combined, dried (MgSO ₄ ) and concentrated in vacuo. Purification by preparative HPLC gave the title compound (51 mg, 66%) as a white powder. MS (ERI): 423.3 ([M+H] ⁺ ).

Example 185

5-[3-(cyclopropylmethoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

a) 5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 5, using azetidin-3-ol hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (101 mg, 62%) which was obtained as an off-white solid. MS (ERI): 355.2 ([M+H] ⁺ ).

b) 5-[3-(cyclopropylmethoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133 5-(3-hydroxyazetidin-1-yl) 2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3- pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted using (bromomethyl)cyclopropane in place of methyl iodide to the title compound (38 mg, 72%) which was obtained as a white solid. MS (ERI): 409.3 ([M+H] ⁺ ).

Example 186

2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-5-[3-(6-methylpyridazin-3-yl)oxyazetidin-1-yl]pyridazin-3-one

As in Example 138, using t-butyl 3-((6-methylpyridazin-3-yl)oxy)azetidine-1-carboxylate instead of t-butyl-7-methyl-5-oxa-2-azaspiro[3.4]octane-2-carboxylate, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyride zin-3-one was converted to the title compound (75 mg, 89%) which was obtained as a white foam. MS (ERI): 446.3 ([M+H] ⁺ ).

Example 188

5-(5-chloro-6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using (5-chloro-6-methoxypyridin-3-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (72 mg, 72%) which was obtained as an off-white solid. MS (ERI): 424.2 ([M+H] ⁺ ).

Example 189

5-(2-chloro-5-fluoro-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

In a similar manner to Example 145, using (2-chloro-5-fluoropyridin-3-yl)boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (78 mg, 46%) which was obtained as an off-white solid th substance. MS (ERI): 412.0 ([M+H] ⁺ ).

Example 190

5-(6-isopropoxy-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

As in Example 145, using [6-(propan-2-yloxy)pyridin-3-yl]boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (109 mg, 68%), which was obtained as form of a white solid. MS (ERI): 418.2 ([M+H] ⁺ ).

Example 191

5-(5-fluoro-2-methoxypyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to Example 67, using (5-fluoro-2-methoxypyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (61 mg, 63%) which was obtained as an off-white foam. MS (ERI): 408.2 ([M+H] ⁺ ).

Example 192

5-(2,6-dimethylpyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2Н)-one

Similar to Example 67, using (2,6-dimethylpyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (66 mg, 72%) which was obtained as an off-white solid. MS (ERI): 388.2 ([M+H] ⁺ ).

Example 193

5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using 7,7-difluoro-5-oxa-2-azoniaspiro[3.4]octane-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5 methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (78 mg, 9 6%) which was obtained as a light yellow solid. MS (ERI): 430.7 ([M+H] ⁺ ).

Example 194

5-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

a) 5-[(2R,3R)-3-hydroxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 5, using (2R,3R)-2-methylazetidin-3-ol hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (489 mg, 94%) which was obtained as an off-white foam. MS (ERI): 368.2 ([M+H] ⁺ ).

b) 5-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133, 5-[(2R,3R)-3-hydroxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5- methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (63 mg, 87%) which was obtained as an off-white foam. MS (ERI): 382.2 ([M+H] ⁺ ).

Example 195

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 3, using 2-azaspiro[3.5]nonane instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one was converted to the title compound (101 mg, 79%) which was obtained as a light yellow foam. MS (ERI): 406.2 ([M+H] ⁺ ).

Example 196

5-(2-ethyl-4-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 145, using (2-ethylpyridin-4-yl)boric acid in place of (6-methoxypyridin-2-yl)boric acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (97 mg, 61%) which was obtained as a colorless viscous oil pure liquid. MS (ERI): 388.1 ([M+H] ⁺ ).

Example 197

5-[(2S,3S)-3-methoxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

a) 5-[(2S,3S)-3-hydroxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 5, using (2S,3S)-2-methylazetidin-3-ona hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (470 mg, 69%) which was obtained as an off-white foam. MS (ERI): 368.2 ([M+H] ⁺ ).

b) 5-[(2S,3S)-3-methoxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133 5-[(2S,3S)-3-hydroxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5- methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (50 mg, 80%) which was obtained as an off-white foam. MS (ERI): 382.2 ([M+H] ⁺ ).

Example 198

5-[(2S,3S)-3-ethoxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133 5-[(2S,3S)-3-hydroxy-2-methylazetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4yl]methyl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5- methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted using iodoethane instead of iodomethane to the title compound (45 mg, 55%) which was obtained as a light brown oily liquid. MS (ESI): 396.3 ([M+H] ⁺ ).

Example 199

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one

Similar to Example 3, using 7-oxa-2-azaspiro[3.5]nonane instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (100 mg, 78%) which was obtained as a light yellow foam. MS (ERI): 408.2 ([M+H] ⁺ ).

Example 200

5-[(7R)-7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (7R)-7-fluoro-5-oxa-2-azoniaspiro[3.4]octane-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (78 mg, 100%) which was obtained as an off-white solid. MS (ERI): 412.2 ([M+H] ⁺ ).

Example 201

5-[(7S)-7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (7S)-7-fluoro-5-oxa-2-azoniaspiro[3.4]octane-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (63 mg, 81%), which was obtained as an off-white solid. MS (ERI): 412.4 ([M+H] ⁺ ).

Example 202

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(methylamino)pyridin-4-yl)pyridazin-3(2H)-one

Similar to Example 67, using N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine in place of phenylboronic acid, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (71 mg, 7 7%), which was obtained as a yellow foam. MS (ERI): 389.2 ([M+H] ⁺ ).

Example 203

5-[(7R)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (7R)-7-(difluoromethoxy)-5-oxa-2-azoniaspiro[3.4]octan-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound ( 98 mg, 90%), which was obtained as a light yellow foam. MS (ERI): 460.2 ([M+H] ⁺ ).

Example 204

5-[(7S)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (7S)-7-(difluoromethoxy)-5-oxa-2-azoniaspiro[3.4]octan-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound ( 97 mg, 89%), which was obtained as a light yellow foam. MS (ERI): 460.3 ([M+H] ⁺ ).

Example 205

5-((2R,6S)-2,6-dimethylmorpholino)-2-((3-(5-(fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similarly, an experiment from example 64, using cis-2.6-dimetylmorpholine instead of n-methylcycopanaminamic oxalat, 5-chlor-2-[[3- (5-fluor-6-methyl-3-piridil) -5-metilizzol-4 il] methyl] pyridasin-3-A (structural element J) turned into a connection indicated in the headline (54 mg, 95%) , which was received in the form of a solid substance of white color. MS (ERI): 414.2 ([M+H] ⁺ ).

Example 206

5-[3-(2,2-difluorethoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133, using 2,2-difluoroethyltrifluoromethanesulfonate instead of iodomethane, 5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (45 mg, 69%) which was obtained as an off-white solid. MS (ERI): 418.3 ([M+H] ⁺ ).

Example 207

2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one

Similar to Example 67, using (2-methoxypyridin-4-yl)boric acid instead of phenylboronic acid, 5-chloro-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block J) was converted to the title compound (42 mg, 69%) which was obtained as a white solid. MS (ERI): 408.2 ([M+H] ⁺ ).

Example 208

2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to Example 64, using 5-oxa-2-azaspiro[3.4]octane oxalate instead of N-methylcyclopropanamine oxalate, 5-chloro-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block J) was converted to the title compound (55 mg, 89%), which was obtained as a white solid. MS (ERI): 412.2 ([M+H] ⁺ ).

Example 209

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to Example 3, using 5-oxa-2-azaspiro[3.4]octane oxalate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (21 mg, 62%) which was obtained as a solid white. MS (ERI): 414.2 ([M+H] ⁺ ).

Example 210

2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(1-propylpyrazol-4-yl)pyridazin-3-one

Similar to Example 145, using 1-propyl-4-(tetramethyl-1,3:,2-dioxaborolan-2-yl)-1H-pyrazole in place of (6-methoxypyridin-2-yl)boric acid and Pd(amphos)Cl ₂ in place of Pd(PPh ₃ ) ₄ , 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4- yl]methyl]pyridazin-3-one was converted to the title compound (41 mg, 34%) which was obtained as a white solid. MS (ERI): 391.1 ([M+H] ⁺ ).

Example 211

6-(1-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-6-oxopyridazin-4-yl)pyridine-2-carbonitrile

Similar to Example 145, using 6-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile in place of (6-methoxypyridin-2-yl)boric acid and Pd(amphos)Cl ₂ in place of Pd(PPh ₃ ) ₄ , 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl ]methyl]pyridazin-3-one was converted to the title compound (18 mg, 18%) which was obtained as a white solid. MS (ERI): 385.1 ([M+H] ⁺ ).

Example 212

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 3, using 3-methoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (23 mg, 65%) which was obtained as an off-white solid. MS (ERI): 388:, 1 ([M+H] ⁺ ).

Example 213

5-(3-ethoxyazetidin-1-yl)-2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similarly, an experiment from example 64, using 3-ecoxiazetidine hydrochloride instead of n-methylcyclopropanamic oxalate, 5-chlor-2-[[3- (5-fluor-6-methyl-3-piridil) -5-metilizzol-4-4-il] methyl] pyridasin-3-О (structural element J) turned into a compound indicated in the headline (32 mg, 38, 38 %) :, which was received in the form of a whitish solid. MS (ERI): 400.2 ([M+H] ⁺ ).

Example 214

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one

a) 4-(2-methoxy-4-pyridyl)-1H-pyridazin-6-one

To a solution of 4-chloro-1H-pyridazin-6-one (125 mg, 0.958 mmol) in ethanol (2.5 ml) under nitrogen at room temperature was added (2-methoxypyridin-4-yl)boric acid (161 mg, 1.05 mmol), Pd(PPh ₃ ) ₄ (55.9 mg, 0.0479 mmol) and aqueous Na ₂ CO ₃ ( 2.0 M, 1.44 ml, 2.87 mmol). The reaction mixture was heated in a microwave oven to 120°C for 10 min and then to 150°C for 10 min. The reaction mixture was evaporated and immediately purified by preparative HPLC to give the title compound (75 mg, 39%) as an off-white solid. MS (ERI): 204.2 ([M+H] ⁺ ).

b) 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one

K ₂ CO ₃ (22.2 mg, 0.160 mmol) and 4-(2-methoxy-4-pyridyl)-1H-pyridazin-6-one (27.6 mg, 0.136 mmol). The mixture was heated to 70°C in an oil bath for 45 min, after which it was cooled to room temperature and diluted with water. The aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) gave the title compound (37 mg, 73%) as a white solid. MS (ERI): 410.1 ([M+H] ⁺ ).

Example 215

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one

a) 4-(1-methylpyrazol-4-yl)-1H-pyridazin-6-one

Similarly, an experiment from example 214 A, using 1-methyl-4- (4.4.5.5-tetramethyl-1,3,2-deioxaborolan-2-IL) -1N-pirazole instead of (2-methoxypyridin-4-il) boric acid, 4-chlor-1n-pyridine-6-O was turned into a compound (471 mg, 37%), which was obtained in the form of a white form), which was obtained in the form of a white form), which was obtained in the form of white. a solid substance. MS (ERI): 177.0 ([M+H] ⁺ ).

b) 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 214 b, using 4-(1-methylpyrazol-4-yl)-1H-pyridazin-6-one instead of 4-(2-methoxy-4-pyridyl)-1H-pyridazin-6-one, 4-(chloromethyl)-3-(6-chloropyridin-3-yl)-5-methylisoxazole was converted to the title compound (37 mg, 78%) which was obtained as a solid white substances. MS (ERI): 383.1 ([M+H] ⁺ ).

Example 216

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 3, using 5-oxa-2-azaspiro[3.5]nonane oxalate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (53 mg, 82%) which was obtained as an off-white solid. MS (ERI): 408.2 ([M+H] ⁺ ).

Example 217

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to Example 3, using 7,7-difluoro-5-oxa-2-azaspiro[3.4]octane-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (structural element D) was converted to the title compound (386 mg, 71%), which was obtained as a light gray solid. MS (ERI): 450.2 ([M+H] ⁺ ).

Example 218

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3(2H)-one

As in Example 67, using 6-bromo-3-methylimidazo[1,2-a]pyridine instead of phenylboronic acid, [1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxopyridazin-4-yl]boric acid (building block Z) was converted to the title compound (28 mg, 29%) which was obtained as a solid light yellow. MS (ERI): 413.2 ([M+H] ⁺ ).

Example 219

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2RS,6SR)-2,6-dimethylmorpholino)pyridazin-3(2H)-one

Similar to the experiment of Example 3, using cis-2,6-dimethylmorpholine in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (53 mg, 77%), which was obtained as a white foam. MS (ERI): 416.1 ([M+H] ⁺ ).

Example 220

2-((3-(6-chloropyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one

Similar to the experiment of Example 3, using 3-ethoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (27 mg, 82%), which was obtained as a yellow solid. MS (ERI): 402.1 ([M+H] ⁺ ).

Example 221

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one

a) 4-(1-ethylpyrazol-4-yl')-1H-pyridazin-6-one

As in Example 214a, using (1-ethyl-1H-pyrazol-4-yl)boric acid in place of (2-methoxypyridin-4-yl)boric acid, 4-chloro-1H-pyridazin-6-one was converted to the title compound (95 mg, 46%) which was obtained as a light yellow solid. MS (ERI): 191.1 ([M+H] ⁺ ).

b) 2-((3-(6-chloropyride in-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one

Similar to Example 214b, using 4-(1-ethylpyrazol-4-yl)-1H-pyridazin-6-one instead of 4-(2-methoxy-4-pyridyl)-1H-pyridazin-6-one, 4-(chloromethyl)-3-(6-chloropyridin-3-yl)-5-methylisoxazole was converted to the title compound (20 mg, 56%) which was obtained as a solid white. MS (ERI): 397.1 ([M+H] ⁺ ).

Example 222

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-cyclopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one

a) 4-(1-cyclopropylpyrazol-4-yl)-1H-pyridazin-6-one

As in Example 214a, using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of (2-methoxypyridin-4-yl)boric acid, 4-chloro-1H-pyridazin-6-one was converted to the title compound (159 mg, 68%) which was obtained as an off-white solid . MS (ERI): 203.1 ([M+H] ⁺ ).

b) 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-cyclopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 214 b, using 4-(1-cyclopropylpyrazol-4-yl)-1H-pyridazin-6-one instead of 4-(2-methoxy-4-pyridyl)-1H-pyridazin-6-one, 4-(chloromethyl)-3-(6-chloropyridin-3-yl)-5-methylisoxazole was converted to the title compound (28 mg, 83%) which was obtained as a solid white substances. MS (ERI): 409.1 ([M+H] ⁺ ).

Example 223

2-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

Similar to the experiment of Example 3, using hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (8.6 mg, 28%) which was obtained as an orange oily liquid. MS (ERI): 441.2 ([M+H] ⁺ ).

Example 224

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-cyclopropoxyazetidin-1-yl)pyridazin-3(2H)-one

Similar to the experiment of Example 3, using 3-cyclopropoxyazetidine instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (39 mg, 46%), which was obtained as a white solid. MS (ERI): 414.1 ([M+H] ⁺ ).

Example 226

2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one

Similar to Example 3, using 3-oxa-9-azaspiro[5.5]undecane instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (107 mg, 78%) which was obtained as a yellow powder. MS (ERI): 436.3 ([M+H] ⁺ ).

Example 227

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one

Similar to the experiment of Example 3, using (S)-2-methylmorpholine hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (16 mg, 47%), which was obtained in the form of light yellow foam. MS (ERI): 402.2 ([M+H] ⁺ ).

Example 228

5-(2-Methoxypyridin-4-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

As in Example 214b, 4-(chloromethyl)-5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazole was converted to the title compound (17 mg, 59%) which was obtained as a white solid. MS (ERI): 445.2 ([M+H] ⁺ ).

Example 229

5-(3-Methoxyazetidin-1-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment of Example 3, using 3-methoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methyl]pyridazin-3-one (building block R) was converted to the title compound (10.8 mg, 39%) which was obtained as a light yellow solid. MS (ERI): 423.1 ([M+H] ⁺ ).

Example 230

(R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to Example 3, using (R)-7-fluoro-5-oxa-2-azaspiro[3.4]octane-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (structural element D) was converted to the title compound (5 mg, 20%) which was obtained as a white foam. MS (ERI): 432.1 ([M+H] ⁺ ).

Example 232

(S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to the experiment of Example 3, using (S)-7-fluoro-5-oxa-2-azaspiro[3.4]octane hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the indicated the title compound (8 mg, 31%) which was obtained as a white solid. MS (ERI): 432.1 ([M+H] ⁺ ).

Example 233

2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one

Similar to Example 3, using 5-oxa-2-azaspiro[3.5]nonane oxalate in place of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (31 mg, 88%) which was obtained as a light yellow solid. MS (ERI): 428.2 ([M+H] ⁺ ).

Example 234

5-(3-(tert-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 5, using 3-(tert-butoxy)azetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (53 mg, 92%) which was obtained as an off-white solid. MS (ERI): 411.3 ([M+H] ⁺ ).

Example 235

2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one

As in Example 5, using 5-oxa-2-azaspiro[3.5]nonane oxalate instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (295 mg, 92%) which was obtained as a solid white. MS (ERI): 409.2 ([M+H] ⁺ ).

Example 236

5-[3-[(2-Chloro-4-pyridyl)oxy]azetidin-1-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 5, using 4-(azetidin-3-yloxy)-2-chloropyridin-2,2,2-trifluoroacetic acid instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (57 mg, 88%) which was obtained as an off-white solid. MS (ERI): 466.2 ([M+H] ⁺ ).

Example 237

5-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 5, using (7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one (building block C) was converted to the title compound (31 mg, 47 %), which was obtained in the form of a whitish foam. MS (ERI): 478.3 ([M+H] ⁺ ).

Example 238

5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 5, using 3-cyclobutoxyazetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (16 mg, 33%) which was obtained as an off-white solid. MS (ERI): 409.3 ([M+H] ⁺ ).

Example 239

5-[3-(cyclopropoxy)azetidin-1-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 5, using 3-cyclopropoxyazetidine instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (2.5 mg, 5%), which was obtained as a colorless oily liquid. MS (ERI): 395.2 ([M+H] ⁺ ).

Example 240

2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]-5-[(7R)-7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl]pyridazin-3-one or enantiomer

Similar to the experiment of Example 5, using racemic 7-methyl-5-oxa-2-azaspiro[3.4]octan-2,2,2-trifluoroacetic acid instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title racemic compound (82 mg, 91%) which was obtained as an off-white foam. MS (ERI): 409.3 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Chiralcel OD) gave the title (-)-compound (29 mg) which was obtained as an off-white foam. MS (ERI): 409.2 ([M+H] ⁺ ).

Example 241

2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]-5-[(7S)-7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl]pyridazin-3-one or enantiomer

Similar to the experiment of Example 240, resolution of the enantiomers by chiral HPLC (column: Chiralcel OD) gave the title (+)-compound (31 mg) which was obtained as an off-white foam. MS (ERI): 409.2 ([M+H] ⁺ ).

Example 242

5-[(7R)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment in Example 3, using (R)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methylpyride azin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to title ( +)-compound (38 mg, 89%) which was obtained as a white solid. MS (ERI): 461.2 ([M+H] ⁺ ).

Example 243

5-((2S,6R)-2,6-dimethylmorpholin-4-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one

Similar to Example 3, using cis-2,6-dimethylmorpholine instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-(fluoromethyl)-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block B) was converted to the title compound (20 mg, 56%) which was obtained as a yellow foam. MS (ERI): 414.2 ([M+H] ⁺ ).

Example 244

5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

a) 5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-[6-trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 5, using azetidin-3-ol hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one instead of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3- it was converted to the title compound (199 mg, 88%) which was obtained as a white foam. MS (ERI): 408.2 ([M+H] ⁺ ).

b) 5-[3-(2.2-difluoroethoxy)azetidin-1-yl]-2-[[5-methyl-3-[b-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one

Similar to Example 133, using 2,2-difluoroethyltrifluoromethanesulfonate instead of methyl iodide, 5-(3-hydroxyazetidin-1-yl)-2-[[5-methyl-3-[6-(trifluoromethyl)-3-pyridyl]isoxazol-4-yl]methyl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3. 4]octan-2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (38 mg, 66%) which was obtained as a colorless amorphous substance. MS (ERI): 472.2 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 3-(2,2-difluoroethoxy)azetidine hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (253 mg, 65%) which was obtained as a white solid. MS (ERI): 438.3 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using (S)-7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to head (-)-compound (35 mg, 81%), which was obtained as a white solid. MS (ERI): 461.2 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 3-oxa-9-azaspiro[5.5]undecane instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (31 mg, 73%) which was obtained as a white solid colors. MS (ERI): 437.1 ([M+H] ⁺ ).

As in Example 3, using 3-oxa-9-azaspiro[5.5]undecane in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (17 mg, 46%), which was obtained as a green oily substance. MS (ERI): 456.3 ([M+H] ⁺ ).

Similar to Example 3, using 3-cyclopropoxyazetidine in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methyl]pyridazin-3-one (building block R) was converted to the title compound (11 mg, 34 %), which was obtained as a white solid. MS (ERI): 449.2 ([M+H] ⁺ ).

Similar to Example 3, using 7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2,2,2-trifluoroacetate in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methyl]pyridazin-3- it (building block R) was converted to the title compound (23 mg, 57%) which was obtained as a white solid. MS (ERI): 485.2 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 3-(trifluoromethoxy)azetidine hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (23 mg, 64 %), which was obtained as a white solid. MS (ERI): 442.1 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 3-methoxyazetidine hydrochloride in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block S) was converted to the title compound (18 mg, 50%), which was obtained as a light yellow solid. MS (ERI): 389.1 ([M+H] ⁺ ).

Similar to the experiment of Example 3, using 3-cyclobutoxyazetidine hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (13.5 mg, 53%) which was obtained as a white solid. MS (ERI): 428.1 ([M+H] ⁺ ).

Similar to Example 3, using 3-(2,2,2-trifluoroethoxy)azetidine-bis(2,2,2-trifluoroacetate) instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5 chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (14 mg, 37%) which was obtained as an off-white solid. MS (ERI): 456.1 ([M+H] ⁺ ).

As in Example 3, using 3-(difluoromethoxy)azetidine in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (7 mg, 22%), which was obtained as a light brown foam. MS (ERI): 424.1 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 1-oxa-8-azaspiro[4.5]decane in place of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (13 mg , 40%), which was obtained in the form of a white foam. MS (ERI): 442.1 ([M+H] ⁺ ).

Similar to the experiment of Example 3, using 7-oxa-2-azaspiro[3.5]nonane hemioxalate instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (structural element D) was converted to the indicated in head compound (16 mg, 50%), which was obtained in the form of a white foam. MS (ERI): 428.1 ([M+H] ⁺ ).

As in Example 3, using 2-oxa-7-azaspiro[3.5]nonane oxalate in place of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (21 mg, 66%) which was obtained as a white foam. MS (ERI): 428.1 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block I) was converted to the title compound (7.6 mg, 19%) which was obtained as whitish solid. MS (ERI): 435.3 ([M+H] ⁺ ).

To a solution of 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one (Example 217, 20 mg, 0.0445 mmol) in anhydrous tetrahydrofuran (0.50 ml) at atmosphere e argon was added a solution of cyclopropylzinc (II) bromide in tetrahydrofuran (0.5 M, 0.107 ml, 53.4 mmol) and Pd(Ph ₃ ) ₄ (5.14 mg, 4.45 μmol). The mixture was heated to 70°C for 4 h, after which it was cooled to room temperature. To the reaction mixture, which was then heated to 70°C for 18 h, was added an additional portion of cyclopropylzinc (II) bromide in THF (0.5 M, 88.9 μl, 44.5 μmol) and Pd(Ph ₃ ) ₄ (5.14 mg, 4.45 μmol). The reaction mixture was cooled to room temperature, after which it was quenched by adding an aqueous solution of NH ₄ Cl 20% wt. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) to give the title compound (3 mg, 15%) as an off-white solid. MS (ERI): 456.3 ([M+H] ⁺ ).

To a mixture of 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F, 33 mg, 0.10 mmol), (3R)-3-tert-butoxypyrrolidine oxalate (49 mg, 0.21 mmol) and potassium carbonate (72 mg, 0.52 mmol) was added acetonite ril (1 ml). The reaction mixture was stirred at 40°C for 18 hours Then the reaction mixture was diluted with EtOAc (20 ml) and water (10 ml). The aqueous layer was extracted from the extract with EtOAc (20 ml). The organic layers were washed with brine (20 ml). The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in EtOAc) gave the title compound (43 mg, 97%) as an off-white foam. MS (ERI): 425.2 ([M+H] ⁺ ).

Similar to Example 3, using 4-methoxy-4-methylpiperidine hydrochloride in place of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (13 mg, 41%) which was obtained as a white foam. MS (ERI): 430.2 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 4-(piperazin-1-yl)pyridazine hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (6 mg, 17%), which was obtained as a light yellow foam. MS (ERI): 465.2 ([M+H] ⁺ ).

Similar to Example 261, using 3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine hydrochloride instead of (3R)-3-t-butoxypyrrolidine oxalate, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (45 mg, 93%) which was obtained as a white solid. MS (ERI): 465.2 ([M+H] ⁺ ).

Similar to the experiment of Example 3, using 3-((1,1,1-trifluoropropan-2-yl)oxy)azetidine-2,2,2-trifluoroacetate instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (of structures element D) was converted to the title racemic compound (307 mg, 88%) which was obtained as a white solid. MS (ERI): 470.1 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Chiralpack AD) gave the title compound enantiomerically pure (130 mg, % ee, >99%) which was obtained as a white solid. MS (ERI): 470.0 ([M+H] ⁺ ).

Similar to the experiment of Example 265, separation of the enantiomers by chiral HPLC (column: Chiralpack AD) gave the title compound, enantiomerically pure (101 mg, % e.e., >99%), which was obtained as a white solid. MS (ERI): 470.0 ([M+H] ⁺ ).

a) 4,5-dichloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one

A mixture of 4-(chloromethyl)-5-methyl-3-(6-methylpyridin-3-yl)isoxazole (100 mg, 0.449 mmol), 4,5-dichloropyridazin-3(2H)-one (81.5 mg, 0.494 mmol) and potassium carbonate (93.1 mg, 0.674 mmol) in N,N-dimethylacetamide (1.0 ml) was heated to 7 0°C for 30 min. The mixture was diluted with water and extracted three times with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) gave the title compound (110 mg, 70%) as a white solid. MS (ERI): 351.0; 353.0 ([M+H] ⁺ ).

b) 4-chloro-5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(b-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

A mixture of 4,5-dichloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (50 mg, 0.142 mmol), 3-ethoxyazetidine hydrochloride (21.6 mg, 0.157 mmol) and potassium carbonate (59 mg, 0.427 mmol) in N,N-dimethylacetamide (1 ml) heated to 70° C. for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted 3 times with ethyl acetate. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 100% EtOAc in heptane) gave the title compound (23 mg, 39%) as a colorless gum. MS (ERI): 416.1 ([M+H] ⁺ ).

Similar to the experiment in Example 268 b, using 7,7-difluoro-5-oxa-2-azaspiro[3.4]octane hydrochloride instead of 3-ethoxyazetidine hydrochloride, 5-chloro-2-[[3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block S) was converted to the title compound (3.5 mg, 19%) which was obtained as a white solid. MS (ERI): 451.2 ([M+H] ⁺ ).

Similar to Example 3, using 1-oxa-7-azaspiro[3.5]nonane oxalate in place of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (13 mg, 51%) which was obtained as a colorless oily liquid. MS (ERI): 428.2 ([M+H] ⁺ ).

Similar to the experiment in Example 268 b, using 3-(tert-butoxy)azetidine hydrochloride instead of 3-ethoxyazetidine hydrochloride, 5-chloro-2-[[3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block S) was converted to the title compound (7.3 mg, 28%) which was obtained as a solid white. MS (ERI): 431.1 ([M+H] ⁺ ).

a) 4,5-dichloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one

As in Example 268a, 4-(chloromethyl)-3-(6-chloro-3-pyridyl)-5-methylisoxazole was converted from 4-(chloromethyl)-5-methyl-3-(6-methylpyridin-3-yl)isoxazole to the title compound (71 mg, 57%) as a white solid. MS (ERI): 436.1; 438.0 ([M+H] ⁺ ).

b) 4-chloro-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 268b, 4,5-dichloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (16 mg, 6 9%) as a white solid. MS (ERI): 436.2; 438.2 ([M+H] ⁺ ).

Similar to Example 261, using a regioisomeric mixture of 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2,2,2-trifluoroacetic acid and 8-fluoro-5-oxa-2-azaspiro[3.5]nonane-2,2,2-trifluoroacetic acid instead of (3R)-3-tert-butoxypyrrolidine oxalate, 5- chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one (building block A) was converted to the title compound as a racemic mixture of regioisomers. Resolution of chiral SFC gave the title compound (66.5 mg, 43%) which was obtained as a brown semi-solid. MS (ERI): 426.2 ([M+H] ⁺ ).

As in Example 273, resolution of chiral SFC gave the title compound (54.1 mg, 35%) which was obtained as a brown semi-solid. MS (ERI): 426.2 ([M+H] ⁺ ).

(R)-7-Fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer (18 6 mg, 1.03 mmol) and potassium carbonate (545 mg, 3.95 mmol). The mixture was stirred at 82°C for 4 h, then partitioned between water and EtOAc. The aqueous layer was extracted three times with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica gradient: 50% to 80% EtOAc in heptane) followed by crystallization in AcOEt/heptane gave the title compound (250 mg, 74%) as a white solid. MS (ERI) m/z: 426.3 ([M+H] ⁺ ).

As in Example 275, using (S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer, 5-chloro-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl) methyl)pyridazin-3(2H)-one (building block A) was converted to the title compound (3.4 mg, 18%) which was obtained as a colorless semi-solid. MS (ERI): 426.2 ([M+H] ⁺ ).

Similar to the experiment of Example 3, using 5-(piperazin-1-yl)pyrimidine hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (5.3 mg, 15%) which was obtained as a white solid. MS (ERI): 465.3 ([M+H] ⁺ ).

Similar to Example 3, using 1-(pyridin-3-yl)piperazine in place of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (14 mg, 41 %), which was obtained as a white solid. MS (ERI): 464.3 ([M+H] ⁺ ).

a) 4-(3-ethoxyazetidin-1-yl)-1H-pyridazin-6-one

To a solution of 5-chloropyridazin-3(2H)-one (130 mg, 0.946 mmol) in N,N-dimethylacetamide (2.5 ml) was added potassium carbonate (654 mg, 4.73 mmol) and 3-ethoxyazetidine hydrochloride (174 mg, 1.23 mmol). The mixture was heated to 60°C for 2 h, after which it was cooled to room temperature. The reaction mixture was immediately purified by preparative HPLC to give the title compound (66 mg, 36%) as a light brown solid. MS (ERI): 196.1 ([M+H] ⁺ ).

b) 5-(3-ethoxyazetidin-1-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one

To a solution of 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazole (25 mg, 0.103 mmol) in N,N-dimethylacetamide (0.50 ml) was added potassium carbonate (15.7 mg, 0.114 mmol) and 4-(3-ethoxyazetidin-1-yl)-1H-pyridazin-6-one (30.3 mg, 0.155 mmol). The mixture was heated to 60°C for 16 h, after which it was left to cool to room temperature. The reaction mixture was filtered on a Buechner funnel and washed with a minimum amount of N,N-dimethylacetamide. The filtrate was immediately purified by preparative HPLC to give the title compound (18 mg, 55%) as a white powder. MS (ERI): 401.1 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 3-methyl-4-(piperazin-1-yl)-1,2,5-oxadiazole hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (5 mg, 14%) which was obtained as a white solid. MS (ERI): 469.3 ([M+H] ⁺ ).

Similar to the experiment of Example 268 b, using 3-methoxyazetidine hydrochloride instead of 3-ethoxyazetidine hydrochloride, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methyl]pyridazin-3-one (building block T) was converted to the title compound (4.7 mg, 39%), which was obtained as a white solid colors. MS (ERI): 423.3 ([M+H] ⁺ ).

a) 4-(5-chloro-6-methoxy-3-pyridyl)-1H-pyridazin-6-one

Similar to Example 67, using (5-chloro-6-methoxypyridin-3-yl)boric acid in place of phenylboronic acid, 4-chloro-1H-pyridazin-3-one in place of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (396 mg, 44%), which was obtained as a white solid. MS (ERI): 238.1 ([M+H] ⁺ ).

b) 5-(5-chloro-6-methoxypyridin-3-yl)-2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one

Similar to the experiment in Example 214 b, using 4-(5-chloro-6-methoxy-3-pyridyl)-1H-pyridazin-6-one instead of 4-(2-methoxy-4-pyridyl)-1H-pyridazin-6-one, 4-(chloromethyl)-3-(6-chloropyridin-3-yl)-5-methylisoxazole was converted to the title compound (19.5 mg, 67%), which was obtained as a white solid. MS (ERI): 445.3; 447.2 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 1-(2-methylpyridin-3-yl)piperazine dihydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (18 mg, 42%) which was obtained as a white foam. MS (ERI): 478.3 ([M+H] ⁺ ).

a) 2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-[(2S,3S)-3-hydroxy-2-methylazetidin-1-yl]pyridazin-3-one

Similar to the experiment in Example 3, using (2S,3S)-2-methylazetidin-3-ol hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (31 0 mg, 69%), which was obtained as a white foam. MS (ERI): 388.5 ([M+H] ⁺ ).

b) 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2S,3S)-3-methoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one

Similar to Example 133, 2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-[(2S,3S)-3-hydroxy-5-methylazetidin-4-yl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl]-2-[[5- methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (8 mg, 26%) which was obtained as a light yellow foam. MS (ERI): 402.2 ([M+H] ⁺ ).

Similar to Example 261, using a regioisomeric mixture of 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2,2,2-trifluoroacetic acid and 8-fluoro-5-oxa-2-azaspiro[3.5]nonane-2,2,2-trifluoroacetic acid instead of (3R)-3-tert-butoxypyrrolidine oxalate, 5- chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title racemic compound as a mixture of two isomers (114 mg, 100%) as a brown oil. MS (ERI): 427.3 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Chiralpak IB 20×250 mm, 5 μm Daicel) gave the title compound (19 mg) which was obtained as an off-white foam. MS (ERI): 427.2 ([M+H] ⁺ ).

As in Example 275, using (S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl] methyl]pyridazin-3-one (building block F) was converted to the title (+)-compound (32 mg, 16%) as a yellow solid. MS (ERI) m/z: 427.6 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using (2R,3R)-2-methylazetidin-3-ol hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-3-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (1 95 mg, 34%), which was obtained as a white foam. MS (ERI): 388.5 ([M+H] ⁺ ).

Similar to Example 133, using iodoethane instead of iodomethane, 2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-[(2S,3S)-3-hydroxy-2-methylazetidin-1-yl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2 -yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (1.0 mg, 3%) which was obtained as a light yellow foam. MS (ERI): 416.6 ([M+H] ⁺ ).

Similar to Example 133, using iodoethane instead of iodomethane, 2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-[(2R,3R)-3-hydroxy-2-methylazetidin-1-yl]pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2 -yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (21 mg, 39%) which was obtained as a white foam. MS (ERI): 416.6 ([M+H] ⁺ ).

a) 4-(5-oxa-2-azaspiro[3.4]octan-2-yl)-1H-pyridazin-6-one

As in Example 279a, using 5-oxa-2-azaspiro[3.4]octane hemioxalate instead of 3-ethoxyazetidine hydrochloride, 5-chloropyridazin-3(2H)-one was converted to the title compound (226 mg, 75%) which was obtained as a white solid. MS (ERI): 208.1 ([M+H] ⁺ ).

b) 2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one

Similar to the experiment in Example 279 b, using 4-(5-oxa-2-azaspiro[3.4]octan-2-yl)-1H-pyridazin-6-one instead of 4-(3-ethoxyazetidin-1-yl)-1H-pyridazin-6-one, 4-(chloromethyl)-5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol was converted to the title ke compound (4.5 mg, 20%) as a white powder. MS (ERI): 413.2 ([M+H] ⁺ ).

Similar to the experiment of Example 3, using a regioisomeric mixture of 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2,2,2-trifluoroacetic acid and 8-fluoro-5-oxa-2-azaspiro[3.5]nonane-2,2,2-trifluoroacetic acid instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[ 3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (structural element D). Separation of the enantiomers by chiral HPLC (column: Chiralpak IB 20×250 mm, 5 μm Daicel) gave the title compound (20 mg, 23%) which was obtained as a white solid. MS (ERI): 446.2 ([M+H]).

In a similar manner to Example 275, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title (-)-compound (5.31 g, 53%) which was obtained as an off-white solid. MS (ERI) m/z: 446.0 ([M+H] ⁺ ).

Similar to Example 275, using (5,)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title (+)-compound (353 mg, 36%) as an off-white foam. MS (ERI) m/z: 446.1 ([M+H] ⁺ ).

As in Example 5, using 1-oxa-9-azaspiro[5.5]undecane hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (38 mg, 92%) which was obtained as an off-white solid substances. MS (ERI): 437.4 ([M+H] ⁺ ).

a) 2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-one

Similar to the experiment in Example 3, using 2-azaspiro[3.3]heptan-6-ol hydrochloride instead of (R)-3-hydroxypyrrolidine and changing the solvent to N,N-dimethylacetamide, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (2 55 mg, 80%) which was obtained as an off-white solid. MS (ERI): 414.1 ([M+H] ⁺ ).

b) 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one

Similar to Example 133, replacing the solvent with tetrahydrofuran, 2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]-5-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-one instead of 5-[(7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octane- 2-yl]-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one was converted to the title compound (25 mg, 81%) which was obtained as a white solid. MS (ERI): 428.2 ([M+H] ⁺ ).

Similar to the experiment in Example 5, using 3-(1-methylcyclopropoxy)azetidine hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (3.5 mg, 18%) which was obtained as an off-white solid. MS (ERI): 409.3 ([M+H] ⁺ ).

Similar to the experiment of Example 3, using 3-(2,2-difluoroethoxy)azetidine hydrochloride instead of (R)-3-hydroxypyrrolidine and replacing the solvent with N,N-dimethylacetamide, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (11 mg, 28%) which was obtained as a white solid. MS (ERI): 419.3 ([M+H] ⁺ ).

Similar to the experiment of Example 5, using 6,6-dimethyl-5-oxa-2-azaspiro[3.4]octane hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (20 mg, 90%), which was obtained in form of a whitish solid. MS (ERI): 423.4 ([M+H] ⁺ ).

Similar to Example 275, using 8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (structural element F) was converted to the title racemic compound (81 mg, 85%) as a yellow oily liquid. Separation of the enantiomers by chiral HPLC (column: Chiralpak AD) gave the title (-)-compound (1.9 mg, 2%) which was obtained as a colorless rubbery substance. MS (ERI) m/z: 477.7 ([M+H] ⁺ ).

As in Example 311, resolution of the enantiomers by chiral HPLC (column: Chiralpak AD) gave the title (+)-compound (3.3 mg, 3%) which was obtained as a colorless rubbery substance. MS (ERI) m/z: 477.7 ([M+H] ⁺ ).

Similar to Example 275, using (R)-7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title (-)-compound (255 mg, 77%) as an orange foam. MS (ERI) m/z: 423.4 ([M+H] ⁺ ).

a) 5-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

Similar to the experiment of Example 5, using 2-azaspiro[3.3]heptan-6-ol hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (177 mg, 95%) which was obtained as an off-white solid substances. MS (ERI): 395.3 ([M+H] ⁺ ).

b) 5-[6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl]-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one

A suspension of 5-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (30 mg, 0.076 mmol) in acetonitrile (0.75 ml) was evacuated and filled three times with argon. Copper (I) iodide (2.9 mg, 0.015 mmol) was then added followed by 2,2-difluoro-2-(fluorosulfonyl)acetic acid (27 mg, 0.153 mmol). The clear solution was stirred in a stoppered tube at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (15 ml) and washed twice with aqueous sodium carbonate (1.0 M, 15 ml). The aqueous layers were extracted with EtOAc (15 ml). The combined organic layers were dried (MgSO ₄ ), filtered and evaporated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in EtOAc) gave the title compound (3.1 mg, 9.3%) as a colorless oily liquid. MS (ERI): 445.3 ([M+H] ⁺ ).

Similar to the experiment in Example 5, using 5-oxa-2-azaspiro[3.6]decane hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title compound (67 mg, 81%) which was obtained as an off-white solid substances. MS (ERI): 423.3 ([M+H] ⁺ ).

Similar to Example 275, using 8-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) converted into the title racemic compound (268 mg, 99%) as an orange solid. Separation of the enantiomers by chiral HPLC (column: Chiralpak AD) gave the title (-)-compound (61 mg, 23%) which was obtained as an off-white solid. MS (ERI) m/z: 423.3 ([M+H] ⁺ ).

Similar to Example 317, resolution of the enantiomers by chiral HPLC (column: Chiralpak AD) gave the title (+)-compound (65 mg, 24%) which was obtained as an off-white solid. MS (ERI) m/z: 423.3 ([M+H] ⁺ ).

As in Example 275, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title (-)-compound (660 mg, 84%) which was obtained as an orange foam. MS (ERI) m/z: 427.3 ([M+H] ⁺ ).

Similar to Example 275, using 7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (structural element F) was converted to the title racemic compound (850 mg, 99%) as an orange oil. Separation of the enantiomers by chiral HPLC (column: Chiralpak OD) gave the title (+)-compound (14.5 mg, 15%) which was obtained as a white solid. MS (ERI) m/z: 477.6 ([M+H] ⁺ ).

As in Example 320, separation of the enantiomers by chiral HPLC (column: Chiralpak OD) gave the title (-)-compound (13.6 mg, 14%) which was obtained as a white solid. MS (ERI) m/z: 477.6 ([M+H] ⁺ ).

Similar to Example 275, using 8-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted into the title racemic compound (86 mg, 99%) as an orange oily liquid. Separation of the enantiomers by chiral HPLC (column: Chiralpak OD) gave the title (-)-compound (40 mg, 45%) which was obtained as a colorless rubbery substance. MS (ERI) m/z: 442.6 ([M+H] ⁺ ).

Similar to Example 275, using 7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title racemic compound (60 mg, 99%) as a yellow oily liquid. Separation of the enantiomers by chiral HPLC (column: Chiralpak OD) gave the title (-)-compound (23 mg, 37%) which was obtained as a colorless rubbery substance. MS (ERI) m/z: 496.6 ([M+H] ⁺ ).

Similar to the experiment in Example 3, using 5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of (R)-3-hydroxypyrrolidine, 5-chloro-2-[[5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block U) was converted to the title compound (19 mg, 97%) which was obtained as a colorless oily liquid. MS (ERI): 423.6 ([M+H] ⁺ ).

As in Example 275, 5-chloro-2-[[5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block U) was converted to the title compound (250 mg, 94%) which was obtained as a white powder. MS (ERI) m/z: 441.5 ([M+H] ⁺ ).

As in Example 275, using 4-fluoro-1-oxa-9-azaspiro[5.5]undecane instead of (R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, 5-chloro-2-[[5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block F) was converted to the title racemic compound (210 mg, 28%) as a white solid. Separation of the enantiomers with chiral SFC (Chiralpak IA) gave the title compound (53.1 mg, 7%) as a light brown solid. MS (ERI) m/z: 455 ([M+H] ⁺ ).

As in Example 326. Separation of the enantiomers with chiral SFC (Chiralpak IA) gave the title compound (63.8 mg, 9%) as a light brown solid. MS (ERI) m/z: 455 ([M+H] ⁺ ).

Similar to Example 5, using 5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-(trifluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block K) was converted to the title compound (23 mg, 58%) which was obtained as a powder white. MS (ERI): 427.5 ([M+H] ⁺ ).

As in Example 275, 5-chloro-2-[[5-(trifluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl]methyl]pyridazin-3-one (building block K) was converted to the title compound (19 mg, 55%) which was obtained as a colorless oily liquid. MS (ERI): 445.3 ([M+H] ⁺ ).

Similar to Example 5, using 4-fluoro-1-oxa-9-azaspiro[5.5]undecane instead of piperidn-4-ol, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title racemic compound (42 mg, 59%) which was obtained as yellow oily liquid. MS (ERI): 474.2 ([M+H] ⁺ ). Separation of the enantiomers by chiral HPLC (column: Chiralcel OD) gave the title compound (12 mg) which was obtained as a gray oil. MS (ERI): 474.2 ([M+H] ⁺ ).

Similar to the experiment of Example 330, separation of the enantiomers by chiral HPLC (column: Chiracel OD) gave the title compound (12 mg) which was obtained as an off-white solid. MS (ERI): 474.2 ([M+H] ⁺ ).

As in Example 275, 5-chloro-2-[[5-methyl-3-[5-(trifluoromethyl)pyrimidin-2-yl]isoxazol-4-yl]methyl]pyride azin-3-one (building block R) was converted to the title compound (205 mg, 68%) which was obtained as a white solid. MS (ERI): 481.6 ([M+H] ⁺ ).

Similar to Example 5, using 1-oxa-9-azaspiro[5.5]undecane hydrochloride instead of piperidn-4-ol, 5-chloro-2-[[3-(6-chloro-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one (building block D) was converted to the title compound (68 mg, 90%) which was obtained as a colorless oil stop the liquid. MS (ERI): 456.2 ([M+H] ⁺ ).

As in Example 275, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methyl]pyridazin-3-one (building block T) was converted to the title compound (30 mg, 99%), which was obtained as a colorless oily liquid. MS (ERI): 481.6 ([M+H] ⁺ ).

Similar to Example 5, using 5-oxa-2-azaspiro[3.5]nonane hydrochloride instead of piperidin-4-ol, 5-chloro-2-[[5-methyl-3-[6-(trifluoromethyl)pyridazin-3-yl]isoxazol-4-yl]methyl]pyridazin-3-one (building block T) was converted to the title compound (26 mg, 89%) which was obtained as free colored oily liquid. MS (ERI): 463.2 ([M+H] ⁺ ).

Claims (581)

1. Compound of Formula (I) or (II) where W is chosen from i) N and ii) CR ⁴ ; Y choose from i) N and ii) CH; Z choose from i) N and ii) CH; R ⁹⁹ choose from i) H and ii) halogen; R ² choose from i) H, ii) C _1-6 -alkyl, iii) C _3-8 -cycloalkyl and iv) halo-C _1-6 -alkyl; R ³ choose from i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from a. pyrrolidinyl, b. piperidinyl, c. morpholinyl, d. piperazinil, e. 2-oxa-6-azaspiro[3.3]heptanyl, f. 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl, g. 3,5,6,7,8,8a-hexahydro-1H-oxazolo[3,4-a]pyrazinyl, h. 2-oxa-7-azaspiro[3.5]nonanil, i. 1-oxa-7-azaspiro[3.5]nonanil, j. 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl, k. 2,6-diazaspiro[3.3]heptanyl, l. 5-oxa-2-azaspiro[3.4]octanyl, m. 7-oxa-2-azaspiro[3.5]nonanil, n. 3-oxa-9-azaspiro[5.5]undecanil, O. 5-oxa-2-azaspiro[3.5]nonanil, R. 1-oxa-9-azaspiro[5.5]undecanil, q. 5-oxa-2-azaspiro[3.6]decanyl, r. 2-azaspiro[3.3]heptanyl, s. 4,7-diazaspiro[2.5]octanyl, t. 2-azaspiro[3.5]nonanil, u. 6-oxa-3-azabicyclo[3.1.1]heptanyl, v. 1-oxa-8-azaspiro[4.5]decanyl, w. 8-oxa-3-azabicyclo[3.2.1]octanyl, X. 3-oxa-6-azabicyclo[3.1.1]heptanyl, y. 3-oxa-8-azabicyclo[3.2.1]octanyl and z. azetidinyl; ii) amino substituted on the nitrogen atom with one or two substituents independently selected from R ⁹ and R ¹⁰ , iii) phenyl substituted with R ¹¹ , R ¹² and R ¹³ where R ¹¹ , R ¹² and R ¹³ are independently selected from a. H, b. C _1-6 -alkoxy, c. halo-C _1-6 -alkyl, d. halogen-C _1-6 -alkoxy and e. halogen; iv) heteroaryl substituted with R ¹¹ , R ¹² and R ¹³ , where R ¹¹ , R ¹² and R ¹³ are independently selected from a. H, b. C _1-6 -alkoxy, c. C _1-6 -alkyl, d. cyano, e. C _3-8 -cycloalkyl, f. halo-C _1-6 -alkyl, g. halogen-C _1-6 -alkoxy, h. amino substituted on the nitrogen atom with one or two substituents independently selected from R ¹⁴ and R ¹⁵ , i. C _3-8 -cycloalkyl-C _1-6 -alkyl, j. heterocycloalkyl substituted with R ¹⁶ , R ¹⁷ and R ¹⁸ where R ¹⁶ , R ¹⁷ and R ¹⁸ are H and where heterocycloalkyl is piperazinyl, k. heterocycloalkoxy, where heterocycloalkoxy is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ , where R ¹⁶ , R ¹⁷ and R ¹⁸ are H, and where heterocycloalkoxy is tetrahydrofuranyloxy, l. heterocycloalkyl-C _1-6 -alkyl, where heterocycloalkyl-C _1-6 -alkyl is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ , where R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from i) H and ii) C _1-6 alkyl; and where heterocycloalkyl-C _1-6 -alkyl represents oxetanyl-C _1-6 -alkyl, m. halogen; and where heteroaryl is selected from pyridinyl, imidazo[1,2-a]pyridinyl and pyrazolyl; R ⁴ choose from i) H and ii) halogen; R ⁵ choose from i) C _1-6 -alkyl, ii) C _3-8 -cycloalkyl, iii) halo-C _1-6 -alkyl and iv) halogen; R ⁶ , R ⁷ and R ⁸ are independently selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _1-6 -alkoxycarbonyl, v) cyano, vi) amino substituted on the nitrogen atom with one or two substituents independently selected from R ²² and R ²³ , vii) C _3-8 cycloalkyl-C _1-6 alkoxy, wherein C _3-8 cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyl; viii) C _3-8 cycloalkylaminocarbonyl wherein C _3-8 cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are H; ix) C _3-8 -cycloalkylcarbonyl, where C _3-8 -cycloalkyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 -alkyl; x) C _3-8 cycloalkyl substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyl; xi) C _3-8 -cycloalkoxy substituted with R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are H; xii) aryloxy, where aryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H and b. halogen; and where aryl is phenyl; xiii) aryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H and b. alkoxy; and where aryl is phenyl; xiv) heteroaryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H and b. C _1-6 -alkyl, and where heteroaryl is selected from imidazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridinyl and oxadiazolyl; xv) heteroaryloxy, where heteroaryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H, b. C _1-6 -alkyl and c. halogen; and where heteroaryl is selected from a. pyridinyl and b. pyridazinyl; xvi) halogen-C _1-6 -alkoxy, xvii) halo-C _1-6 -alkyl, xviii) halogen, xix) oxo, xx) hydroxy and xxi) hydroxy-C _1-6 -alkyl; R ⁹ and R ¹⁰ are independently selected from i) H, ii) C _1-6 -alkyl, iii) heterocycloalkyl substituted with R ³⁰ , R ³¹ and R ³² , where R ³⁰ , R ³¹ and R ³² are independently selected from i) H and ii) C _3-8 cycloalkyl; and where heterocycloalkyl is selected from azetidinyl and oxetanyl, iv) heterocycloalkyl-C _1-6 -alkyl, where heterocycloalkyl-C _1-6 -alkyl is substituted by R ³⁰ , R ³¹ and R ³² , where R ³⁰ , R ³¹ and R ³² are H, and where heterocycloalkyl-C _1-6 -alkyl is tetrahydropyranyl-C _1-6 -alkyl, v) hydroxy-C _1-6 -alkyl and vi) C _3-8 cycloalkyl; R ¹⁴ and R ¹⁵ are independently selected from i) H and ii) C _1-6 alkyl; R ²² and R ²³ are independently selected from i) C _1-6 -alkyl and ii) C _1-6 -alkylcarbonyl; or pharmaceutically acceptable salts. 2. The compound of formula (I) according to claim 1, in which W is CR ⁴ ; Y is N; Z is selected from i) N and ii) CH; R ⁹⁹ is H; R ² is methyl; R ³ is selected from iii) azetidinyl substituted with R ⁶ , R ⁷ and R ⁸ and iv) 5-oxa-2-azaspiro[3.5]nonanyl substituted with R ⁶ , R ⁷ and R ⁸ ; R ⁴ is H, R ⁵ selected from v) methyl and vi) fluorine; R ⁶ , R ⁷ and R ⁸ are independently selected from vii) tert-butoxy, viii) H, ix) fluorine; or pharmaceutically acceptable salts. 3. A compound according to claim 1 or 2, wherein R ² is selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, and halo-C _1-6 alkyl. 4. The connection according to any one of paragraphs. 1-3, in which R ³ is selected from i) heterocycloalkyl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heterocycloalkyl is selected from a. pyrrolidinyl, b. piperidinyl, c. morpholinyl, d. piperazinil, e. 2-oxa-6-azaspiro[3.3]heptanyl, f. 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl, g. 3,5,6,7,8,8a-hexahydro-1H-oxazolo[3,4-a]pyrazinyl, h. 2-oxa-7-azaspiro[3.5]nonanil, i. 1-oxa-7-azaspiro[3.5]nonanil, j. 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl, k. 2,6-diazaspiro[3.3]heptanyl, l. 5-oxa-2-azaspiro[3.4]octanyl, m. 7-oxa-2-azaspiro[3.5]nonanil, n. 3-oxa-9-azaspiro[5.5]undecanil, O. 5-oxa-2-azaspiro[3.5]nonanil, R. 1-oxa-9-azaspiro[5.5]undecanil, q. 5-oxa-2-azaspiro[3.6]decanyl, r. 2-azaspiro[3.3]heptanyl, s. 4,7-diazaspiro[2.5]octanyl, t. 2-azaspiro[3.5]nonanil, u. 6-oxa-3-azabicyclo[3.1.1]heptanyl, v. 1-oxa-8-azaspiro[4.5]decanyl, w. 8-oxa-3-azabicyclo[3.2.1]octanyl, X. 3-oxa-6-azabicyclo[3.1.1]heptanyl, y. 3-Oxa-8-azabicyclo[3.2.1]octanyl and z. azetidinyl; And ii) heteroaryl substituted with R ⁶ , R ⁷ and R ⁸ , wherein the heteroaryl is selected from a. pyridinyl, b. imidazo[1,2-а]pyridinyl and c. pyrazolyl. 5. Connection according to any one of paragraphs. 1-4, in which R ⁵ is selected from C _1-6 -alkyl, C _3-8 -cycloalkyl, halo-C _1-6 -alkyl and halogen. 6. The connection according to any one of paragraphs. 1-5, wherein R ⁶ , R ⁷ and R ⁸ are independently selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _1-6 -alkoxycarbonyl, v) cyano, vi) amino substituted on the nitrogen atom with one or two substituents independently selected from R ²² and R ²³ , vii) C _3-8 -cycloalkyl-C _1-6 -alkoxy, where C _3-8 -cycloalkyl is substituted with R ²⁴ , R ²⁵ and R ²⁶ , while R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 -alkyl; viii) C _3-8 -cycloalkylaminocarbonyl, where C _3-8 -cycloalkyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ , while R ²⁴ , R ²⁵ and R ²⁶ represent H; ix) C _3-8 -cycloalkylcarbonyl, where C _3-8 -cycloalkyl is substituted by R ²⁴ , R ²⁵ and R ²⁶ , while R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 -alkyl; x) C _3-8 cycloalkyl substituted with R ²⁴ , R ²⁵ and R ²⁶ , where R ²⁴ , R ²⁵ and R ²⁶ are independently selected from H and C _1-6 alkyl; xi) C _3-8 -cycloalkoxy substituted with R ²⁴ , R ²⁵ and R ²⁶ where R ²⁴ , R ²⁵ and R ²⁶ are H; xii) aryloxy, where aryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , while R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H and b. halogen; and where aryl is phenyl; xiii) aryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , where R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H and b. alkoxy; and where aryl is phenyl; xiv) heteroaryl substituted with R ²⁷ , R ²⁸ and R ²⁹ , wherein R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H and b. C _1-6 -alkyl, and where heteroaryl is selected from imidazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridinyl and oxadiazolyl; xv) heteroaryloxy, where heteroaryl is substituted with R ²⁷ , R ²⁸ and R ²⁹ , while R ²⁷ , R ²⁸ and R ²⁹ are independently selected from a. H, b. C _1-6 -alkyl and c. halogen; and where heteroaryl is selected from a. pyridinyl and b. pyridazinyl; xvi) halogen-C _1-6 -alkoxy, xvii) halo-C _1-6 -alkyl, xviii) halogen, xix) oxo, xx) hydroxy and xxi) hydroxy-C _1-6 -alkyl. 7. Connection according to any one of paragraphs. 1-6, which is characterized in that R ⁶ is selected from i) H, ii) C _1-6 -alkyl, iii) C _1-6 -alkoxy, iv) C _3-8 -cycloalkyl, v) C _3-8 -cycloalkoxy and vi) halogen. 8. Connection according to any one of paragraphs. 1-7, in which R ⁷ is selected from i) H, ii) C _1-6 -alkyl and iii) halogen. 9. Connection according to any one of paragraphs. 1-8 in which R ⁸ is H. 10. Connection selected from N-methyl-N-((3S)-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)pyrrolidin-3-yl)acetamide; N-methyl-N-((3R)-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)pyrrolidin-3-yl)acetamide; 5-((3R)-3-hydroxypyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 5-((3S)-3-hydroxypyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 5-(4-hydroxypiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 5-(2,2-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 5-((2S,6R)-2,6-dimethylmorpholin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; ethyl 1-(1-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)-6-oxopyridazin-4-yl)piperidine-4-carboxylate; 5-(4-(cyclopropanecarbonyl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)-5-morpholinopyridazin-3(2H)-one; 5-(cis-2,6-dimethylmorpholino)-2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one; 2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(trifluoromethyl)pyridazin-3(2H)-one; 5-(t-butyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-isopropyl-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-ethyl-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; tert-butyl 4-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-morpholinopyridazin-3(2H)-one; 5-(3,6-dihydro-2H-pyran-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-cyclopropylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; N-cyclopropyl-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)piperidine-4-carboxamide; 5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((2S,6S)-2,6-dimethylmorpholino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((2R,6R)-2,6-dimethylmorpholino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(cis-2,6-dimethylmorpholino)-2-((3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)piperidine-4-carbonitrile; 5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-cyclopropylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-cyclopropyl-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazin-3(2H)-one; 5-(cis-2,6-dimethylmorpholino)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(cis-2,6-dimethylmorpholino)-2-((3-(3-fluoropyridin-4-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(3-fluoropyridin-4-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 2-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one; 7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one; 5-(dimethylamino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3(2H)-one; (R)-7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (S)-7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylpiperazin-1-yl)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylpiperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(5-chloro-3-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one; 2-((3-(5-chloro-3-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)-2-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-N-cyclopropyl-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-carboxamide; (S)-N-cyclopropyl-1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-3-carboxamide; 5-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(4-cyclopropyl-3-methylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(4-cyclopropyl-3-methylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-(2-methoxyphenyl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)-5-(cis-2,6-dimethylmorpholino)pyridazin-3(2H)-one; 5-(4-cyclopropylpiperazin-1-yl)-2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)pyridazin-3(2H)-one; 5-(cyclopropyl(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(methyl(oxetan-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-cyclopropylpiperazin-1-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-phenylpyridazin-3(2H)-one; 5-(4-fluorophenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-azaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one; 5-((2-hydroxy-2-methylpropyl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(2-fluorophenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one; 5-(cis-2,6-dimethylmorpholino)-2-((3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(2-methoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4,7-diazaspiro[2.5]octan-7-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(piperazin-1-yl)pyridazin-3(2H)-one; 5-(4-methoxyphenyl)-2-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methyl]pyridazin-3-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(methylamino)pyridazin-3(2H)-one; 5-(4-ethoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-fluoro-4-methoxyphenyl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one; 5-(5-methoxypyridin-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 1-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)azetidine-3-carbonitrile; 2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one; 5-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one; (R)-5-(3-(t-butoxy)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(2-methylmorpholino)-2-((3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(2-methylmorpholino)-2-((3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-phenoxyazetidin-1-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 5-((1-cyclopropylazetidin-3-yl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-hydroxy-3-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-(2-methoxypyridin-3-yl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(dimethylamino)-2-[[3-(5-fluoro-6-methyl-3-pyridyl)-5-methylisoxazol-4-yl]methyl]pyridazin-3-one; 2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(1-methylpyrazol-4-yl)pyridazin-3-one; 5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-hydroxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-methylpyridin-4-yl)pyridazin-3(2H)-one; 5-(2-methoxypyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyridin-4-yl)pyridazin-3(2H)-one; 5-(4-(2-ethyl-1H-imidazol-1-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-(2-methyl-1H-imidazol-1-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-(cyclopropylmethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-isopropoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3,4-dimethoxyphenyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)pyridazin-3-one; 5-(4-isopropoxyphenyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-[6-(dimethylamino)-3-pyridyl]-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-hydroxy-4-methylpiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((3S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 2-ethyl-7-(1-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((3aS,6aS)-tetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)pyridazin-3(2H)-one; 5-(3-(4-fluorophenoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridazin-3(2H)-one; 5-((3aR,6aS)-hexahydro-1H-furo[3,4-b]pyrrol-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(pyridin-3-yloxy)azetidin-1-yl)pyridazin-3(2H)-one; 5-(3-(3-fluorophenoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-(2-fluorophenoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(pyridin-4-yloxy)azetidin-1-yl)pyridazin-3(2H)-one; 5-(3-((5-chloropyridin-2-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(7-hydroxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(7-ethoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-cyclopropoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((1-cyclopropylazetidin-3-yl)(methyl)amino)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-((6-chloropyridin-3-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-methoxypiperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one; (5-(3-cyclopropylmethoxy)azetidin-1-yl)-2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)pyridazin-3(2H)-one; 2-((5,5'-dimethyl-[3,3'-biisoxazol]-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(cyclopropylmethoxy)azetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(5-chloropyridin-2-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 5-(6-methoxy-2-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 5-(3-((2-chloropyridin-4-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(5-chloro-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-(6-(difluoromethoxy)pyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(6-ethoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(1-ethyl-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(2-(dimethylamino)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)pyridazin-3(2H)-one; 5-(4-(4-methoxypyrimidin-5-yl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(piperazin-1-yl)pyridin-4-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one; 5-(4-(3-methoxypyridazin-4-yl)piperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(4-(1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-(difluoromethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 5-(1-isobutylpyrazol-4-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one; 5-(6-cyclopropyl-3-pyridyl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one; 5-(6-(methylamino)-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-(2-(difluoromethoxy)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylpyrrolidin-1-yl)pyridazin-3(2H)-one; 5-(5,6-dimethoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(6-ethoxy-5-methylpyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-fluoroazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-(difluoromethyl)-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-((2S,6R)-2,6-dimethylmorpholino)pyridazin-3(2H)-one; 5-(5-fluoro-6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(4-isopropyl-3-methylpiperazin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-(cyclopropylmethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-((6-methylpyridazin-3-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one; 5-(2-(azetidin-1-yl)pyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(5-chloro-6-methoxypyridin-3-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(2-chloro-5-fluoro-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-(6-isopropoxy-3-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-(5-fluoro-2-methoxypyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(2,6-dimethylpyridin-4-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((2R,3R)-3-methoxy-2-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 5-(2-ethyl-4-pyridyl)-2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-((2S,3S)-3-methoxy-2-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((2S,3S)-3-ethoxy-2-methylazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(2-(methylamino)pyridin-4-yl)pyridazin-3(2H)-one; (R)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((2R,6S)-2,6-dimethylmorpholino)-2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one; 2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methoxyisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-5-(1-propylpyrazol-4-yl)pyridazin-3-one; 6-(1-((5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl)methyl)-6-oxo-pyridazin-4-yl)pyridine-2-carbonitrile; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one; 5-(3-ethoxyazetidin-1-yl)-2-((3-(5-fluoro-6-methylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2RS,6SR)-2,6-dimethylmorpholino)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-cyclopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one; 2-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-cyclopropoxyazetidin-1-yl)pyridazin-3(2H)-one; (S)-7-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; (S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-methylmorpholino)pyridazin-3(2H)-one; 5-(2-methoxypyridin-4-yl)-2-((5-methyl-3-(5-trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; (R)-7-(1-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-6-oxo-1,6-dihydropyridazin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 5-(3-((2-chloropyridin-4-yl)oxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-cyclobutoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(3-cyclopropoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; (R)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-((2S,6R)-2,6-dimethylmorpholin-4-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl)methyl)pyridazin-3-one; 5-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(2,2-difluoroethoxy)azetidin-1-yl)pyridazin-3(2H)-one; (S)-5-(7-(difluoromethoxy)-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; 5-(3-cyclopropoxyazetidin-1-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(trifluoromethoxy)azetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-methoxyazetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-cyclobutoxyazetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-(difluoromethoxy)azetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-oxa-8-azaspiro[4.5]decan-8-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3(2H)-one; 2-((5-cyclopropyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-cyclopropylpyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; (R)-5-(3-(t-butoxy)pyrrolidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-methoxy-4-methylpiperidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(pyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one; (S or R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one; (R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((6-methoxy-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3(2H)-one; 4-chloro-5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3(2H)-one; 5-(3-(t-butoxy)azetidin-1-yl)-2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 4-chloro-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(3-ethoxyazetidin-1-yl)pyridazin-3(2H)-one; (S)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(pyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(pyridin-3-yl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(3-ethoxyazetidin-1-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-methyl-1,2,5-oxadiazol-3-yl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(3-methoxyazetidin-1-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(5-chloro-6-methoxypyridin-3-yl)-2-((3-(6-chloropyridazin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-methylpyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(4-(3-chloropyridazin-4-yl)piperazin-1-yl)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(2-methylpyridin-3-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2S,3S) or (2R,3R)-3-methoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one; (S)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2R,3R) or (2S,3S)-3-hydroxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methyl-1,2-oxazol-4-yl)methyl)-5-(4-(4-methoxypyrimidin-5-yl)piperazin-1-yl)pyridazin-3-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2S,3S) or (2R,3R)-3-ethoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-cyclopropylpyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one; 5-(4-(5-chloropyridazin-4-yl)piperazin-1-yl)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-((2R,3R) or (2S,3S)-3-ethoxy-2-methylazetidin-1-yl)pyridazin-3(2H)-one; 2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3(2H)-one; (R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(8-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (S or R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(3-methylpyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(4-chloropyrimidin-5-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(5-methylpyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-(3-methoxypyridazin-4-yl)piperazin-1-yl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(3-(1-methylcyclopropoxy)azetidin-1-yl)pyridazin-3(2H)-one; 5-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (S)-5-(7-ethyl-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 5-(6,6-dimethyl-5-oxa-2-azaspiro[3.4]octan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 5-(6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.6]decan-2-yl)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(8-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (S)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(8-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-(trifluoromethyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 2-((5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-2-((5-ethyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 5-((4S)-4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3-one; 5-((4R)-4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3-one; 2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; (R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-(fluoromethyl)-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; (R)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; (S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(4-fluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; (R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridazin-3(2H)-one; (R)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)-2-((5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; 2-((5-methyl-3-(6-(trifluoromethyl)pyridazin-3-yl)isoxazol-4-yl)methyl)-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; or pharmaceutically acceptable salts. 11. The connection according to any one of paragraphs. 1-10, where said compound is (R or S)-2-((3-(6-chloropyridin-3-yl)-5-methylisoxazol-4-yl)methyl)-5-(7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3(2H)-one; 5-(3-(t-butoxy)azetidin-1-yl)-2-((5-methyl-3-(6-methylpyridazin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one; or pharmaceutically acceptable salts. 12. Connection according to any one of paragraphs. 1-11 for use as a therapeutically active substance. 13. A pharmaceutical composition having the activity of a positive allosteric modulator of GABA _A α5 receptors, containing an effective amount of a compound according to any one of paragraphs. 1-11 and a therapeutically inert carrier. 14. The connection according to any one of paragraphs. 1-11 for the treatment or prevention of Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, fragile X disorder ohms.