Antiviral compounds

Abstract

The present application provides antiviral compounds of formula (1), especially active against coronavirus, as well as pharmaceutical compositions comprising the same. Also provided are methods of use and manufacture of the antiviral compounds and associated compositions.

Description

[0001] ANTIVIRAL COMPOUNDS FIELD The present application provides antiviral compounds, as well as pharmaceutical compositions comprising the same. Also provided are methods of use and manufacture of the antiviral compounds and associated compositions. BACKGROUND The COVID-19 pandemic caused by SARS-CoV-2 virus presented a global health crisis, prompting the need for effective treatments. In response to the crisis, various pre-existing antiviral medications have been developed and authorized for emergency use to combat the virus. Emergency use authorization has for example been granted for remdesivir in severe cases of COVID-19. The COVID-19 crisis spurred research into antiviral compounds against coronaviruses and has led to several approved antiviral treatments summarized in Meyerowitz and Li, Clinical Infectious Diseases, COVID Antiviral Therapy Review, 2023 https: / / doi.org / 10.1093 / cid / ciad685. However, despite the global efforts in developing appropriate treatment for SARS-CoV-2 infections and related disease, there remains a need for pharmaceutical compounds effective against coronavirus infection. SUMMARY OF THE INVENTION The present invention relates to antiviral compounds and compositions comprising the same that are effective in reducing or preventing virus replication of a coronavirus, and are thus useful for the treatment and / or prevention of infections or diseases caused by coronaviruses, in particular, by a SARS-CoV-2 virus. Accordingly, the invention relates to compounds of formula I or a salt thereof as defined herein. Accordingly, the invention relates to antiviral compounds of formula I or a salt thereof as defined in the claims. The invention also relates to pharmaceutical compositions comprising a compound, being an antiviral compound, as defined herein or pharmaceutically acceptable salt thereof, in an amount effective in reduction or preventing coronavirus replication and / or coronavirus infection associated disease in a subject. The invention also relates to a method of using the compounds of formula I as defined herein as antiviral compound, for the prevention or treatment of a viral infection in a subject, mammal or human. In an embodiment, a method of inhibiting replication of a coronavirus is provided. In another embodiment, a method of treating or preventing a coronavirus infection in a subject is provided. Such method may include a step of administering a subject an effective amount of an antiviral compound as defined herein, or a pharmaceutically acceptable salt thereof, or administering a subject a pharmaceutical composition comprising an antiviral compound as defined herein or pharmaceutically acceptable salt thereof, in an amount effective in reducing or preventing coronavirus replication in a subject. In a further embodiment, said subject may be identified as suffering a coronavirus infection or said subject may be exposed to an infective amount of a coronavirus. The invention relates to the compounds of formula I as defined herein for use in the prevention and / or treatment of a viral infection in a subject, mammal or human. The present invention provides compounds for the treatment and / or prevention of infections or diseases caused by coronaviruses, in particular, by a SARS-CoV-2 virus. FIGURES Figure 1: efficacy of Cpd-052 in a SARS-Cov-2 mouse model in accordance with example 26. DETAILED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. “A”, “an” and “the” as used herein refers to both singular and plural referents unless the context clearly dictates otherwise. By way of example, “an excipient” refers to one or more than one excipients. “Comprise”, “comprising”, “comprises” and the like as used herein are synonymous to “include”, “including”, “includes” and the like, or, “contain”, “containing”, “contains” and the like and are inclusive or open-ended terms that specify the presence of what follows and do not exclude the presence of additional, non-recited components, features, elements, members, steps,… known in the art or disclosed herein. Whereas the terms “one or more” or “at least one”, such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any ≥3, ≥4, ≥5, ≥6 or ≥7 etc. of said members, and up to all said members. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination. Compounds Embodiments described herein relate to a compound having formula (I) or a salt, such as pharmaceutically acceptable salt, thereof, wherein: R1is according to -X1-R4, X1is selected from a bond, -O-, -S-, -NR5-, -CO-, -CO-NR5- and -CO-O-, R4is selected from: - hydrogen provided X1is not a bond, - alkyl, alkenyl or alkynyl, each optionally substituted by one or more groups independently selected from o halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, o cycloalkyl, cycloalkenyl or cycloalkynyl, each optionally further substituted by one or more group selected from halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, alkyl, haloalkyl, alkenyl and alkynyl, o heterocyclyl optionally further substituted by one or more groups independently selected from halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, - CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, =O, =S, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and, o aryl and heteroaryl each optionally further substituted by halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, - CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - heterocyclyl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - cycloalkyl optionally substituted by one or more groups independently selected from halogen, alkyl, alkenyl, alkynyl, =O, =S, -OR6, -SR6-NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - aryl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and, - heteroaryl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, R2is selected from alkyl optionally substituted by one or more group independently selected from halogen and – OR9, -SR9and -NR10R11, and, R3is selected from - halogen, - alkyl, alkenyl or alkynyl, each optionally substituted by one or more group independently selected from halogen, =O, =S, -OR12, -SR12, -NR13R14, -SO2-R12, -CO- R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, cycloalkyl or heterocyclyl wherein each cycloalkyl and heterocyclyl is optionally further substituted with one or more groups independently selected from halogen, - OR12, alkyl, alkenyl, alkynyl, haloalkyl, aryl and heteroaryl, and, aryl or heteroaryl wherein each aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, -OR12, -SR12, -CN, - NO2, -SF5, -NR13R14, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, cycloalkyl, heterocyclyl, aryl and heteroaryl, - cycloalkyl, heterocyclyl, aryl or heteroaryl, each optionally substituted with one or more groups independently selected from halogen, -OR12, -SR12, -CN, -SO2-R12, - NR13R14, -SF5, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally further substituted with one or more groups independently selected from halogen, alkyl, - OR12, -SR12, -NR13R14, -SF5, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14and - SO(NR5)-NR13R14, and, each R5, R6, R9, R10, R11, R12, R13and R17are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more groups independently selected from halogen, alkyl, -OR15, -SR15, -NR15R16, =O, =S, cycloalkyl, heterocyclyl, aryl and heteroaryl, each R7, R8and R14are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, -CN, -SF5, -CO- R12, -CO-OR12, -CO-NR13R17, -SO2-NR13R17and -SO(NR5)-NR13R17, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, and, each R15and R16are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl. As used herein for the terms alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined herein below, the notion or pre-fix Cx-ymeans that the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl consists of x to y carbon or heteroatoms composing the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. This does not include the carbon and / or heteroatoms of (optional) substituents. The term “alkyl” as used herein means normal, secondary, or tertiary, linear, branched or straight hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1- propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu), 2-dimethyl-2- propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl- 2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n- nonadecyl, and n-icosyl. In particular embodiments, the term alkyl refers to C1-12alkyl, yet more in particular to C1-9alkyl, yet more in particular to C1-6alkyl, yet more in particular C1-4alkyl as further defined herein above. The term “alkenyl” as used herein is a normal, secondary or tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (- CH2CH2CH2CH2CH=CH2). The double bond may be in the cis or trans configuration. In particular embodiments, the term alkenyl refers to C2-12alkenyl, yet more in particular to C2-9alkenyl, still more in particular to C2-6alkenyl, still more in particular C2-4-alkenyl as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. The term “alkynyl” as used herein refers to a normal, secondary, tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (-C≡CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CH2C≡CH). In particular embodiments, the term alkynyl refers to C2-12alkynyl, yet more in particular to C2-9alkynyl, yet more in particular to C2-6alkynyl, yet more in particular to C2-4alkynyl as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. The term "haloalkyl" as a group or part of a group, refers to an alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1- trifluoroethyl and the like. In particular embodiments, haloalkyl refers tofluoromethyl, difluoromethyl or trifluoromethyl, more in particular trifluoromethyl. The term “cycloalkyl” as used herein and unless otherwise stated means a non-aromatic hydrocarbon monovalent group having from 3 to 18 carbon atoms consisting of or comprising a C3-10monocyclic or C7-18polycyclic saturated hydrocarbon. Examples of fully saturated cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like. In particular embodiments, the term cycloalkyl refers to C3-12cycloalkyl, yet more in particular to C3-9cycloalkyl, still more in particular to C3-6cycloalkyl as further defined herein above. Also in particular embodiments, the cycloalkyl is a saturated hydrocarbon or comprises one or more double bonds. In more particular embodiments, the cycloalkyl is fully saturated. Examples of cycloalkyl groups comprising at least one double bond (sp2) include cyclopentenyl, cyclopentenylpropylene, methylcyclohexenylene and cyclohexenyl. Examples of cycloalkyl groups comprising at least one triple bond (sp) include cyclohept-1-yne, 3-ethyl-cyclohept-1-ynylene, 4- cyclohept-1-yn-methylene and ethylene-cyclohept-1-yne. For the avoidance of doubt, fused systems of a cycloalkyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. The term “aryl” as used herein means a mono-valent aromatic hydrocarbon of 6-20 carbon atoms. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like. In particular embodiments, the term aryl refers to a 6-14 carbon atoms membered aromatic cycle, yet more in particular refers to a 6-10 carbon atoms membered aromatic cycle. Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofurane, dihydrobenzothiophene and the like are considered as heterocycle according to the invention. Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. The term “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system, such as mono-cyclic or bicyclic moiety, including at least one N, O, S, or P. At least one ring of the heterocycle or heterocyclyl may have 1, 2, 3 or 4 heteroatoms selected from N, O and / or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one carbonyl (C=O), in particular at a position adjacent to a ring heteroatom. Unless otherwise specified, the heterocyclyl may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of bi- or multi-ring heterocyclyls or heterocycles may be fused, bridged and / or joined through one or more spiro atoms. In some embodiments, the heterocyclyl is a C3-9-heterocyclyl, C5-9-heterocyclyl or C3-6- heterocyclyl. Fused systems of a heterocycle or heterocyclyl with an aryl ring are considered as heterocycle or heterocyclyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycle or heterocyclyl with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4- dihydrobenzo[b]pyranyl), 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H- quinolizinyl, 2-oxopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H- pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5- dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The term “heteroaryl” refers to an aromatic ring system of 5 to 18 atoms including at least one N, O, S, or P, containing 1 or 2 rings which can be fused together or linked covalently, each ring typically containing 5 to 6 atoms; at least one of said rings is aromatic, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. In some embodiments, the heteroaryl is a C5-11- heteroaryl. Fused systems of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a heteroaryl ring with a heterocycle are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a hetero aryl ring with an aryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non-limiting examples of such heteroaryl, include: triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5- a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1- benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3- benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro- benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl and thiazolyl ; more preferably, said heteroaryl group is selected from from the group comprising pyridyl, pyrazinyl, pyrimidinyl, indolyl and benzimidazolyl. The term “halogen” as used herein means any atom selected from the group consisting offluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In particular embodiments, the halogen is selected fromfluorine or chlorine, more in particularfluorine. As used herein, the term “substituted” is used to indicate, unless otherwise specified or clear from the context, that one or more hydrogen, such as 1 to 3 hydrogens, 1 or 2 hydrogens or 1 hydrogen on the atom or radical to which the “substituted” applies are replaced with a selection from the indicated group, provided the normal valency is not exceeded and that the substitution results in a chemically stable compound. If substituents are described as “independently” having one or more variable, each instance of a substituent is selected independent of the other(s) from the list of variables available. Each substituent may therefore be the same as or different from the other substituent(s). Likewise, if substituents are described as “independently selected” from a group, each instance of a substituent is selected independent of the other(s). Each substituent therefore may be identical to or different from the other substituent(s). In some embodiments, X1is selected from a bond, -O-, -CO- and -CO-NR5-. In a further embodiment X1is -CO-NR5-. In some embodiments, R4is selected from: - hydrogen provided X1is not a bond, - C1-6-alkyl, C1-6-alkenyl or C1-6-alkynyl, each optionally substituted by one or more groups independently selected from o halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, o C3-6-cycloalkyl, C3-6-cycloalkenyl or C3-6-cycloalkynyl, each optionally further substituted by one or more group selected from halogen, -OR6, -SR6, -NR7R8, - SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl and C1-4-alkynyl, o C3-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-OR6, - CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, =O, =S , C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10- aryl and C5-9-heteroaryl, and, o C6-10-aryl and C3-10heteroaryl each optionally further substituted by halogen, - OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, - SO(NR5)-NR7R8, -CN, -NO2, -SF5, C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl, C1-4- alkynyl, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C5-9-heteroaryl, - C3-9-heterocyclyl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO- NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, C1-4-alkyl, C1-4-haloalkyl, C1-4- alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C3-10heteroaryl, - C3-6-cycloalkyl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6-NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl, C1-4- alkynyl, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C3-10heteroaryl, - C6-10-aryl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl, C1-4- alkynyl, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C3-10heteroaryl, and, - C3-9-heteroaryl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl, C1-4- alkynyl, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C3-10heteroaryl. In further embodiments, R4is selected from: - hydrogen provided X1is not a bond, - C1-6-alkyl, C1-6-alkenyl or C1-6-alkynyl, each optionally substituted by one or more groups independently selected from o halogen (such asfluorine), -OR6, -SR6, -NR7R8, -SO2-C1-4-alkyl, o C3-6-cycloalkyl optionally further substituted by one or more group selected from halogen, C1-4-alkenyl, C1-4-alkynyl, -OR6, -SR6and -NR7R8, o C5-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen, -OR6, -SR6, -NR7R8, =O, C1-4-alkyl, C1-4- alkenyl, C1-4-alkynyl and -CO-C1-4-alkyl, and, o C6-10-aryl or C5-9-heteroaryl wherein each is optionally further substituted by one or more groups independently selected from halogen, C1-4-alkyl, C1-4- alkenyl, C1-4-alkynyl, -OR6, -SR6and -NR7R8, - C5-9-heterocyclyl optionally substituted by one or more groups independently selected from halogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, -CO-C1-4-alkyl, =O, -OR6, - SR6and -NR7R8, and, - C3-6-cycloalkyl optionally substituted by one or more groups independently selected from halogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C1-4-alkanoyl, =O, -OR6, -SR6and - NR7R8. In other embodiments, R4is selected from: - hydrogen provided X1is not a bond, - C1-6-alkyl optionally substituted by one or more groups independently selected from o halogen (such asfluorine or chloride), o -OR6, -NR7R8, -SO2-C1-4-alkyl, o C3-6-cycloalkyl optionally further substituted by one or more group selected from halogen and -OR6, o C5-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen, - OR6, =O, C1-4-alkyl and C1-4-alkanoyl, and, o C6-10-aryl and C5-9-heteroaryl optionally further substituted by C1-4-alkyl, - C5-9-heterocyclyl optionally substituted by one or more groups independently selected from halogen, C1-4-alkyl and -OR6, and, - C3-6-cycloalkyl optionally substituted by one or more groups independently selected from halogen, C1-4-alkyl, C1-4-alkanoyl, =O and -OR6. In yet other embodiments, R4is selected from C1-6-alkyl optionally substituted by one or more groups independently selected fromfluor, -OR6, -NR7R8, C5-9-heterocyclyl, phenyl and C5-9-heteroaryl, wherein said C5-9-heterocyclyl is optionally further substituted by one or more groups independently selected from halogen such asfluorine, -OR6, =O, C1-4- alkyl and C1-4-alkanoyl, and wherein said phenyl and C5-9-heteroaryl are optionally further substituted by C1-4-alkyl. In yet other embodiments, R4is selected from C1-6-alkyl optionally substituted by one or more groups independently selected from - C5-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen such asfluorine, -OR6, =O, C1-4-alkyl and C1-4-alkanoyl, - phenyl and - C5-9-heteroaryl optionally further substituted by C1-4-alkyl. In yet other embodiments, R4is selected from C1-6-alkyl optionally substituted by one or more groups independently selected from - C5-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen such asfluorine, -OR6, - phenyl and - C5-9-heteroaryl. In yet other embodiments, R4is selected from C1-6-alkyl optionally substituted by one or more groups independently selected from C5-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen such asfluorine, -OR6. In yet other embodiments, R4is selected from C5-9-heterocyclyl optionally substituted by one or more groups independently selected from halogen, C1-4-alkyl and -OR6. In yet other embodiments, R4is a C5-9-heterocyclyl optionally substituted with C1-4-alkyl. In yet other embodiments, R4is a C5-9-heterocyclyl optionally substituted with C1-3-alkyl. In further embodiments R4is a C5-9-heterocyclyl wherein at least one heteroatom is oxygen, such as tetrahydrofuran, and wherein the heterocyclyl is optionally further substituted with one or morefluorine. In yet other embodiments, R4is selected from C3-6-cycloalkyl optionally substituted by one or more groups independently selected from halogen, C1-4-alkyl, C1-4-alkanoyl, =O and -OR6. In yet other embodiments, R4is a C3-6-cycloalkyl, optionally substituted with one or more groups selected from halogen, such asfluorine or chloride, and -OR6, such as hydroxy or methoxy. In yet further embodiments, R4is a C4-5-cycloalkyl, optionally substituted with one or more groups selected from halogen, such asfluorine or chloride, and -OR6, such as hydroxy or methoxy. In some embodiments, R2is selected from C1-4-alkyl optionally substituted by one or more group independently selected from halogen and – OR9, -SR9and -NR10R11. In further embodiments, R2is a C1-4-alkyl. In some embodiments, R3is selected from - halogen, - C1-6-alkyl, C1-6-alkenyl or C1-6-alkynyl, each optionally substituted by one or more group independently selected from halogen, =O, =S, -OR12, -SR12, -NR13R14, -SO2-R12, - CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, C3-6-cycloalkyl or C3-9-heterocyclyl wherein each cycloalkyl and heterocyclyl is optionally further substituted with one or more groups independently selected from halogen, -OR12, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C1-4-haloalkyl, C6-10-aryl and C5-9- heteroaryl, and, C6-10-aryl or C5-9-heteroaryl wherein each aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, , -OR12, -SR12, -CN, -NO2, -SF5, -NR13R14, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C5-9- heteroaryl, - C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl or C5-9-heteroaryl, each optionally substituted with one or more groups independently selected from halogen, -OR12, - SR12, -CN, -SO2-R12, -NR13R14, -SF5, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, - SO(NR5)-NR13R14, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C6-10-aryl, C5-9- heteroaryl and C3-9-heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally further substituted with one or more groups independently selected from halogen, C1-4-alkyl, -OR12, -SR12, -NR13R14, -SF5, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14and -SO(NR5)-NR13R14. In further embodiments, R3is selected from - halogen, - C1-6-alkyl, C1-6-alkenyl or C1-6-alkynyl, each optionally substituted by one or more group independently selected from halogen, oxo, -OR12, -SR12, -NR13R14, C3-6-cycloalkyl or C5-9-heterocyclyl each optionally further substituted with one or more groups independently selected from C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl and C1-4-alkanoyl, and, aryl or heteroaryl each optionally further substituted with one or more groups selected from halogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C1-4-alkanoyl, - OR12, -SR12and -NR13R14, - C3-6-cycloalkyl, C5-9-heterocyclyl, C6-10-aryl or C5-9-heteroaryl, each optionally further substituted with one or more groups independently selected from halogen, -OR12, - SR12, -CN, -SO2-C1-4-alkyl, -NR13R14, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl and C3-6- cycloalkyl, wherein each C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl and C3-6-cycloalkyl is optionally further substituted with one or more groups independently selected from halogen, -OR12, -SR12and -NR13R14. In other embodiments, R3is selected from - halogen, - C1-6-alkyl optionally substituted by one or more group independently selected from o halogen, o oxo, o aryl optionally further substituted with one or more groups selected from halogen, -OR12, o -NR13R14, o C3-6-cycloalkyl, o C5-9-heterocyclyl optionally further substituted with one or more groups independently selected from C1-4-alkyl and C6-10-aryl, - C3-6-cycloalkyl, - C6-10-aryl (such as phenyl) optionally further substituted with one or more group selected from halogen, -OR12, -CN, -SO2-C1-4-alkyl, -NR13R14, C1-4-alkyl optionally further substituted with one or more groups independently selected from halogen and -OR12and C3-6-cycloalkyl, and, - C5-9-heteroaryl optionally substituted one or more group independently selected from C1-4-alkyl and -OR12. In yet other embodiments, R3is C1-6-alkyl optionally substituted by one or more group independently selected from o C6-10-aryl optionally further substituted with one or more groups selected from halogen and -OR12, o -NR13R14, whereby at least one of the independently selected R13and R14is C1-6-alkyl and C3-6-cycloalkyl, o C5-9-heterocyclyl optionally further substituted with one or more groups independently selected from C1-4-alkyl and aryl. In still other embodiments, R3is C6-10-aryl, such as phenyl, optionally further substituted with one or more group selected from halogen, -OR12, C3-6-cycloalkyl, C1-4-haloalkyl and C1-4-alkyl. In still other embodiments, R3is C5-9-heteroaryl, such as pyridine, optionally substituted by one or more -OR12, such as alkoxy, e.g. methoxy. In still other embodiments, R3is C1-6-alkyl optionally substituted by one or more group independently selected from halogen, oxo, C6-10-aryl (such as phenyl) optionally further substituted with one or more groups selected from halogen, -OR12, -NR13R14, C3-6- cycloalkyl, C5-9-heterocyclyl optionally further substituted with one or more groups independently selected from C1-4-alkyl, and, C6-10-aryl, and, at least one of the independently selected R13and R14is C1-6-alkyl optionally further substituted by one or more halogen or phenyl, and, C3-6-cycloalkyl. Each R5, R6, R9, R10, R11, R12, R13and R17are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, alkenyl and alkynyl is optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, =O, =S, cycloalkyl, heterocyclyl, aryl and heteroaryl, and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more groups independently selected from halogen, alkyl, -OR15, -SR15, - NR15R16, =O, =S, cycloalkyl, heterocyclyl, aryl and heteroaryl. In some embodiments, R5, R6, R9, R10, R11, R12, R13and R17are independently selected from hydrogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C3-6-heterocyclyl, C6-10-aryl and C5-9-heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more groups independently selected from halogen, C1-4-alkyl, -OR15, -SR15, -NR15R16, =O, =S, C3-6-cycloalkyl, C3-9- heterocyclyl, C6-10-aryl and C5-9-heteroaryl. In some embodiments, R5, R6, R9, R10, R11, R12, R13and R17are independently selected from hydrogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C3-6-heterocyclyl, C6-10-aryl and C5-9-heteroaryl, wherein alkyl, alkenyl and alkynyl is optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, =O, =S, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C5-9-heteroaryl, and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more groups independently selected from halogen, C1-4-alkyl, -OR15, -SR15, - NR15R16, =O, =S, C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C5-9-heteroaryl. In some embodiments, R5is selected from hydrogen and C1-4-alkyl optionally further substituted with one or more groups independently selected from halogen such as fluorine, -OR15, -SR15, -NR15R16, =O and =S. In further embodiments, R5is selected from hydrogen and C1-4-alkyl. In some embodiments, R6is selected from hydrogen, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, wherein alkyl, alkenyl and alkynyl is optionally further substituted with one or more groups independently selected from C3-6-cycloalkyl, C3-9-heterocyclyl, C6-10-aryl and C5-9- heteroaryl. In some embodiments, R9, R10and R11are independently selected from hydrogen and C1-4-alkyl optionally further substituted with one or more groups independently selected from halogen, OR15, -SR15and -NR15R16. In some embodiments, R12, R13and R17are independently selected from hydrogen and C1-4-alkyl optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15and -NR15R16. In some embodiments R7, R8and R14are independently selected from hydrogen, C1-4- alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C3-6-heterocyclyl, C6-10-aryl and C5-9- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, -CN, -SF5, -CO-R12, -CO-OR12, -CO-NR13R17, -SO2-NR13R17and -SO(NR5)-NR13R17, C6-10-aryl, C5-9-heteroaryl, C1-4-alkyl, C1-4-alkenyl, C1-4- alkynyl, C3-6-cycloalkyl and C3-6-heterocyclyl. In further embodiments, R7, R8and R14are independently selected from hydrogen, C1-4- alkyl, C3-6-cycloalkyl, C3-6-heterocyclyl, C6-10-aryl and C5-9-heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, C6-10-aryl, C5-9- heteroaryl, C1-4-alkyl, C3-6-cycloalkyl and C3-6-heterocyclyl. In further embodiments, R7, R8and R14are independently selected from hydrogen, C1-4- alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl, C5-9-heterocyclyl, aryl and heteroaryl, wherein each C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl and C5-9-heterocyclyl are optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, -CN, aryl, heteroaryl, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl and C5-9-heterocyclyl, and, wherein each aryl and heteroaryl is optionally substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, -CN, C1-4-alkyl, C1-4-alkenyl, C1-4-alkynyl, C3-6-cycloalkyl and C5-9-heterocyclyl. In some embodiments, R15and R16are independently selected from hydrogen, C1-4-alkyl, C1-4-haloalkyl, C1-4-alkenyl, C1-4-alkynyl and C3-6-cycloalkyl. In further embodiments, R15and R16are independently selected from hydrogen and C1-4-alkyl. The term " salt(s)" or “salt thereof”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds described herein. The compounds used in the methods of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids, i.e. acid addition salts. The compounds used in the methods of the invention that are acidic in nature are capable of forming a wide variety of salts with various inorganic and organic bases, i.e. base addition salts. The term “pharmaceutically acceptable salt(s)” and terms related thereto as used herein, are those salts that form non-toxic addition salts, i.e., salts containing pharmacologically acceptable acid or base counterions. The pharmaceutically acceptable acid addition salts of compounds of Formula (I) containing a basic group can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of Formula (I) and other formulas and embodiments herein containing an acidic proton may also be converted into their non- toxic base, e.g. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form. The compounds disclosed herein can be prepared while using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified in the examples. The synthetic protocols provided herein are only meant as examples and are by no means to be construed to limit the scope of the embodiments described herein. In some embodiments, the compounds of formula (I) and other formulas and embodiments herein are prepared according to the general procedures outlined in Scheme 1 wherein all R1, R2, R3are as described for the compounds of formula (I) and its embodiments and formulae, PG = protecting group, and LG = leaving group. Scheme 1 NH R3R3PG N N N R3N R 10 N NPG2 removalN N P2G2G L N N HN 12 8 R211 R2N N R Cl 1 PG N R31R P N N N N PG1G N R NH 2 N N removal N N NH LG N N 8 N N NR1Cl R1N R1N R1R2N 13R279 R2PG N NH 4R2-LG16 N PG1N N R1N H 5 Chloropyridazines of general formula 1, commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below, may react with the N- protected 4-amino-piperidines of general formula 2 wherein PG1is a protecting group (e.g. BOC or cBz), via SNAr reaction in presence of an organic or an inorganic base (e.g. DIPEA, DBU, K2CO3, Cs2CO3, K3PO4 and the like) in a suitable solvent (e.g. DMSO, CH3CN, NMP, DMAc and the like) at a temperature raising from 50 to 140°C to provide intermediates of general formula 3. In situ formation of the fluoro intermediate of 1 by addition of fluoride reagents (e.g. CsF, KF, TBAF and the like) may increase the conversion to compounds of general formula 3 as described in Org. Process Res. Dev. 2012, 1416. Alternatively intermediates of general formula 3 may be obtained via a two-step sequence involving SNAr reaction with the N-protected 4-amino-piperidines of general formula 4 using conditions previously described for the SNAr reaction with the 4-amino-piperidines of general formula 2 followed by N-alkylation with alkylating agents of general formula 6 (commercially available or synthesized) wherein LG1is a leaving group such as Cl, Br, I, OTf, OMs and OTos in a polar aprotic solvent (e.g. DMSO, DMF and the like) and in presence of a base (e.g. KOH, NaH and the like). Removal of the N-protecting group may be performed following procedures known to the skilled in the art (e.g treatment in presence of an acid such as HCl or TFA if PG1= BOC, hydrogenolysis if PG1= cBz). More information can be found in T.W. Greene and P.G. M. Wuts in Protective Groups in Organic Chemistry, 3rded., John Wiley and Sons, 1999. Compounds of interest having a general formula 9 may be obtained from intermediates of general formula 7 via a SNAr reaction with pyrimidines of general formula 8, commercially available or synthesized by procedures known to the skilled in the art or as set forth examples below, wherein LG2is a leaving group such as Cl, SO2Me, OTf or OTos and using conditions previously described for the SNAr reaction with pyridazines of general formula 1. Alternatively compounds of interest having a general formula 9 may also be synthesized via a three-step sequence involving SNAR reaction from pyrimidines of general formula 8 with N- protected 4-amino-piperidines of general formula 10 wherein PG2is a protecting group (e.g. BOC or cBz), N-protecting group removal and SNAr reaction with pyridazines of general formula 1. Examples of the compounds or formula (I) are provided in Table 1 and are considered specified embodiments described herein. The numbering of the compounds is adhered to for the description of the examples. Names were generated by ChemBioDraw 22.2.0, thus on the basis of their chemical structure. Table 1

[0002] CodeStructure NameCodeStructure NameN-(1-(5-isobutyl-4,6- N-(3,3-dimethylbutyl)-6- N dimethylpyri ((1-(5-(4-fluorophenyl)-4,6- CPD-Nmidin-2- NN NCPD- dimethylpyrimidin-2- 001 yl)piperidin-4-yl)-N,5- 114 N dimethylpyridazin-3- yl)piperidin-4- amine yl)(methyl)amino) pyridazine-4-carboxamide N-(1-(5-benzyl-4,6- (6-((1-(5-(4-fluorophenyl)- N dimethylpyrimidin- 4,6-dimethylpyrimidin-2- CPD-N2- NN Nyl)piperidi CPD- yl)piperidin-4- 002 n-4-yl)-N,5- 115 dimethylpyridazi yl)(methyl)amino)pyridazin N n-3- amine -4-yl)(pyrrolidin-1- yl)methanone 6-((1-(5-(4-fluorophenyl)- N-ethyl- 4,6-dimethylpyrimidin-2- N N-(1-(5-isobutyl- CPD-NNN N4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4-003 yl)pi 116 yl)(methyl)amino)-N- N peridin-4-yl)-5- methylpyridazin-3-amine (2,2,2- trifluoroethyl)pyridazine-4- carboxamide 6-((1-(5-(4-fluorophenyl)- 5-et 4,6-dimethylpyrimidin-2- N hyl-N-(1-(5-isobutyl- CPD-N004 NN N4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- yl)piperidin-4-yl)-N- 117 yl)(methyl)amino)-N-((5- N methylpyridazin-3-amine methyl-1,2,4-oxadiazol-3- yl)methyl)pyridazine-4- carboxamide N-(1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- N d 4,6-dimethylpyrimidin-2- CPD- imethylpyrimidin-2- N NN Nyl)piperidin-4 CPD- yl)piperidin-4-005 -yl)-5- 118 meth yl)(methyl)amino)-N-(2- MeO N oxy-N- methylpyridazin-3-amine (methylsulfonyl)ethyl)pyrid azine-4-carboxamide N-(1-(4,6-dimethyl-5- 6-((1-(5-(4-fluorophenyl)- ((tetrahydr 4,6-dimethylpyrimidin-2- N o-2H-pyran-4- CPD-Nyl)methyl)pyrimidin-2- CPD- yl)piperidin-4- 006 NN N Oyl)piperidin-4-yl)-N,5- 119 yl)(methyl)amino)-N-((5- N dimethylpyridazin-3- methyl-1,3,4-oxadiazol-2- amine yl)methyl)pyridazine-4- carboxamide (S)-6-((1-(5-(4- N-(1-(5-isobutyl-4,6- fluorophenyl)-4,6- N CPD-Ndimethylpyrimidin-2- dimethylpyrimidin-2- 007 NN Nyl)piperidin-4-yl)-N- CPD- 120 yl)piperidin-4- N methyl-5-propylpyridazin- yl)(methyl)amino)-N-(3- 3-amine hydroxybutyl)pyridazine-4- carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- N 4,6-dim CPD- di ethylpyrimidin-2- N methylpyrimidin-2- N 08N Nyl)pi CPD- yl)piperidin-4- 0 peridin-4- H N 121 N yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(3- O ne-4-carboxamide hydroxypropyl)pyridazine- 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- dimethylpyrimidin 4,6-dimethylpyrimidin-2- N -2- CPD- N yl)piperidin-4- C yl)piperidin-4- N 009 HN NPD- y 122 yl)(methyl)amino)-N-(2-(2- N N l)(methyl)amino)-N- m oxoimidazolidin-1- O ethylpyridazine-4- carboxamide yl)ethyl)pyridazine-4- carboxamide 6-((1-(5-isobutyl-4,6- N-(3,3-difluorocyclobutyl)- N CPD- dimethylpyrimidin-2- 6-((1-(5-(4-fluorophenyl)- N NN Nyl)pi CPD- 4,6-dimethylpyrimidin-2- 010 peridin-4- 123 yl)(methy yl)piperidin-4- HOOC N l)amino)pyridazi ne-4-carboxylic acid yl)(methyl)amino) pyridazine-4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- N dimethylpyrimidin-2- 4,6-dimethylpyrimidin-2- CPD- N N yl)piperidin-4- CPD- yl)piperidin-4- 011N NN N yl)(methyl)amino)-N,N- 124 yl)(methyl)amino)-N- O dimethylpyridazine-4- neopentylpyridazine-4- carboxamide carboxamide (S)-6-((1-(5-(4- N-(1-(5-(3-chlorobenzyl)- fluorophenyl)-4,6- CPD- 4,6-dimethylpyrimidin-2- dimethylpyrimidin-2- yl)piper CPD- yl)piperidin-4- 012 idin-4-yl)-5- 125 methoxy-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine oxoazepan-3- yl)pyridazine-4- carboxamide N-(1-(5- 6-((1-(5-(4-fluorophenyl)- N (cyclopentylmethyl)-4,6- 4,6-dimethylpyrimidin-2- CPD- N dimethylpyrimidin-2- CPD- yl)piperidin-4- 013 NN NN yl)piperidin-4-yl)-5- 126 yl)(methyl)amino)-N-(3- MeO methoxy-N- (methylsulfonyl)propyl)pyri methylpyridazin-3-amine dazine-4-carboxamide N-(1-(5- 6-((1-(5-(4-fluorophenyl)- (cyclo 4,6-dimethylpyrimidin-2- N butylmethyl)-4,6- CPD-Ndimethylpyrimidin-2- yl)piperidin-4- 014 NN NCPD- yl)piperidin-4-yl)-N,5- 127 yl)(methyl)amino)-N-(3-(2- N dimethylpyridazin-3- oxopyrrolidin-1- amine yl)propyl)pyridazine-4- carboxamide 6-((1-(5-(4-fluorophenyl)- N-ethyl-6-((1-(5-isobutyl- 4,6-dimethylpyrimidin-2- N CPD- N 4,6-dimethylpyrimidin-2- yl)piperidin-4- N 015 HN Nyl)piperidin-4- CPD- 12 yl)(methyl)amino)-N-((1- N 8 N yl)(methyl)amino)pyridazi methyl-1H-imidazol-2- O ne-4-carboxamide yl)methyl)pyridazine-4- carboxamide 6-((1-(5-(3-chlorobenzyl)- 6-((1-(5-(4-fluorophenyl)- 4,6-dimethylpyrimidin-2- 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- CPD- yl)piperidin-4- 016 yl)(methyl)amino)-N- 129 yl)(methyl)amino)-N- methylpyridazine-4- (isoxazol-3- carboxamide ylmethyl)pyridazine-4- carboxamide 6-((1-(5- (cyclopentylmethyl)-4,6- 6-((1-(5-(4-fluorophenyl)- N dimethylpyrimidin 4,6-dimethylpyrimidin-2- CPD- N -2- NN Nyl)pipe CPD- yl)piperidin-4- 017 H ridin-4- N 130 N yl)(methyl)amino)-N- yl)(methyl)amino)-N-(3- O methylpyridazine-4- methoxypropyl)pyridazine- carboxamide 4-carboxamide N-benzyl-6-((1-(5- 6-((1-(5-(4-fluorophenyl)- isobutyl-4,6- 4,6-dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- CPD- yl)piperidin-4- 018 yl)piperidin-4- 131 yl)(methyl)amino)-N- yl)(methyl)amino)pyridazi (pyrimidin-2- ne-4-carboxamide ylmethyl)pyridazine-4- carboxamide N-(2-(3,3- N-(cyclopropylmethyl)-6- difluoropyrrolidin-1- ((1-(5-isobutyl-4,6- yl)ethyl)-6-((1-(5-(3- CPD- dimethylpyrimidin-2- CPD- methoxyphenyl)-4,6- 019 yl)piperidin-4-132dimethylpyrimidin-2- yl)(methyl)amino)pyridazi yl)piperidin-4-yl) ne-4-carboxamide (methyl)amino)pyridazine- 4-carboxamide 6-((1-(5-isobutyl-4,6- N-(2-(1H-imidazol-5- dimethylpyrimidin-2- yl)ethyl)-6-((1-(5-(4- CPD- yl)piperidin-4- CPD- fluorophenyl)-4,6- 020 yl)(methyl)amino)-N-(2- 133 dimethylpyrimidin-2- methoxyethyl)pyridazine- yl)piperidin-4-yl) 4-carboxamide (methyl)amino)pyridazine- 4-carboxamide (4,6-dimethyl-2-(4- N-cyclopentyl-6-((1-(5-(4- NOHfl CPD-N(methyl(5- uorophenyl)-4,6- NN Nmethylpyridazin-3 CPD- dimethylpyrimidin-2- 021 - 134 N yl)amino)piperidin-1- yl)piperidin-4-yl) yl)pyrimidin-5-yl)methanol (methyl)amino)pyridazine- 4-carboxamide N-(1-(4,6-dimethyl-5- 6-((1-(5-(4-fluorophenyl)- (pipe 4,6-dimethylpyrimidin-2- NNridin-1- CPD-Nylmethyl)pyrimidin-2- yl)piperidin-4- 022 NN NCPD- yl)piperidin-4-yl)-N,5- 135 yl)(methyl)amino)-N-(2- N dimethylpyridazin-3- oxopiperidin-3- amine yl)pyridazine-4- carboxamide 6-((1-(5-(4-fluorophenyl)- N-(1-(5-(2-fluorophenyl)- 4,6-dimethylpyrimidin-2- CPD- N 4,6-dimethylpyrimidin-2- yl)piperidin-4- NFyl)piperidin-4-yl)-N,5 CPD- 023 NN N- 136 yl)(methyl)amino)-N-((1- N dimethylpyridazin-3- methyl-5-oxopyrrolidin-2- amine yl)methyl)pyridazine-4- carboxamide 6-((1-(5-(4-fluorophenyl)- N-(1-(5-(3-fluorophenyl)- 4,6-dimethylpyrimidin-2- CPD- N F 4,6-dimethylpyrimidin-2- yl)piperidin-4- N 024 NN Nyl)piperidin-4-yl)-N,5- CPD- 137 yl)(methyl)amino)-N-(5- N dimethylpyridazin-3- oxopyrrolidin-3- amine yl)pyridazine-4- carboxamide OH 1-(4,6-dimethyl-2-(4- 6-((1-(4,6-dimethyl-5-(o- N (methyl(5- tolyl)pyrimidin-2- CPD- N methylpyridazin-3- CPD- yl)piperidin-4- 025 NN Nyl)amino)piperidin-1- 138 yl)(methyl)amino)-N-(2- N yl)pyrimidin-5-yl)-2- methoxyethyl)pyridazine- methylpropan-1-ol 4-carboxamide 1-(4,6-d 6-((1-(5-(4-fluorophenyl)- O imethyl-2-(4- ( 4,6-dimethylpyrimidin-2- N methyl(5- CPD- yl)piperid N methylpyridazin-3- CPD- in-4- 026 NN Nyl)amino)piperidin-1- 139 yl)(methyl)amino)-N-(2- N yl)pyrimidin-5-yl)-2- (tetrahydro-2H-pyran-4- methylpropan-1-one yl)ethyl)pyridazine-4- carboxamide 5-(benzyloxy)-N-(1-(5- 6-((1-(5-(2-chlorophenyl)- CPD- isobutyl-4,6- 4,6-dimethylpyrimidin-2- dimeth CPD- yl)piperidin-4- 027 ylpyrimidin-2- 140 yl)piperidin-4-yl)-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine methoxyethyl)pyridazine- 4-carboxamide F N-(1-(5-(4-fluorophenyl)- 6-((1-(4,6-dimethyl-5-(m- 4,6-dimethylpyrimidin-2- tolyl)pyrimidin-2- CPD- N N yl)piperidin-4 CPD- yl)piperidin-4- 028 NN N-yl)-N,5- 141 dimethylpyridazin- yl)(methyl)amino)-N-(2- N 3- amine methoxyethyl)pyridazine- 4-carboxamide N-(1-(5-(3- 6-((1-(5-(3- methoxyphenyl)-4,6- cyclopropylphenyl)-4,6- CPD- NOMeN dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 029 NN Nyl)piperidin-4-yl)-N,5- 142 yl)piperidin-4- N dimethylpyridazin-3- yl)(methyl)amino)-N-(2- amine methoxyethyl)pyridazine- 4-carboxamide N-(1-(4,6-dimethyl-5- 6-((1-(4,6-dimethyl-5-(3- phenylp (trifluoromethoxy)phenyl)p CPD- N yrimidin-2- N yl)piperidin CPD- yrimidin-2-yl)piperidin-4- 030 NN N-4-yl)-N,5- dimethylpyridazi143yl)(methyl)amino)-N-(2- N n-3- amine methoxyethyl)pyridazine- 4-carboxamide N-(2- (dimethylamino)ethyl)-6- 6-((1-(4,6-dimethyl-5-(p- tolyl)pyrimidin-2- CPD- ((1-(5-isobutyl-4,6- dimethylpyrimidi CPD- yl)piperidin-4- 031 n-2- 144 yl)piperidin-4- yl)(methyl)amino)-N-(2- yl)(methyl)amino)pyridazi methoxyethyl)pyridazine- ne-4-carboxamide 4-carboxamide 6-((1-(5-(3,5- N N-(1-(5-isobutyl-4,6- difluorophenyl)-4,6- N CPD- NN Ndimethylpyrimidin-2- dimethylpyrimidin-2- yl)piperidin-4-yl)-N-(3 CPD- 032 N - 145 yl)piperidin-4- methoxypropyl)-5- yl)(methyl)amino)-N-(2- OMe methylpyridazin-3-amine methoxyethyl)pyridazine- 4-carboxamide N-(1-(5-(2- 6-((1-(5-(4-fluorophenyl)- methoxyphenyl)-4,6- 4,6-dimethylpyrimidin-2- CPD- N dimethylpyrimidin-2- yl)piperid 033NCPD- in-4- NN N OMeyl)piperidin-4-yl)-N,5- 146 yl)(methyl)amino)-N-(2- N dimethylpyridazin-3- methoxypropyl)pyridazine- amine 4-carboxamide N-(1- 6-((1-(5-(4-fluorophenyl)- OMe (5-(4- methoxyphenyl)-4,6- 4,6-dimethylpyrimidin-2- CPD- N N dimethylpyrimidin-2- CPD- yl)piperidin-4- 034 NN Nyl)piperidin-4-yl)-N,5- 147 yl)(methyl)amino)-N- N dimethylpyridazin-3- (pyrazin-2- amine ylmethyl)pyridazine-4- carboxamide 6-((1-(5-(3-(2- N-(1-(5-(cyclohex-1-en-1- hydroxyethyl)phenyl)-4,6- CPD- N yl)-4,6-dimethylpyrimidin- C dimethylpyrimidin-2- N 2-yl)p PD- 035 NN Niperidin-4-yl)-N,5- yl)piperidin-4- N dimethylpyridazin-3-148yl)(methyl)amino)-N-(2- amine methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(3-cyanophenyl)- N 5-ethoxy-N-(1-(5-isobutyl- 4,6-dimethylpyrimidin-2- CPD- N 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- 036 NN Nyl)piperidin-4- 149 EtO N yl)-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine methoxyethyl)pyridazine- 4-carboxamide 5-(cyclopropylmethoxy)- N-(2-methoxyethyl)-6-((1- N (5-(3-methoxyphen CPD- N-(1-(5-isobutyl-4,6- yl)-4,6- N NN Ndimethylpyrimidin CPD- dimethylpyrimidin-2- 037 -2- yl)piperidin150yl)piperidin-4-yl) O N -4-yl)-N- methylpyridazin-3-amine (methyl)amino)pyridazine- 4-carboxamide N-(2-hydroxyethyl)-6-((1- 6-((1-(5-(3- (5-isobutyl-4,6- (ethylsulfonyl)phenyl)-4,6- CPD- dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 038 yl)piperidin-4-151yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(2-fluoro-6- N 2-((1-(5-isobutyl-4,6- methoxyphenyl)-4,6- N CPD- NN Ndimethylpyrimidin-2- dimethylpyrimidin-2- 039 N yl)piperidin-4-yl)(5- CPD- 152 yl)piperidin-4- methylpyridazin-3- yl)(methyl)amino)-N-(2- OH yl)amino)ethan-1-ol methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(5-fluoro-2- methyl 6-((1-(5-isobutyl- methoxyphenyl)-4,6- N CPD- N 4,6-dimethylpyrimidin-2- dimethylpyrimidin-2- NN Ny CPD- 040 l)piperidin-4- yl)piperidin-4- MeO 153 N yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- O ne-4-carboxylate methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(3,5- 2-((6-((1-(5-isobutyl-4,6- dimethoxyphenyl)-4,6- CPD- dimethylpyrimidin-2- dimethylpyrimidin-2- yl)piperidin-4-y CPD- 041 l) 154 yl)piperidin-4- (methyl)amino)pyridazin- yl)(methyl)amino)-N-(2- 4-yl)oxy)ethan-1-ol methoxyethyl)pyridazine- 4-carboxamide 3-((6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- 4,6-dim CPD- dimethylpyrimidin-2- ethylpyrimidin-2- y CPD- yl)piperidin-4- 042 l)piperidin-4-yl) 155 (methyl)amino)pyridazin- yl)(methyl)amino)-N-(2- 4-yl)oxy)propan-1-ol hydroxypropyl)pyridazine- 4-carboxamide 6-((1-(5-(4-fluoro-3- 5-(3-(benzyloxy)propoxy)- methoxyphenyl)-4,6- CPD- N-(1-(5-isobutyl-4,6- dimethylpyrimidin-2- 043 dimethylpyrimidin-2- CPD- 156 yl)piperidin-4- yl)piperidin-4-yl)-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(4-fluorophenyl)- N-(1-(4,6-dimethyl-5- 4,6-dimethylpyrimidin-2- CPD- N phenylpyrimidin-2- yl)piperidin-4- N yl)piperidi CPD- 044 NN Nn-4-yl)-5- 157 yl)(methyl)amino)-N-((6- MeO N methoxy-N- oxo-1,6-dihydropyridin-3- methylpyridazin-3-amine yl)methyl)pyridazine-4- carboxamide N-(1-(5- 6-((1-(5-(3-chlorophenyl)- NN((benzylamino)methyl)- 4,6-dimethylpyrimidin-2- CPD-NH 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- 045 NN Nyl)pipe 158 N ridin-4-yl)-N,5- yl)(methyl)amino)-N-(2- dimethylpyridazin-3- methoxyethyl)pyridazine- amine 4-carboxamide N-(1-(5- 6-((1-(5-(3-chloro-5- ((benzyl(methyl)amino)m methoxyphenyl)-4,6- NNCPD-Nethyl)-4,6- CPD- dimethylpyrimidin-2- 046 NN Ndimethylpyrimidin-2- 159 yl)piperidin-4- N yl)piperidin-4-yl)-N,5- yl)(methyl)amino)-N-(2- dimethylpyridazin-3- methoxyethyl)pyridazine- amine 4-carboxamide 6-((1-(4,6-dimethyl-5- N-(2-methoxyethyl)-6-((1- phenylpyrimidin-2- (5-(2-methoxypyridin-4-yl)- CPD- yl)piperidin-4- CPD- 4,6-dimethylpyrimidin-2- 047 yl)(methyl)amino)-N-(2-160yl)piperidin-4- (dimethylamino)ethyl)pyri yl)(methyl)amino)pyridazin dazine-4-carboxamide e-4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- dimethylpyrimidin-2- 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- CPD- yl)piperidin-4- 048 yl)(methyl)amino)-N-(1- 161 yl)(methyl)amino)-N-(3- methylpiperidin-4- hydroxy-2,2- yl)pyridazine-4- dimethylpropyl)pyridazine- carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- dimethylpyrimidin-2- 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- CPD- yl)piperidin-4- 049 yl)(methyl)amino)-N- 162 yl)(methyl)amino)-N-((1- ((tetrahydrofuran-3- hydroxycyclopropyl)methyl yl)methyl)pyridazine-4- )pyridazine-4-carboxamide carboxamide N-(2- (R)-6-((1-(5-(4- (dimethylamino)ethyl)-6- fluorophenyl)-4,6- CPD- ((1-(5-(4-fluorophenyl)- dimethylpyrimidi 050 ethylpyrimidin-2- C n-2- 4,6-dim PD- 163 yl)piperidin-4- yl)piperidin-4- yl)(methyl)amino)-N-(2- yl)(methyl)amino)pyridazi hydroxypropyl)pyridazine- ne-4-carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(4,6-dimethyl-5-(2- dimethylpyrimidin-2- (trifluoromethyl)phenyl)pyri CPD- yl)piperidin-4- CPD- midin-2-yl)piperidin-4- 051 yl)(methyl)amino)-N-(2- 164 yl)(methyl)amino)-N-(2- morpholinoethyl) methoxyethyl)pyridazine- pyridazine-4-carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(3-fluoro-5- dimethylpyrimidin-2- methoxyphenyl)-4,6- CPD- yl)piperidin-4- C dimethylpyrimidin-2- yl)(met PD- 052 hyl)amino)-N-(2- 165 yl)piperidin-4- (pyrrolidin-1- yl)(methyl)amino)-N-(2- yl)ethyl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide N-(2- (dimethylamino)ethyl)-6- N-(2-methoxyethyl)-6-((1- ((1-(5 (5-(5-methoxypyridin-3-yl)- CPD- -(3-methoxyphenyl)- 53 4,6-di CPD- 4,6-dimethylpyrimidin-2- 0 methylpyrimidin-2- 166 yl)piperidin-4- yl)piperidin-4-yl) yl)(methyl)amino)pyridazi (methyl)amino)pyridazine- ne-4-carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- dimethylpyrimidin-2- 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- yl)piperidin-4- yl)(methyl)amino)-N-(( CPD- 054 1- 167 yl)(methyl)amino)-N-(2- methylpyrrolidin-2- hydroxy-2- yl)methyl)pyridazine-4- methylpropyl)pyridazine-4- carboxamide carboxamide 5-(2- 6-((1-(4,6-dimethyl-5-(3- (dimethylamino)ethoxy)- (trifluoromethyl)phenyl)pyri CPD- N-(1-(5-isobutyl-4,6- CPD- midin-2-yl)piperidin-4- 055 dimethylpyrimidin-2- 168 yl)(methyl)amino)-N-(2- yl)piperidin-4-yl)-N- methoxyethyl)pyridazine- methylpyridazin-3-amine 4-carboxamide 5-(3- (S)-6-((1-(5-(4- (dimethylamino)propoxy)- fluorophenyl)-4,6- CPD- N-(1-(5-isobutyl-4,6- CPD- dimethylpyrimidin-2- 056 dimethylpyrimidin-2- 169 yl)piperidin-4- yl)piperidin-4-yl)-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine hydroxypropyl)pyridazine- 4-carboxamide N-(2-aminoethyl)-6-((1-(5- (R)-6-((1-(5-(4- isobutyl-4,6- fluorophenyl)-4,6- CPD- dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 057 yl)piperidin-4-yl) 170 yl)piperidin-4- (methyl)amino) yl)(methyl)amino)-N-(2- pyridazine-4-carboxamide methoxypropyl)pyridazine- 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(4-fluorophenyl)- dimethylpyrimidin-2- 4,6-dimethylpyrimidin-2- CPD- yl)piperidin-4- yl)piperidin-4- 058 yl)(methyl)amino)-N-(1- CPD- 171 yl)(methyl)amino)-N-((1- methylpyrrolidin-3- methoxycyclopropyl) yl)pyridazine-4- methyl)pyridazine-4- carboxamide carboxamide 6-((1-(5-isobutyl-4,6- dimethylpyrimidin-2- 6-((1-(5-(4-fluorophenyl)- 4,6-dime CPD- yl)piperidin-4- thylpyrimidin-2- yl) CPD- yl)piperidin-4- 059 (methyl)amino)-N- 172 (tetrahydrofuran-3- yl)(methyl)amino)-N-(2- yl)pyridazine-4- hydroxyethyl)pyridazine-4- carboxamide carboxamide N-(1-(5-isobutyl-4,6- (S)-6-((1-(5-(4- dimethylpyrimidin-2- fluorophenyl)-4,6- CPD- yl)piperidin-4-yl)-N- CPD- dimethylpyrimidin-2- 060 methyl-5-(3- 173 yl)piperidin-4- (methylamino)propoxy)py yl)(methyl)amino)-N-(2- ridazin-3-amine methoxypropyl)pyridazine- 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(4,6-dimethyl-5-(3- dimethylpyrimidin-2- (trifluoromethoxy)phenyl) CPD- yl)piperidin-4- pyrimidin-2-yl)piperidin-4- 061 yl)(methyl)amino)-N- CPD- 174 yl)(methyl)amino)-N-((1- ((tetrahydrofuran-2- hydroxycyclopropyl) yl)methyl)pyridazine-4- methyl)pyridazine-4- carboxamide carboxamide 6-((1-(5-isobutyl-4,6- cis-6-((1-(5-(4- dimethylpyrimidin-2- fluorophenyl)-4,6- CPD- yl)piperidin-4- dimethylpyrimidi 062 hyl)amino)-N- C n-2- yl)(met PD- 175 yl)piperidin-4- (pyridin-2- yl)(methyl)amino)-N-(3- ylmethyl)pyridazine-4- methoxycyclobutyl) carboxamide pyridazine-4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(3- dimethylpyrimidin-2- (difluoromethoxy)phenyl)- CPD- yl)piperidin-4- CPD 4,6-dimethylpyrimidin-2- yl)(methyl)amino)-N - 063 - yl)piperidin-4- (pyridin-3-176yl)(methyl)amino)-N-(2- ylmethyl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- dimethylpyrimidin-2- N-(3-fluorocyclobutyl)-6- yl)piperi ((1-(5-(4-fluorophenyl)-4,6- CPD- din-4- yl)( CPD- dimethylpyrimidin-2- 064 methyl)amino)-N-((1- 177 methylpiperidin-4- yl)piperidin-4- yl)methyl)pyridazine-4- yl)(methyl)amino) carboxamide pyridazine-4-carboxamide 6-((1-(5-isobutyl-4,6- trans-6-((1-(5-(4- dimethylpyrimidin-2- fluorophenyl)-4,6- CPD- yl)piperidin-4- dimethylpyrimidin-2- yl)(methyl)ami CPD- 065 no)-N- 178 yl)piperidin-4- ((tetrahydro-2H-pyran-4- yl)(methyl)amino)-N-(3- yl)methyl)pyridazine-4- hydroxycyclobutyl)pyridazi carboxamide ne-4-carboxamide 6-((1-(5-isobutyl-4,6- trans-6-((1-(5-(4- dimethylpyrimidin-2- fluorophenyl)-4,6- CPD- yl)piperidin-4- dimethylpyrimidin-2-yl) 066 yl)(methyl)amino)-N-((1- CPD- 179 piperidin-4-yl) methyl-1H-pyrazol-3- (methyl)amino)-N-(3- yl)methyl)pyridazine-4- methoxycyclobutyl) carboxamide pyridazine-4-carboxamide N-(1-(5-isobutyl-4,6- 6-((1-(4,6-dimethyl-5-(3- CPD- dimethylpyrimidin-2- (trifluoromethoxy)phenyl)p yl)piperidin-4- CPD- yrimidin-2-yl)piperidin-4- 067 yl)-5-(2- 180 methoxyethoxy)-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine hydroxypropyl)pyridazine- 4-carboxamide 5-(3-aminopropoxy)-N-(1- N-(3,3-difluorocyclobutyl)- 6-((1-(4,6-dimethyl-5-(3- CPD- (5-isobutyl-4,6- dimethyl CPD- (trifluoromethoxy)phenyl) 068 pyrimidin-2- 181 yl)piperidin-4-yl)-N- pyrimidin-2-yl)piperidin-4- methylpyridazin-3-amine yl)(methyl)amino) pyridazine-4-carboxamide N-(1,3-dihydroxypropan- 6-((1-(4,6-dimethyl-5-(3- 2-yl)-6-((1-(5-isobutyl-4,6- (trifluoromethoxy)phenyl)p CPD- dimethylpyrimidin-2- CPD- yrimidin-2-yl)piperidin-4- 069 yl)piperidin-4- 182 yl)(methyl)amino)-N- yl)(methyl)amino)pyridazi (isoxazol-3- ne-4-carboxamide ylmethyl)pyridazine-4- carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(3- dimethylpyrimidin-2- cyclopropylphenyl)-4,6- yl)piperid dimethylpyrimidin-2- CPD- in-4- yl)(methyl CPD- yl)piperidin-4- 070 )amino)-N- 183 (pyridin-4- yl)(methyl)amino)-N- ylmethyl)pyridazine-4- (isoxazol-3- carboxamide ylmethyl)pyridazine-4- carboxamide 6-((1-(5-(3- N-(1-(5-isobutyl-4,6- cyclopropylphenyl)-4,6- CPD- dimethylpyrimidin-2- dimethylpyrimidin-2- yl CPD- 071 )piperidin-4-yl)-5-(3- 184 yl)piperidin-4- methoxypropoxy)-N- yl)(methyl)amino)-N-(2- methylpyridazin-3-amine hydroxypropyl)pyridazine- 4-carboxamide 2-((6-((1-(5-(3- cis-6-((1-(5-(4- methoxyphenyl)-4,6- fluorophenyl)-4,6- CPD- dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 072 yl)piperidin-4-yl) 185 yl)piperidin-4- (methyl)amino)pyridazin- yl)(methyl)amino)-N-(3- 4-yl)oxy)ethan-1-ol hydroxycyclobutyl)pyridazi ne-4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5-(3- dimethylpyrimidin-2- cyclopropylphenyl)-4,6- CPD- yl)piperidin-4- CPD- dimethylpyrimidin-2- 073 yl)(methyl)amino)-N-(2- 186 yl)piperidin-4- (methylamino)ethyl)pyrida yl)(methyl)amino)-N-(3,3- zine-4-carboxamide difluorocyclobutyl)pyridazi ne-4-carboxamide N-((1-ethyl-1H-pyrazol-4- yl)methyl)-6-((1-(5- N Br 6-((1-(5-bromo-4,6- dimethylpyrimidin- CPD- isobutyl-4,6- N 2- dimethylpyrim CPD- H NN NN yl)piperidin-4- 074 idin-2- 187 MeO N yl)piperidin-4- O yl)(methyl)amino)-N-(2- yl)(methyl)amino)pyridazi methoxyethyl)pyridazine- ne-4-carboxamide 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 4,6-dimethylpyrimidin-2- 6-((1-(5-(4-fluorophenyl)- CPD- yl)piperidin-4- 4,6-dimethylpyrimidin-2- yl)(methyl)amino CPD- yl)piperidin-4- 075 )-N-(2- 188 (pyrrolidin-1- yl)(methyl)amino)-N-(2- yl)ethyl)pyridazine-4- (trifluoromethoxy)ethyl)pyri carboxamide dazine-4-carboxamide 6-((1-(5-(3- 6-((1-(5-(3- methoxyphenyl)-4,6- (hydroxymethyl)-5- dimethylpyrimidin-2- methylphenyl)-4,6- CPD- yl)piperidin-4- CPD- dimethylpyrimidin-2- 076 yl)(methyl)amino)-N-(2- 189 yl)piperidin-4- (pyrrolidin-1- yl)(methyl)amino)-N-(2- yl)ethyl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide N-(3- 6-((1-(5-(2- (dimethylamino)propyl)-6- (hydroxymethyl)-5- methylphe CPD- ((1-(5-isobutyl-4,6- nyl)-4,6- dimethylpyrim CPD- dimethylpyrimidin-2- 077 idin-2- 190 yl)piperidin-4- yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide N-(3-hydroxy-2- 6-((1-(5-(3-(2- (hydroxymethyl)-2- hydroxyethyl)-5- methylpropyl)-6-((1-(5- methylphenyl)-4,6- CPD- isobutyl-4,6- CPD- dimethylpyrimidin-2- 078 dimethylpyrimidin-2- 191 yl)piperidin-4- yl)piperidin-4- yl)(methyl)amino)-N-(2- yl)(methyl)amino)pyridazi methoxyethyl)pyridazine- ne-4-carboxamide 4-carboxamide 6-((1-(5-(3-(2- 2-((6-((1-(5-isobutyl-4,6- hydroxypropan-2-yl)-5- CPD- dimethylpyrimidin-2- methylphenyl)-4,6- yl)piperidin-4 CPD- dimethylpyrimidin-2- 079 -yl) 192 (methyl)amino)pyridazin- yl)piperidin-4- 4-yl)amino)ethan-1-ol yl)(methyl)amino)-N-(2- methoxyethyl)pyridazine- 4-carboxamide 2-((6-((1-(5-isobutyl-4,6- N-(2-methoxyethyl)-6-((1- dimethylpyrimidin-2- (5-(3-(2-methoxyethyl)-5- CPD- yl)piperidin-4- CPD- methylphenyl)-4,6- 080 yl)(methyl)amino) 193 dimethylpyrimidin-2-yl) pyridazin-4-yl) piperidin-4-yl) (methyl)amino)ethan-1-ol (methyl)amino)pyridazine- 4-carboxamide 2-((6-((1-(5-(4- N-(2-methoxyethyl)-6-((1- fluorophenyl)-4,6- (5-(2-(methoxymethyl)-5- CPD- dimethylpyrimidin-2- CPD- methylphenyl)-4,6- 081 yl)piperidin-4-yl) 194 dimethylpyrimidin-2- (methyl)amino)pyridazin- yl)piperidin-4-yl) 4-yl)oxy)ethan-1-ol (methyl)amino)pyridazine- 4-carboxamide N-(1-(5-(2,2- N-(2-methoxyethyl)-6-((1- F difluor (5-(3-(2-methoxypropan-2- N oethyl)-4,6- CPD- N F dimethylpyrimidi yl)-5-methylphenyl)-4,6- 082 NN Nn-2- CPD- yl)piperidin-4-yl)-N,5- 195 dimethylpyrimidin-2- N dimethylpyridazin-3- yl)piperidin-4-yl) amine (methyl)amino)pyridazine- 4-carboxamide 6-((1-(5-((3,3- N-(1-(4,6-dimethyl-5- dimethylpyrrolidin-1-yl) F N F (2,2,2- methyl)-4,6- CPD- N F N trifluoroethyl)pyrimidin-2- CPD- dimethylpyrimidin-2-yl) 083N Nyl)piperidin-4-yl)-N,5-196piperidin-4-yl) N dimethylpyridazin-3- (methyl)amino)-N-(2- amine methoxyethyl)pyridazine- 4-carboxamide N-(1-(5-(4-fluorophenyl)- N-(2-methoxyethyl)-6-((1- 4,6-dimethylpyrimidin-2- (5-(3-(methoxymethyl)-5- CPD- yl)piperidin-4-yl)-N- CPD- methylphenyl)-4,6- 084 methyl-5-(3- 197 dimethylpyrimidin-2-yl) (methylamino)propoxy)py piperidin-4-yl) ridazin-3-amine (methyl)amino)pyridazine- 4-carboxamide N-(1-(5-(3- N-(2-methoxyethyl)-6-((1- methoxyphenyl)-4,6- (5-(2-(2-methoxyethyl)-5- CPD- dimethylpyrimidin-2- methylphenyl)-4,6- 085 yl)piperidin-4-yl)-N- CPD- 198 dimethylpyrimidin-2-yl) methyl-5-(3- piperidin-4-yl) (methylamino)propoxy)py (methyl)amino)pyridazine- ridazin-3-amine 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(5- dimethylpyrimidin-2- ((benzyl(methyl)amino)me thyl)-4,6 CPD- yl)piperidin-4- - yl)(methyl)amino) CPD- dimethylpyrimidin-2- 086 -N-(2- (4-methoxypiperidin-1-199yl)piperidin-4- yl)ethyl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide N-(2-(4-hydroxypiperidin- 6-((1-(4,6-dimethyl-5- 1-yl)ethyl)-6-((1-(5- (piperidin-1- CPD- isobutyl-4,6- CP ylmethyl)pyrimidin-2- dimethylpyrimidin- D- 087 2-2yl)piperidin-4- yl)piperidin-4-yl)00yl)(methyl)amino)-N-(2- (methyl)amino)pyridazine methoxyethyl)pyridazine- -4-carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- 6-((1-(4,6-dimethyl-5- dimethylpyrimidin-2- ((methyl(neopentyl)amino) CPD- yl)piperidin-4- methyl)pyrimidin-2- 088 yl)(methyl)amino)-N-(2- CPD- 201yl)piperidin-4- (3-methoxypyrrolidin-1- yl)(methyl)amino)-N-(2- yl)ethyl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide N-(2-(3-fluoropyrrolidin-1- 6-((1-(4,6-dimethyl-5-(3- yl)ethyl)-6-((1-(5-isobutyl- (trifluoromethoxy)phenyl) CPD- 4,6-dimethylpyrimidin-2- CPD- pyrimidin-2-yl)piperidin-4- 089 yl)piperidin-4- 202 yl)(methyl)amino)-N-(2- yl)(methyl)amino)pyridazi hydroxybutyl)pyridazine-4- ne-4-carboxamide carboxamide N-(2-(3-hydroxypyrrolidin- 1-yl)ethyl)-6-((1-(5- N-(2-methoxyethyl)-6-((1- CPD- isobutyl-4,6- (5-(6-methoxypyridin-2-yl)- dimethylpyr CPD- 4,6-dimethylpyrimidin-2- 090 imidin-2- yl)piperidin-4-203yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)pyridazin ne-4-carboxamide e-4-carboxamide N-(2-(1,1- 6-((1-(5-(2-(2- dioxidothiomorpholino)eth hydroxyethyl)-5- methylphen CPD- yl)-6-((1-(5-isobutyl-4,6- yl)-4,6- dimethylpyrimidin-2 CPD- dimethylpyrimidin-2- 091 - 204 yl)piperidin-4- yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5- N-(2-(3-fluoropiperidin-1- ((benzyl(methyl)amino)me yl)ethyl)-6-((1-(5-isobutyl- thyl)-4,6- CPD- 4,6-dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 092 yl)piperidin-4-205yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide hydroxy-2- methylpropyl)pyridazine-4- carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(5- 4,6-dimethylpyrimidin-2- (((cyclopentylmethyl)(meth CPD- yl)piperidin-4- yl)amino)methyl)-4,6- yl)( CPD- 093 methyl)amino)-N-2dimethylpyrimidin-2- ((tetrahydro-2H-pyran-4-06yl)piperidin-4- yl)methyl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(3- methoxyphenyl)-4,6- 6-((1-(4,6-dimethyl-5- dimethylpyrimidin-2- ((methyl(2,2,2- CPD- yl)piperidin-4- CPD- trifluoroethyl)amino)methyl 094 yl)(methyl)amino)-N-207)pyrimidin-2-yl)piperidin-4- ((tetrahydro-2H-pyran-4- yl)(methyl)amino)-N-(2- yl)methyl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(5- 4,6-dimethylpyrimidin-2- (((cyclopropylmethyl)(meth CPD- yl)piperidin-4- yl)amino)methyl)-4,6- yl)(methyl)am CPD- dimethylpyrimidin-2- 095 ino)-N-((1- methyl-1H-pyrazol-3-208yl)piperidin-4- yl)methyl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(3- methoxyphenyl)-4,6- 6-((1-(4,6-dimethyl-5- dimethylpyrimidin-2- ((methyl(propyl)amino)met CPD- yl)piperidin-4- CPD- hyl)pyrimidin-2- 096 yl)(methyl)amino)-N-((1-209yl)piperidin-4- methyl-1H-pyrazol-3- yl)(methyl)amino)-N-(2- yl)methyl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide 6-((1-(5-isobutyl-4,6- N-(2-methoxyethyl)-6-((1- dimethylpyrimidin-2- (5-(((2-methoxyethyl) CPD- yl)piperidin-4- (methyl)amino)methyl)- yl)(methyl)amino)-N-(2- CPD- 097 l-3-oxopiperazin-24,6-dimethylpyrimidin-2- (4-methy10yl)piperidin-4-yl) 1-yl)ethyl)pyridazine-4- (methyl)amino)pyridazine- carboxamide 4-carboxamide 6-((1-(5- 6-((1-(5-(4-fluorophenyl)- ((cyclopropyl(methyl)amin 4,6-dimethylpyrimidin-2- o)methyl)-4,6- CPD- yl)piperidin-4- CPD- dimethylpyrimidin-2- 098 yl)(methyl)amino)-N-(2-211yl)piperidin-4- methoxyethyl)pyridazine- yl)(methyl)amino)-N-(2- 4-carboxamide methoxyethyl)pyridazine- 4-carboxamide (6-((1-(5-(4-fluorophenyl)- 6-((1-(4,6-dimethyl-5-((2- 4,6-dimethylpyrimidin-2- phenylpyrrolidin-1- CPD- yl)piperidin-4- yl)methyl)pyrimidin-2- 099 yl)(methyl)amino) CPD- 212 yl)piperidin-4- pyridazin-4-yl)(3- yl)(methyl)amino)-N-(2- methoxypyrrolidin-1- methoxyethyl)pyridazine- yl)methanone 4-carboxamide 6-((1-(4,6-dimethyl-5- 6-((1-(5-(4-fluorophenyl)- ((methyl(tetrahydro-2H- 4,6-dimethylpyrimidin-2- pyran-3- CPD- yl)piperidin-4- CPD- yl)amino)methyl)pyrimidin- 100 yl)(methyl)amino)-N-(2-2132-yl)piperidin-4- isopropoxyethyl) yl)(methyl)amino)-N-(2- pyridazine-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide N-(2-(3,3- 6-((1-(4,6-dimethyl-5- difluoropyrrolidin-1- ((methyl(phenethyl)amino) CPD- yl)ethyl)-6-((1-(5-isobutyl- methyl)pyrimidin-2- 4,6-dimethy CPD- 101 lpyrimidin-2- piperidin-4-2yl)piperidin-4- yl)14yl)(methyl)amino)-N-(2- yl)(methyl)amino)pyridazi methoxyethyl)pyridazine- ne-4-carboxamide 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(4,6-dimethyl-5-((3- 4,6-dimethylpyrimidin-2- phenylpyrrolidin-1- CPD- yl)piperidin-4- CPD- yl)methyl)pyrimidin-2- 102 yl)(methyl)amino)-N-(2-215yl)piperidin-4- sulfamoylethyl)pyridazine yl)(methyl)amino)-N-(2- -4-carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(5-((3,3- 4,6-dimethylpyrimidin-2- dimethylpiperidin-1- CPD- yl)piperidin-4- yl)methyl)-4,6- yl)(methyl)amin CPD- dimethylpyrimidin-2- 103 o)-N-(1- methoxy-2-methylpropan-216yl)piperidin-4- 2-yl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-((7- N-(2-(1,4-oxazepan-4- azaspiro[3.5]nonan-7- yl)ethyl)-6-((1-(5-isobutyl- yl)methyl)-4,6- CPD- 4,6-dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 104 yl)piperidin-4-217yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5- N-(2-(4-acetylpiperazin-1- ((cyclohexyl(methyl) yl)ethyl)-6-((1-(5-isobutyl- amino)methyl)-4,6- CPD- 4,6-dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 105 yl)piperidin-4- 218 yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(((2- 6-((1-(5-isobutyl-4,6- (dimethylamino)-1- dimethylpyrimidin-2- phenylethyl)(methyl) CPD- yl)piperidin-4- amino)methyl)-4,6- 106 yl)(methyl)amino)-N-(2- CPD- 219dimethylpyrimidin-2- (3-oxopiperazin-1- yl)piperidin-4- yl)ethyl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5- N-(2-(4-fluoropiperidin-1- (((cyclohexylmethyl)(meth yl)ethyl)-6-((1-(5-isobutyl- yl)amino)methyl)-4,6- CPD- 4,6-dimethylpyrimidin-2- CPD- dimethylpyrimidin-2- 107 yl)piperidin-4-220yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide N-(2-(4,4- 6-((1-(4,6-dimethyl-5- difluoropiperidin-1- ((methyl(1- yl)ethyl)-6-((1-(5-isob phenylcyclopropyl)amino) CPD- utyl- 4,6-d CPD- methyl)pyrimidin-2- 108 imethylpyrimidin-2- yl)piperidin-4-221yl)piperidin-4- yl)(methyl)amino)pyridazi yl)(methyl)amino)-N-(2- ne-4-carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(5- 4,6-dimethylpyrimidin-2- ((benzyl(isopropyl)amino) yl)pip methyl)-4,6- CPD- eridin-4- CPD- dimethylpyrimidin-2- 109 yl)(methyl)amino)-N-(2- (pyridin-2-222yl)piperidin-4- yl)ethyl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide (S)-6-((1-(5-(4- fluorophenyl)-4,6- 6-((1-(4,6-dimethyl-5- dimethylpyrimidin-2- ((methyl(1- CPD- yl)piperidin-4- CPD- phenylethyl)amino)methyl) 110 yl)(methyl)amino)-N-223pyrimidin-2-yl)piperidin-4- (tetrahydrofuran-3- yl)(methyl)amino)-N-(2- yl)pyridazine-4- methoxyethyl)pyridazine- carboxamide 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(4,6-dimethyl-5- 4,6-dimethylpyrimidin-2- ((methyl((1- CPD- yl)piperidin-4- methylcyclohexyl)methyl)a yl)(methyl CPD- mino)methyl)pyrimidin-2- 111 )amino)-N- (pyrimidin-5-224yl)piperidin-4- ylmethyl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(5- 4,6-dimethylpyrimidin-2- ((benzyl(cyclopropyl)amin yl)pi o)methyl)-4,6- CPD- peridin-4- yl)(methyl)amino) CPD- dimethylpyrimidin-2- 112 -N-(1- methoxypropan-2-225yl)piperidin-4- yl)pyridazine-4- yl)(methyl)amino)-N-(2- carboxamide methoxyethyl)pyridazine- 4-carboxamide 6-((1-(5-(4-fluorophenyl)- 6-((1-(4,6-dimethyl-5- 4,6-dimethylpyrimidin-2- ((methyl(2-phenylpropan- yl)piperidin- 2- CPD- 4- y CPD- yl)amino)methyl)pyrimidin- 113 l)(methyl)amino)-N-(2- methoxy-2-2262-yl)piperidin-4- methylpropyl)pyridazine- yl)(methyl)amino)-N-(2- 4-carboxamide methoxyethyl)pyridazine- 4-carboxamide Pharmaceutical compositions As used herein, a “pharmaceutical composition” comprising a specified compound is a mixture of substances (i.e. “formulation”) including the specified compound or pharmaceutically acceptable salt thereof, and, (a) pharmaceutically acceptable excipient(s) and / or carrier, which mixture is suitable for administering the specified compound to a subject. As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood. As used herein, “pharmaceutically acceptable” means that the therapeutically active compound and other ingredients used in the pharmaceutical compositions and methods defined herein are suitable for use in contact with the tissues of the subject to which the composition is administered, in particular humans, without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. In a further embodiment a pharmaceutically acceptable carrier or excipient is approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. Such pharmaceutically acceptable carriers and excipients are well known in the art (see for example: Remington – The Science and Practice of Pharmacy, 23rd edition, Adeboye Adejare; Handbook of Pharmaceutical Excipients, 9th edition, David J. Goldfarb). The proper formulation of a pharmaceutical composition as provided herein, is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection, inhalation and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. As described herein, compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions. Methods of use In some embodiments, methods of using the compounds of formula I as defined herein as antiviral compound are described, namely antiviral compounds primarily active against coronaviruses. A Coronavirus is any virus belonging to the Coronaviridae family. Club-shaped glycoprotein spikes in the envelope give the viruses a crownlike, or coronal, appearance. The coronavirus genome consists of a single strand of positive-sense RNA. Coronaviruses can cause a variety of illnesses in animals, including humans. In some embodiments, the coronavirus is a beta-coronavirus, such as a beta- coronavirus lineage B. In further embodiments, the coronavirus is a human coronavirus, such as selected from human coronavirus 229E (HCoV-229E), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS- CoV-1, or SARS-CoV-2, Middle East respiratory syndrome-related coronavirus (MERS- CoV), or human enteric coronavirus (HECoV). In some embodiments, the coronavirus is a sarbecovirus, more in particular is a Severe acute respiratory syndrome-related coronavirus, yet more in particular is a SARS-CoV-2 virus, such as a SARS-CoV-2 variant. In alternative embodiments, the coronavirus is coronavirus known to infect non- human subjects, such as domesticated animals including but not limited to avian species (such as chicken, turkey, pheasant, quail), cattle, sheep, goat, dogs, cats, monkeys, ferrets, pigs, mice, rats or rabbits. In some embodiments, the compounds or pharmaceutically acceptable salts thereof as described herein are effective against two or more coronaviruses, or, two or more variants of a coronavirus species. Examples of SARS-CoV-2 variants include, but are not limited to, the alpha-variant (B.1.1.7), beta-variant (B1.351), gamma variant (P.1), delta-variant (B1.617.2) and omicron variant (B.1.1.529). All viruses, including SARS-CoV-2, change over time. Most changes have little to no impact on the virus’s properties, including infectiousness or disease inducing abilities. However, some changes may affect the virus’s properties, including sensitivity to antiviral compounds. The data provided herein demonstrate activity of compounds of the invention across coronavirus variants. According to an embodiment, a method of inhibiting replication of a coronavirus is provided. Said method may include contacting a cell infected with the coronavirus with an effective amount of a compound or pharmaceutically acceptable salt thereof, as described herein, or, a composition that includes an effective amount of a compound or pharmaceutically acceptable salt thereof, as described herein, for the use of inhibiting the replication of the coronavirus. Another embodiment relates to the use of a compound as described herein or a (pharmaceutically acceptable) salt thereof, in the manufacture of a composition, such as a pharmaceutical composition or medicament, for inhibiting replication of a coronavirus. Yet another embodiment provides the use of a compound as described herein or a (pharmaceutically acceptable) salt thereof as described herein, for inhibiting replication of a coronavirus. In another embodiment, a method of treating or preventing a coronavirus infection in a subject is provided. Such method may include a step of administering a subject an effective amount of an antiviral compound as defined herein, or a pharmaceutically acceptable salt thereof, or administering a subject a pharmaceutical composition comprising an antiviral compound as defined herein or pharmaceutically acceptable salt thereof. In a further embodiment, said compound is administered in an amount effective in reducing or preventing coronavirus replication in a subject. In a further embodiment, said subject may be identified as suffering a coronavirus infection or said subject may be exposed to an infective amount of a coronavirus. In another embodiment, a method of treating or preventing a disease or disease symptoms in a subject that is developed in said subject because of a coronavirus infection. Such disease may be COVID-19, i.e. an infectious disease caused by the virus severe respiratory syndrome coronavirus 2 (SARS-CoV-2), or a disease or syndrome caused by another coronavirus such as SARS (known to be caused by SARS-CoV), MERS (known to be caused by MERS-CoV) or HCoV-OC43 induced common cold. Another embodiment relates to the use of a compound as described herein or a (pharmaceutically acceptable) salt thereof, in the manufacture of a composition, such as a pharmaceutical composition or medicament, for treating or preventing a disease or disease symptoms in a subject that is developed in said subject because of a coronavirus infection. Yet another embodiment provides the use of a compound as described herein or a (pharmaceutically acceptable) salt thereof as described herein, for treating or preventing a disease or disease symptoms in a subject that is developed in said subject because of a coronavirus infection. Further to embodiments relating to methods of use of compounds described herein, both therapeutic as well as prophylactic use in such methods is contemplated. Prophylactic use, i.e. comprising administration of a compound as described herein before exposure to the virus takes place, is considered in particular for a subject suffering a pre-existing condition rendering the subject more susceptible to infection by a coronavirus or more susceptible to develop disease symptoms upon infection by a coronavirus, compared to subjects not suffering said condition. Also, in further embodiments to the therapeutic use of the compounds, thefirst administration of the compound to the subject takes place no later than 20 days followingfirst exposure to the coronavirus, or, following 10 days, more in particular 7 days, yet more in particular 5 days, still more in particular 3 days following thefirst observation of disease symptoms due to the coronavirus infection. As used herein, the terms “treat”, “treating, “treatment”, “therapeutic” or “therapeutically” do not necessarily mean total cure or abolition of the infection or disease associated. Any alleviation of undesired effects or symptoms of an infection or associated disease as well as reduction of progress of infection (increasing levels of infection) or associated disease (increasing severity of disease symptoms) are considered treatment and / or therapy. Likewise, terms related to prevention or prophylactic treatment for uses or methods described herein, do not necessarily mean total or absolute prohibition of occurrence of infection, signs of infection or disease symptoms to develop when exposure to coronaviral particles occurs following administration of the compound or pharmaceutically acceptable salt thereof. For example, the compound may not prevent the subject from being infected but may not develop disease symptoms upon infection when treated with the compound described herein. As used herein, the term “subject” refers to an animal that is the object of treatment or method of use, wherein “animal” includes in particular mammals. “Mammal” includes without limitation mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular humans. In some embodiments, the subject is human, for example a human that is at least 50, at least 60 or at least 65 years of age, or, a human otherwise suffering a pre-existing condition rendering the subject more susceptible to infection by a coronavirus or more susceptible to develop disease symptoms upon infection by a coronavirus, compared to subjects not suffering said condition. Examples of such pre- existing conditions include but are not limited by asthma, COPD, immunocompromising conditions such as cancer, HIV, genetic immune deficiencies or subjects under immunosuppressive therapy (e.g. systemic corticosteroid treatment or (other) chemotherapy e.g. in cancer treatment suppressing immunity), diabetes, heart disease, hypertension and obesity. As used herein, the term “effective amount” is used to indicate an amount of the compound or pharmaceutically acceptable salt thereof that elicits the response indicated. For example, an effective amount of compound for the methods and uses contemplated herein, can be the amount needed to prevent a coronavirus to replicate in a cell or in a subject, the amount needed to reduce the level of infection by a coronavirus (e.g. reducing the viral load), or reducing or alleviating the disease symptoms associated with a coronavirus infection in a subject. This response may occur in a cell, a tissue, a system, animal or human. Determination of the effective amount is well within the capability of those skilled in the art, in view of the disclosure, e.g. the antiviral activity data, provided herein. Abbreviations used in the description, particularly in the Schemes and Examples, are as follows: Ac acetyl Me methyl Ac2O acetic anhydride Me2NH dimethylamine ACE2 angiotensin-converting enzyme 2 MeI iodomethane AcOH acetic acid MeMgBr methyl magnesium bromide AcOK potassium acetate MeNH2 methyl amine aq. aqueous MeOH methanol Bn benzyl min minute Boc tert-butyloxycarbonyl MOI multiplicity of infection br broad MOM methoxymethyl ether cBz carboxybenzyl MOMCl chloromethyl methyl ether cBzCl benzyl chloroformate Ms methanesulfonyl CPE cytopathic effect MsCl mesyl chloride 3-(4,5-dimethylthiazol-2-yl)-5-(3- d day MTS carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium DBU1,8-diazabicyclo[5.4.0]undec-7-ene m / z mass-to-charge ratioDIPEA diisopropylethylamine NaBH(OAc)3 sodium triacetoxyborohydride DMAc dimethylacetamide NEt3 triethylamine DMAP 4-dimethylaminopyridine NMP N-methyl-2-pyrrolidone DMEMDulbecco's modified Eaglemedium Pd / C palladium on carbonDMF N,N-dimethylformamide Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichlorideDMSO dimethyl sulfoxide Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)PF1,1'-bis(diphe[1,3-Bis(2,6-Diisopropylphenyl) DPnylphosphino)ferrocene PEPSI-IPrimidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride eq equivalent PG protecting group Et ethyl p.i. post infection Et2O diethyl ether PPh3triphenylphosphine EtBr ethyl bromide Rtretention time EtOAc ethyl acetate sat. saturated EtOH ethanol T temperature EtONa sodium ethoxide T3P propylphosphonic anhydride FA formic acid TBAF tetrabutylammonium fluoride FCS fetal calf serum tBu tert-butyl Fe(acac)2iron (II) acetylacetonate tBuOK potassium tert-butanol h hour TFA trifluoroacetic acid O-(7-aza-1H-benzotriazol-1-yl)- HATU N,N,N',N'-tetramethyl-uronium THF tetrahydrofuran hexafluorophosphate hCoV human coronavirus Tos toluene sulfonyl HPLChigh performance liquidchromatography Tf trifluoromethanesulfonyliPr iso-propyl TMPRSS2 transmembrane serine protease 2 iPrMgCl isopropylmagnesium chloride XPhos2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenylmethanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i- LG leaving group XPhos PdG4 propyl-1,1'-biphenyl)(2'-methylamino- 1,1'-biphenyl-2-yl)palladium(II) EXAMPLES The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention. Part A illustrates the preparation of the compounds of formula (I) (intermediates and final compounds) whereas Part B illustrates the pharmacological activity of the compounds of formula (I). Part A The LC / MS analyses mentioned in the experimental part were performed on a Waters system combining a Waters Acquity UPLC H-Class equipped with an Acquity UPLC PDA Detector and an Acquity TQ Detector (ESI). LCMS method codes Method Flow Colu----- Run codemn Mobile phase GradientColumn T time Waters: BEH C18 A: 10mM CH3COONH4in From 95% A to 10% A i 0.8 mL / min LC-A (1.7 µm, H2O (pH 7) / CH3CN (95 / 5) n 1.5 min, held for 1 min ---- 2.5 min 2.1*30 mm) B: CH3CN 40°C Waters: A: 10mM CH COONH in From 100% A to 52% A 0.5 C-B BEH3 4mL / min L C18 (1.7 µm, H2O (pH 7) / CH3CN (95 / 5) in 3.18 min, to 10% A in ---- 5 min 2.1*50 mm) B: CH3CN 0.82 min, held for 1 min 40°C Waters: BEH C18 A: 10mM CH3COONH4in From 84% A to 42% A in 0.5 mL / min LC-C (1.7 µm, H2O (pH 7) / CH3CN (95 / 5) 3.4 min, to 10% A in 0.6 ---- 5 min 2.1*50 mm) B: CH3CN min, held for 1 min 40°C Waters: BEH C18 A: 10mM CH3COONH4in From 0.5 mL / min LC-D H O (pH 7) / CH CN (9 52% A to 10% A in (1.7 µm,2 35 / 5) 3.5 min, he ---- 5 min ) B: CH ld for 1.5 min 2.1*50 mm 3CN 40°C Waters: HSS C18 A: 0.1% From 80% A to 40% A in 0.5 mL / min LC-E FA in H2O (1.8 µm, B: CH 3.4 min, to 10% A in 0.6 ---- 5 min 3CN 2.1*50 mm) min, held for 1 min 40°C All the preparative HPLC purifications mentioned in the experimental part were carried out either with an Autopurification Waters system combining a Waters 2489 UV / Visible Detector, a Waters 2545 Binary Gradient Module, a Waters 2767 Sample Manager Injector and Collector (Instrument 1) or with a Gilson GX system combining a Gilson 156 UV / Visible Detector, a Gilson 333 / 334 Pump and a Gilson GX-281 Fraction Collector (Instrument 2). Preparative HPLC method codes Method Mobil Detection codeInstrument Columne phase Wave- Gradient Flow lengths YMC A: 20 mM From 60% A to 30% A in 3 min, from 30% A to p-A 1 Actus C18 NH H 20% A Pre4CO3220 and 16 (5 µm, 20*250 in H2O 254 nm in 17 min, from 20% A to 5% A in 1 min, h mL / min mm) B: CH C eld for 1 3 N min YMC A: 20 mM From 60% A to 35% A in 3 p-B 1 Actus C18 NH H min, from 30% A to 20% A Pre4CO3220 and 16 (5 µm, 20*250 in H in 17 min, from 20% A to 2O 254 nm 5% A in 1 min, h mL / min mm) B: CH3CN eld for 1 min Phenomenex A: 25 mM Gemini C18 NH4HCO3 Prep-C 2 100A in H2O254From 49% A to 6% A in 2040 (5 µm, 30*100 B: CH3CN / nm minmL / min mm) MeOH (1 / 1) Phenomenex A: 25 mM Gemini C18 NH4HCO3Prep-D 2 100A in H2O254 nmFrom 49% A to 17% A in40 (5 µm, 30*100 B: CH20 minmL / min 3CN / mm) MeOH (1 / 1) Examples Of The Preparation Of Intermediates 6-Chloro-N-methylpyridazine-4-carboxamide To a solution of 6-chloropyridazine-4-carboxylic acid (1.00 g; 6.31 mmol), DIPEA (7.69 mL; 44.2 mmol) and HATU (4.80 g; 12.3 mmol) in DMF (10 mL) was added 2N MeNH2in THF (25.2 mL; 50.4 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3.The phases were separated. The organic phase was washed with sat. NH4Cl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Two purification by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2furnished 0.784 g (72%) of the desired compound as a yellow solid. LCMS (method LC-A): Rt= 0.43 min; m / z 172 [M+H]+. The intermediate listed in the below table was prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structure N H N N Me2N Cl O 6-Chloro-N-(2-(pyrrolidin-1-yl)ethyl)pyridazine-4-carboxamide To a solution of 6-chloropyridazine-4-carboxylic acid (0.600 g; 3.71 mmol) and NEt3(2.07 mL; 14.8 mmol) in CH2Cl2(2 mL) was added 50% T3P solution in EtOAc (2.65 mL; 4.45 mmol). The reaction mixture was stirred at room temperature for 5 min. 2-(Pyrrolidin-1-yl)ethan-1- amine (0.480 mL; 3.71 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into sat. NaHCO3and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 16%) in CH2Cl2furnished 0.774 g (82%) of the desired compound as a white solid. LCMS (method LC-B): Rt= 1.16 min; m / z 255 [M+H]+; 253 [M-H]- . The intermediates listed in the below table were prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structures N N N N N N N N H H H H N N N N N CMeO NC FN CNCO O O O S O MeO O N N N N H N O H NNNN N H F H F N N N N Cl Cl N ClFNC O O O O N N N N H N H N N H H N N O N N N N Cl N ClMeOClHOCl O O HN O O O NON N N H NNH N N N H H N N N N F Cl Cl HOCl HOCl F O O O O 3-Chloro-5-(cyclopropylmethoxy)pyridazine To a solution of cyclopropylmethanol (0.118 mL; 1.48 mmol) in DMF (8.3 mL) cooled at 0°C was added tBuOK (0.194 g; 2.01 mmol). The reaction mixture was stirred at 0°C for 45 min. 3,5-Dichloropyridazine (0.200 g; 1.34 mmol) was added and the reaction mixture was stirred at 0°C for 30 min. The reaction mixture was partitioned between EtOAc and water. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 20%) in heptane to afford 0.208 g (80%) of the desired compound as a white solid.1H NMR (300 MHz, CDCl3) δ 8.84 (d, 1 H), 6.90 (d, 1 H), 3.93 (d, 2 H), 1.31 (m, 1 H), 0.71 (m, 2 H), 0.41 (m, 2 H). The intermediates listed in the below table were prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structures N N N N O O O Cl O O Cl 2-Chloro-4,6-dimethyl-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine Step 1: To a solution of pentane-2,4-dione (2.00 g; 20.0 mmol) in benzene (25 mL) were added dropwise DBU (3.0 mL; 20.0 mmol) and a solution of 4-(bromomethyl)tetrahydro- 2H-pyran (3.58 g; 20.0 mmol) in benzene (5 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 10%) in hexane to afford 0.650 g (15%) of 3- ((tetrahydro-2H-pyran-4-yl)methyl)pentane-2,4-dione as a yellow liquid. Step 2: To a solution of 3-((tetrahydro-2H-pyran-4-yl)methyl)pentane-2,4-dione (0.650 g; 3.28 mmol) in EtOH (7 mL) were added urea (0.650 g; 9.84 mmol) and dropwise 12N HCl (0.7 mL). The reaction mixture was heated at 90°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL), basified with 28% NH4OH until pH~8 and extracted with 10% MeOH in CH2Cl2(2 x 25 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2to afford 0.300 g (41%) of 4,6-dimethyl-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-ol as an off- white solid.1H NMR (400 MHz, DMSO-d6) δ 11.55 (br. s., 1 H), 3.80 (m, 2 H), 3.22 (m, 2 H), 2.30 (m, 2 H), 2.16 (s, 6 H), 1.58 (m, 1 H), 1.50 (m, 2 H), 1.24 (m, 2 H). Step 3: To a suspension of 4,6-dimethyl-5-((tetrahydro-2H-pyran-4- yl)methyl)pyrimidin-2-ol (0.300 g; 1.35 mmol) in POCl3(3.16 mL; 33.7 mmol) was added dropwise DIPEA (0.94 mL; 5.39 mmol). The reaction mixture was heated at 100°C for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was carefully taken up with 28% NH4OH and extracted with EtOAc (3 x 20 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 30%) in hexane to afford 0.150 g (46%) of the desired compound as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 3.80 (m, 2 H), 3.21 (m, 2 H), 2.59 (d, 2 H), 2.45 (s, 6 H), 1.73 (m, 1 H), 1.45 (m, 2 H), 1.35 (m, 2 H). The intermediates listed in the below table were prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structures Cl N N N Cl N Cl N Cl N N-(2-(Dimethylamino)ethyl)-6-(methyl(piperidin-4-yl)amino)pyridazine-4-carboxamide trihydrochloride Step 1: A mixture 6-chloro-N-(2-(dimethylamino)ethyl)pyridazine-4-carboxamide (0.900 g; 3.86 mmol), CsF (1.76 g; 11.6 mmol), tert-butyl 4-(methylamino)piperidine-1- carboxylate (1.65 g; 7.71 mmol) and DIPEA (2.0 mL; 11.6 mmol) in DMSO (11 mL) was heated at 120oC for 2 h in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with brine and extracted EtOAc (x3). The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 3.5N NH3in MeOH (0% to 10%) in CH2Cl2. A further purification by flash chromatography on silica gel using a gradient of 3.5N NH3in MeOH (0% to 15%) in EtOAc furnished 0.658 g (42%) of tert-butyl 4-((5-(2- (dimethylamino)ethylcarbamoyl]pyridazin-3-yl)-methyl-amino)piperidine-1-carboxylate as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.82 (m, 2 H), 7.29 (d, 1 H), 4.68 - 4.82 (m, 1 H), 3.99 - 4.22 (m, 2 H), 3.31 - 3.43 (m, 2 H), 2.75 - 3.00 (m, 5 H), 2.40 (t, 2 H), 2.18 (s, 6 H), 1.59 - 1.73 (m, 4 H), 1.43 (s, 9 H). Step 2: To a solution of tert-butyl 4-((5-(2-(dimethylamino)ethylcarbamoyl)pyridazin-3- yl)-methyl-amino)piperidine-1-carboxylate (0.658 g; 1.62 mmol) in dioxane (6 mL) and MeOH (6.0 mL) was added 4N HCl in dioxane (12.1 mL; 48.4 mmol). The reaction mixture was stirred at room temperature overnight and was concentrated under reduced pressure to afford quantitatively the desired compound as a beige solid which was used in the next step without further purification. LCMS (method LC-A): Rt= 0.70 min; m / z 307 [M+H]+; 305 [M-H]-. The intermediates listed in the below table were prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structures N N N NH N HCl O H N NH H N NH HO N O N N N HClHClN N OHClHClHCl O HCl NNNNNH NNH H NH F N N F N N N HClO HClHClOHCl HClBenzyl (2-aminoethyl)(methyl)carbamate hydrochloride Step 1: To a solution of tert-butyl N-(2-(methylamino)ethyl)carbamate (1.00 g; 5.74 mmol) and NEt3(1.76 mL; 12.6 mmol) in THF (14 mL) cooled at 0°C was added dropwise benzyl chloroformate (1.10 g; 6.31 mmol) and the reaction mixture was stirred at 0°C for 4 h. The reaction mixture was diluted with water (50 mL) and was extracted with EtOAc (3 x 50 mL). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 5% NH4OH in MeOH (0% to 20%) in CH2Cl2to afford 0.400 g (23%) of benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamate as a colourless oil.1H NMR (DMSO-d6) δ 7.30 - 7.36 (m, 5 H), 6.86 (d, 1 H), 5.05 (s, 2 H), 3.26 (m, 2 H), 3.06 (m, 2 H), 2.86 (m, 3 H), 1.36 (s, 9 H). Step 2: To a solution of benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamate (0.396 g; 1.28 mmol) in dioxane (4.8 mL) cooled at 0°C was added 4N HCl in dioxane (3.21 mL; 12.8 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and was co-evaporated with CH2Cl2(2 x 5 mL) to afford 0.283 g (90%) of the desired compound as a white solid. 1-(4,6-Dimethyl-5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)-N-methylpiperidin-4- amine dihydrochloride Step 1: A mixture of 5-bromo-2-chloro-4,6-dimethylpyrimidine (2.15 g; 9.33 mmol), DIPEA (7.2 mL; 42.0 mmol), CsF (4.26 g; 28.0 mmol) and tert-butyl N-methyl-N-(4- piperidyl)carbamate (2.00 g; 9.33 mmol) in CH3CN (80 mL) was heated in a sealed tube at 100°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (2% to 17%) in heptane to afford 3.32 g (89%) of tert-butyl N-(1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate as a white solid. LCMS (method LC-A): Rt= 1.98 min; m / z 399 [M+H]+. Step 2: A mixture of (3-(trifluoromethoxy)phenyl)boronic acid (0.632 g; 2.48 mmol), tert- butyl N-(1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.500 g; 1.21 mmol), Pd(PPh3)4(0.134 g; 0.12 mmol), K3PO4(1.031 g; 4.86 mmol) and XPhos (0.110 g; 0.19 mmol) in dioxane (13 mL) and water (1.5 mL) was degazed with argon and the reaction mixture was heated overnight at 90°C. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (2% to 18%) in heptane to afford 0.550 g (67%) of tert-butyl N-(1-(4,6-dimethyl-5-(3- (trifluoromethoxy)phenyl]pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate as a white solid. LCMS (method LC-A): Rt= 2.08 min; m / z 481 [M+H]+. Step 3: To a solution of tert-butyl N-(1-(4,6-dimethyl-5-(3- (trifluoromethoxy)phenyl)pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.130 g; 0.27 mmol) in dioxane (1.3 mL) and methanol (1.3 mL) was added 4N HCl in dioxane (1.35 mL; 5.40 mmol). The reaction mixture was stirred at room temperature overnight and was concentrated under reduced pressure to afford quantitatively the desired compound as a yellow solid. LCMS (method LC-A): Rt= 1.45 min; m / z 381 [M+H]+. The intermediates listed in the below table were prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structures N OCHF2N OH N OMe NNN N N NN HCl H HCl N HCl N HCl H HCl H HCl OMe N N NN OMe N NN HCl N HCl H HCl H HCl 2-Bromo-1-((methoxymethoxy)methyl)-4-methylbenzene To a solution of (2-bromo-4-methyl-phenyl)methanol (0.311 g; 1.55 mmol) and DIPEA (0.269 mL; 1.55 mmol) in CH2Cl2(1.3 mL) cooled at 0°C was added MOMCl (0.117 mL; 1.55 mmol). The reaction mixture was stirred at 0°C for 3 h and at room temperature for 3 d. After cooling to 0°C, MOMCl (0.059 mL; 0.77 mmol) was added again and the reaction mixture was stirred at 0°C for 5 min and at room temperature for 1.5 h. The reaction mixture was washed with 1N HCl. The phases were separated. The aqueous phase was extracted with CH2Cl2. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of CH2Cl2(0% to 40%) in heptane to afford 0.220 g (55%) of the desired compound as an orange oil.1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1 H), 7.36 (m, 1 H), 7.13 (d, 1 H), 4.76 (s, 2 H), 4.64 (s, 2 H), 3.44 (s, 3 H), 2.33 (s, 3 H). The intermediate listed in the below table was prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structure MOMO Br 1-Bromo-3-(2-methoxyethyl)-5-methylbenzene A solution of 2-(3-bromo-5-methyl-phenyl)ethanol (0.440 g; 2.05 mmol) and trimethyloxonium tetrafluoroborate (0.348 g; 2.35 mmol) in CH2Cl2(20 mL) was stirred at room temperature for 16 h. Trimethyloxonium tetrafluoroborate (0.300 g; 2.03 mmol) was added again and the reaction mixture was stirred at room temperature for 16 h. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 0.420 g (90%) of the desired compound as a colourless oil which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 7.19 (s, 2 H), 6.97 (m, 1 H), 3.59 (t, 2 H), 3.36 (s, 3 H), 2.82 (t, 2 H), 2.31 (s, 3 H). The intermediate listed in the below table was prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structure MeO Br 1-Bromo-3-(2-methoxypropan-2-yl)-5-methylbenzene To a solution of 2-(3-bromo-5-methyl-phenyl)propan-2-ol (0.450 g; 1.96 mmol) in DMF (28 mL) cooled at 0°C was added NaH (0.128 g; 3.20 mmol). The reaction mixture was stirred at 0°C for 30 min and at room temperature for 15 min. MeI (0.526 mL; 8.45 mmol) was added and the reaction mixture was stirred at room temperature for 2 d. The reaction was quenched by addition of water. The reaction mixture was diluted with EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of CH2Cl2(0% to 7%) in heptane to afford 0.370 g (77%) of the desired compound as a colourless oil.1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1 H), 7.23 (s, 1 H), 7.14 (s, 1 H), 3.09 (s, 3 H), 2.35 (s, 3 H), 1.50 (s, 6 H). The intermediate listed in the below table was prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structure OMe Br 2-(3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol A mixture of 2-(3-bromo-5-methyl-phenyl)ethanol (0.250 g; 1.16 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.295 g; 1.16 mmol), AcOK (0.342 g; 3.49 mmol) and Pd(dppf)Cl2(0.085 g; 0.12 mmol) in dioxane (11.6 mL) was purged with N2and was heated at 80°C for 5.5 h. After cooling to room temperature, the reaction mixture was filtered through celite. The solids were washed with EtOAc. The filtrate was concentrated under reduced pressure and was coevaporated with toluene to afford the desired compound as a brown oil which was used in the next step without further purification. The intermediates listed in the below table were prepared following a similar procedure (use of appropriate reagents and purification methods known to the skilled in the art) to the one described above. Structures MOMO MeO MOMO MeO OBOBOBOBO O O O OMe OH OMe OMe O B O BOBO O OOBO Examples Of The Preparation Of Compounds Of The Invention Example 1: Preparation of N-(1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4-yl)- N,5-dimethylpyridazin-3-amine (CPD-001) Step 1: A mixture of 3-chloro-5-methylpyridazine (1.00 g; 7.78 mmol), tert-butyl-4- (methylamino)piperidine-1-carboxylate (2.00 g; 9.33 mmol) and K2CO3(3.23 g; 23.3 mmol) in NMP (20 mL) was heated at 130°C for 7 d in a sealed tube. After cooling to room temperature, the reaction mixture was poured into sat. NH4Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 90%) in hexane to afford 0.250 g (10%) of tert-butyl 4-(methyl(5-methylpyridazin-3-yl)amino]piperidine-1-carboxylate as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1 H), 6.90 (s, 1 H), 4.66 (m, 1 H), 4.06 (m, 2 H), 2.75 - 2.90 (m, 5 H), 2.19 (s, 3 H), 1.55 -1.65 (m, 4 H), 1.39 (s, 9 H). Step 2: To a solution of tert-butyl 4-(methyl(5-methylpyridazin-3-yl)amino)piperidine-1- carboxylate (0.250 g; 0.82 mmol) in dioxane (3 mL) cooled at 0°C was added 4N HCl in dioxane (5.0 mL; 20.0 mmol). The reaction mixture was stirred at room temperature for 2 h and was concentrated under reduced pressure to afford 0.205 g (90%) of N,5-dimethyl-N- (piperidin-4-yl)pyridazin-3-amine dihydrochloride as a brown oil which was used in the next step without further purification. Step 3: A mixture of 2-chloro-5-isobutyl-4,6-dimethylpyrimidine (0.140 g; 0.71 mmol), Cs2CO3(0.918 g; 2.82 mmol) and N,5-dimethyl-N-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.068 g; 0.24 mmol) in CH3CN (10 mL) was heated at 100°C for 3 d in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and filtered through celite. The solids were washed with EtOAc (3 x 50 mL). The filtrate was concentrated under reduced pressure. Purification by preparative HPLC (method Prep-A) furnished 0.104 g (40%) of the desired compound as an off-white solid.1H NMR (400 MHz,DMSO-d6) δ 8.37 (s, 1 H), 6.98 (s, 1 H), 4.83 (m, 2 H), 4.75 (m, 1 H), 2.79 - 2.95 (m, 5 H), 2.37 (m, 2 H), 2.28 (s, 6 H), 2.22 (s, 3 H), 1.60 - 1.81 (m, 5 H), 0.88 (d, 6 H). LCMS (method LC- D): Rt= 1.99 min (100%); m / z 369 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the section EXAMPLES OF THE PREPARATION OF INTERMEDIATES. Code LCMSLCMS RT [M+H]+methodPurity1(min) (m / z) H NMR (δ ppm) (%) (400 mHz, DMSO-d6) 8.37 (s, 1 H), 7.28 (m, 2 H), 7.18 CPD- LC-D 1.(m, 1 H), 7.06 (d, 2 H), 6.92 (s, 1 H), 4.88 (m, 2 H), 4.78 00281 99.8 403(m, 1 H), 3.91 (s, 2 H), 2.91 (m, 2 H), 2.85 (s, 3 H), 2.22 (m, 9 H), 1.63 -1.76 (m, 4 H) (400 mHz, DMSO-d6) 8.41 (d, 1 H), 6.89 (s, 1 H), 4.74 - CPD- LC-4.89 (m, 3 H), 2.81 - 2.96 (m, 5 H), 2.57 (m, 2 H), 2.38 004D 2.29 100 383(m, 2 H), 2.28 (s, 6 H), 1.75 (m, 1 H), 1.61 - 1.71 (m, 4 H), 1.19 (t, 3 H), 0.89 (d, 6 H) (400 MHz, DMSO-d6) 8.37 (s, 1 H), 6.93 (s, 1 H), 4.84 CPD- (m, 2 H), 4.76 (m, 1 H), 3.82 (m, 2 H), 3.23 (t, 2 H), 2.81 006LC-C 3.34 98.6 411- 2.94 (m, 5 H), 2.44 (d, 2 H), 2.30 (s, 6 H), 2.22 (s, 3 H), 1.58 - 1.73 (m, 5 H), 1.47 (m, 2 H), 1.29 (m, 2 H) (400 MHz, DMSO-d6) 8.36 (s, 1 H), 6.93 (s, 1 H), 4.83 CPD- L (m, 2 H), 4.74 (m, 1 H), 2.79 - 2.95 (m,5 H), 2.61 (d, 2 014C-D 2.11 99.7 381H), 2.45 (m, 1 H), 2.30 (s, 6 H), 2.22 (s, 3 H), 1.88 - 2.01 (m, 2 H), 1.56 - 1.84 (m, 8 H) Example 2: Preparation of N-ethyl-N-(1-(5-isobutyl-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)-5-methylpyridazin-3-amine (CPD-003) Step 1: A mixture of 3-chloro-5-methylpyridazine (0.45 g; 3.40 mmol), DIPEA (1.7 mL; 10.2 mmol), CsF (1.55 g; 10.2 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.36 g; 6.79 mmol) in DMSO (9 mL) was heated at 160°C for 3 h under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (x3). The organic phases were combined, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 5%) in CH2Cl2followed by crystallization from CH3CN furnished 0.658 g (66%) of tert-butyl 4-((5-methylpyridazin-3-yl)amino)piperidine-1- carboxylate as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1 H), 6.60 (d, 1 H), 6.56 (s, 1 H), 3.94 - 4.07 (m, 1 H), 3.88 (m, 2 H), 2.92 (m, 2 H), 2.14 (s, 3 H), 1.91 (dd, 2 H), 1.41 (s, 9 H), 1.21 - 1.36 (m, 2 H). LCMS (method LC-A): Rt= 1.15 min; m / z 293 [M+H]+. Step 2: To a solution of tert-butyl 4-((5-methylpyridazin-3-yl)amino]piperidine-1- carboxylate (0.100 g; 0.34 mmol) in DMSO (9 mL) cooled at 5°C was added KOH (0.903 g; 13.7 mmol) and the reaction mixture was stirred at room temperature for 45 min. A solution of EtBr (0.077 mL; 1.03 mmol) in DMSO (1 mL) was added and stirring was maintained at room temperature for 30 min. Water was added and the mixture was extracted with EtOAc (x2). The organic phases were combined, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. Purification by flash chromatography on silica using a gradient of MeOH (0% to 5%) in CH2Cl2furnished 0.069 g (63%) of tert-butyl 4-(ethyl-(5-methylpyridazin- 3-yl)amino)piperidine-1-carboxylate as an oil.1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1 H), 6.84 (s, 1 H), 4.64 (m, 1 H), 4.07 (m, 2 H), 3.39 (q, 2 H), 2.85 (m, 2 H), 2.21 (s, 3 H), 1.54 - 1.73 (m, 4 H), 1.42 (s, 9 H), 1.09 (t, 3 H). LCMS (method LC-A): Rt= 1.36 min; m / z 321 [M+H]+. Step 3: To a solution of tert-butyl 4-(ethyl-(5-methylpyridazin-3-yl)amino)piperidine-1- carboxylate (0.100 g; 0.31 mmol) in dioxane (2.5 mL) was added 4N HCl in dioxane (2.3 mL; 9.2 mmol). The reaction mixture was stirred at room temperature for 1 h and was concentrated under reduced pressure to afford quantitatively N-ethyl-5-methyl-N-(4-piperidyl)pyridazin-3- amine dihydrochloride as a beige solid which was used in the next step without further purification. LCMS (method LC-A): Rt = 0.74 min; m / z 221 [M+H]+. Step 4: A mixture of 2-chloro-4,6-dimethyl-5-(2-methylpropyl)pyrimidine (0.065 g; 0.31 mmol), Cs2CO3(0.404 g; 1.24 mmol), N-ethyl-5-methyl-N-(4-piperidyl)pyridazin-3-amine dihydrochloride (0.091 g; 0.31 mmol) in CH3CN (4.5 mL) was heated at 130oC for 24 h in a sealed tube. After cooling to room temperature, water was added and the reaction mixture was extracted with CH2Cl2(x2). The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 5%) in EtOAc furnished 0.090 g (74%) of the desired compound as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1 H), 6.86 (s, 1 H), 4.84 (d, 2 H), 4.74 (m, 1 H), 3.36 - 3.46 (m, 2 H), 2.87 (t, 2 H), 2.39 (d, 2 H), 2.29 (s, 6 H), 2.22 (s, 3 H), 1.57 - 1.82 (m, 5 H), 1.09 (t, 3 H), 0.90 (d, 6 H). LCMS (method LC-D): Rt= 2.41 min (97.3%); m / z 383 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the section EXAMPLES OF THE PREPARATION OF INTERMEDIATES. LCMS RT [M+H+ -Code LCMS] [M-H] methodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 mHz, DMSO-d6) 8.35 (s, 1 H), 6.87 (s, 1 H), 4.83 (m, 2 H), 4.70 (m, 1 H), 3.34 - 3.41 (m, CPD- 032LC-D 2.35 99.7 4274 H), 3.22 (s, 3 H), 2.86 (m, 2 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 2.21 (s, 3 H), 1.58 - 1.83 (m, 7 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.36 (d, 1 H), 6.95 (s, 1 H), 4.83 (m, 2 H), 4.77 (t, 1 H), 4.62 (m, 1 H), CPD- 039aLC-C 3.94 100 399 3973.47 (m, 2 H), 3.37 (m, 2 H), 2.87 (t, 2 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 2.21 (s, 3 H), 1.57 - 1.83 (m, 5 H), 0.90 (d, 6 H)ausing 2-(tert-butoxy)ethyl 4-methylbenzene-1-sulfonate for step 2 Example 3: Preparation of N-(1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4-yl)-5- methoxy-N-methylpyridazin-3-amine (CPD-005) Step 1: A mixture of 3-chloro-5-methoxypyridazine (0.300 g; 2.08 mmol), DIPEA (1.0 mL; 6.23 mmol), CsF (0.946 g; 6.23 mmol) and (tert-butyl-4-(methylamino)piperidine-1- carboxylate (0.890 g; 4.15 mmol) in DMSO (8 mL) was heated at 120°C for 16 h in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (x3). The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 50%) in hexane to afford 0.100 g (15%) of tert-butyl 4-((5-methoxypyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1 H), 6.41 (s, 1 H), 4.77 (m, 1 H), 4.06 (m, 2 H), 3.86 (s, 3 H), 2.75 - 2.91 (m, 5 H), 1.54 - 1.68 (m, 4 H), 1.42 (s, 9 H). Step 2: To a solution of tert-butyl 4-((5-methoxypyridazin-3- yl)(methyl)amino)piperidine-1-carboxylate (0.120 g; 0.37 mmol) in dioxane (3 mL) cooled at 0°C was added 4N HCl in dioxane (3.0 mL; 12.0 mmol). The reaction mixture was stirred at room temperature for 3 h and was concentrated under reduced pressure to afford 0.108 g (90%) of 5-methoxy-N-methyl-N-(piperidin-4-yl)pyridazin-3-amine dihydrochloride as an off- white solid which was used in the next step without further purification. Step 3: A mixture of 2-chloro-5-isobutyl-4,6-dimethylpyrimidine (0.060 g; 0.30 mmol), Cs2CO3(0.394 g; 1.21 mmol) and 5-methoxy-N-methyl-N-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.107 g, 0.36 mmol) in CH3CN (7 mL) was heated at 110°C for 3 d in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through celite. The solids were washed with EtOAc. The filtrate was concentrated under reduced pressure. Purification by preparative HPLC (method Prep-B) furnished 0.044 g (38%) of the desired compound as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, 1 H), 6.44 (d, 1 H), 4.76 - 4.93 (m, 3 H), 3.86 (s, 3 H), 2.80 - 2.95 (m, 5 H), 2.38 (m, 2 H), 2.28 (s, 6 H), 1.74 (m, 1 H), 1.61 - 1.71 (m, 4 H), 0.89 (d, 6 H). LCMS (method LC-D): Rt= 1.82 min (95.7%); m / z 385 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the section EXAMPLES OF THE PREPARATION OF INTERMEDIATES. LCMS RT [M+H]+[M- -Code LCMSH] methodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.40 (s, 1 H), 6.90 (s, 1 H), 4.72 - 4.92 (m, 3 H), 2.86 - 2.97 (m, 2 CPD- 007LC-D 2.68 98.1 397H), 2.85 (s, 3 H), 2.47 - 2.51 (m, 2 H), 2.39 (d, 2 H), 2.29 (s, 6 H), 1.53 - 1.82 (m, 7 H), 0.81 - 0.98 (m, 9 H) (400 MHz, DMSO-d6) 8.28 (d, 1 H), 7.33 (m, 1 H), 7.26 (m, 1 H), 7.11 (br. s., 1 H), CPD- LC-D 2.03 96.47.02 (d, 1 H), 6.45 (d, 1 H), 4.82 - 4.96 (m, 0124533 H), 3.94 (s, 2 H), 3.87 (s, 3 H), 2.93 (m, 2 H), 2.87 (s, 3 H), 2.23 (s, 6 H), 1.63 - 1.75 (m, 4 H) (400 MHz, DMSO-d6) 8.28 (d, 1 H), 6.44 (d, 1 H), 4.78 - 4.93 (m, 3 H), 3.87 (s, 3 H), CPD- LC-D 2.32.82 - 2.95 (m, 5 H), 2.44 - 2.58 (m, 2 H), 0138 100 4112.31 (s, 6 H), 1.88 - 2.02 (m, 1 H), 1.57 - 1.74 (m, 8 H), 1.42 - 1.56 (m, 2 H), 1.13 - 1.30 (m, 2 H) (400 MHz, DMSO-d6) 8.74 - 8.85 (m, 2 H), 7.33 (m, 2 H), 7.26 (m, 1 H), 7.11 (s, 1 H), CPD- 016LC-C 4.08 96.1 480 4787.02 (d, 1 H), 4.90 (d, 2 H), 4.82 (m, 1 H), 3.94 (s, 2 H), 2.87 - 3.04 (m, 5 H), 2.82 (d, 3 H), 2.23 (s, 6 H), 1.65 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.74 - 8.83 (m, 2 H), 7.33 (d, 1 H), 4.73 - 4.92 (m, 3 H), 2.85 - CPD- 017LC-D 1.64 100 438 4362.98 (m, 5 H), 2.82 (d, 3 H), 2.31 (s, 6 H), 1.95 (m, 1 H), 1.56 - 1.77 (m, 8 H), 1.42 - 1.57 (m, 2 H), 1.13 - 1.33 (m, 4 H) (400 MHz, DMSO-d6) 8.33 (d, 1 H), 7.47 (m, 2 H), 7.36 - 7.44 (m, 3 H), 6.56 (d, 1 H), CPD- LC-D 2.91 1005.24 (s, 2 H), 4.73 - 4.92 (m, 3 H), 2.82 - 027461 4592.90 (m, 5 H), 2.33 - 2.43 (d, 2 H), 2.28 (s, 6 H), 1.75 (m, 1 H), 1.60 - 1.70 (m, 4 H), 0.90 (d, 6 H) (400 MHz, DMSO-d6) 8.68 - 8.84 (m, 2 H), 7.31 (d, 1 H), 4,79 - 4.89 (m, 3 H), 3.32 - CPD- 031LC-C 3.57 100 469 4673.44 (m, 2 H), 2.81 - 3.00 (m, 5 H), 2.36 - 2.44 (m, 4 H), 2.29 (s, 6 H), 2.18 (s, 6 H), 1.60 - 1.83 (m, 5 H), 0.90 (d, 6 H) (400 MHz, DMSO-d6) 8.26 (d, 1 H), 6.42 (d, 1 H), 4.78 - 4.92 (m, 3 H), 4.16 (q, 2 H), CPD- 036LC-D 2.25 99.9 399 3972.80 - 2.94 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.75 (m, 1 H), 1.62 - 1.70 (m, 4 H), 1.34 (t, 3 H), 0.89 (d, 6 H) (400 MHz, DMSO-d6) 8.28 (d, 1 H), 6.41 (d, 1 H), 4.78 - 4.90 (m, 3 H), 3.96 (d, 2 H), CPD- LC-D 2.66 92.81 - 2.95 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 0378.1 4256 H), 1.74 (m, 1 H), 1.60 - 1.70 (m, 4 H), 1.23 (m, 1 H), 0.89 (d, 6 H), 0.60 (m, 2 H), 0.35 (m, 2 H) (400 mHz, DMSO-d6) 8.82 (d, 1 H), 7.40 (d, CPD- LC-D 2.18 931 H), 4.79 - 4.91 (m, 3 H), 3.91 (s, 3 H),040a.7 4132.85 - 3.00 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.64 - 1.83 (m, 5 H), 0.90 (d, 6 H) (400 MHz, DMSO-d6) 8.27 (d, 1 H), 6.45 (d, 1 H), 4.94 (t, 1 H), 4.77 - 4.92 (m, 3 H), CPD- 041LC-C 3.79 99.3 4154.12 (t, 2 H), 3.72 (q, 2 H), 2.80 - 2.96 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.74 (m, 1 H), 1.59 - 1.70 (m, 4 H), 0.89 (d, 6 H) (400 MHz, CDCl3) 8.29 (d, 1 H), 7.28 - 7.36 (m, 5 H), 6.11 (d, 1 H), 4.93 - 5.14 (m, 3 H), CPD- 4.53 (s, 2 H), 4.17 (t, 2 H), 3.66 (t, 2 H), 0433.01 (m, 2 H), 2.87 (s, 3 H), 2.34 - 2.45 (m, 8 H), 2.12 (m, 2 H), 1.70 - 1.90 (m, 5 H), 0.95 (d, 6 H) (400 MHz, DMSO-d6) 8.29 (d, 1 H), 6.47 (d, 1 H), 4.77 - 4.92 (m, 3 H), 4.25 (m, 2 H), CPD- 067LC-D 1.86 100 4293.68 (m, 2 H), 3.31 (s, 3 H), 2.81 - 2.93 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.75 (m, 1 H), 1.59 - 1.71 (m, 4 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.70 - 8.80 (m, 2 H), 7.29 (d, 1 H), 4.75 - 4.90 (m, 3 H), 3.37 (m, 2 H), 3.21 (s, 3 H), 3.14 (m, 1 H), 2.84 - CPD- 086LC-C 3.99 100 539 5372.96 (m, 5 H), 2.70 (m, 2 H), 2.43 - 2.50 (m, 2 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 2.09 - 2.14 (m, 2 H), 1.64 - 1.87 (m, 7 H), 1.40 (m, 2 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.77 - 8.80 (m, 2 H), 7.30 (d, 1 H), 4.75 - 4.93 (m, 3 H), 3.82 (m, 1 H), 3.38 (m, 2 H), 3.16 (s, 3 H), 2.83 - CPD- 088LC-C 3.96 100 525 5232.97 (m, 5 H), 2.71 (m, 1 H), 2.54 - 2.63 (m, 4 H), 2.41 - 2.47 (m, 1 H), 2.37 - 2.39 (m, 2 H), 2.29 (s, 6 H), 1.96 (m, 1 H), 1.58 - 1.81 (m, 6 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.81 (t, 1 H), 8.78 (d, CPD- 9LC-1 H), 7.30 (d, 1 H), 5.10 - 5.27 (m, 1 H), 08C 4.97 95.0 513 5114.75 - 4.90 (m, 3 H), 3.40 (m, 2 H), 2.79 - 2.96 (m, 6 H), 2.57 - 2.72 (m, 3 H), 2.43 - 2.51 (m, 1 H), 2.32 - 2.42 (m, 3 H), 2.29 (s, 6 H), 2.03 - 2.19 (m, 1 H), 1.69 - 1.93 (m, 6 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.78 (d, 1 H), 8.75 (t, 1 H), 7.29 (d, 1 H), 4.74 - 4.94 (m, 3 H), CPD- LC-C 3.73 97.9 559 5573.40 (m, 2 H), 3.07 (m, 4 H), 2.98 (m, 4 H), 0912.83 - 2.94 (m, 5 H), 2.68 (m, 2 H), 2.38 (m, 2 H), 2.29 (s, 6 H), 1.65 - 1.82 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.77 (d, 1 H), 8.74 (t, 1 H), 7.29 (d, 1 H), 4.74 - 4.91 (m, 3 H), 4.51 - 4.69 (m, 1 H), 3.39 (m, 2 H), 2.86 - CPD- 092LC-C 4.38 99.7 527 5252.93 (m, 5 H), 2.79 (m, 1 H), 2.52 - 2.57 (m, 3 H), 2.35 - 2.44 (m, 3 H), 2.26 (m, 7 H), 1.69 - 1.87 (m, 7 H), 1.47 (m, 2 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.82 (t, 1 H), 8.78 (d, 1 H), 7.30 (d, 1 H), 4.78 - 4.87 (m, 3 H), CPD- LC-D 1.73 93.40 (m, 2 H), 2.86 - 2.98 (m, 7 H), 2.75 (m, 1019.3 531 5292 H), 2.62 (m, 2 H), 2.39 (m, 2 H), 2.29 (s, 6 H), 2.22 (m, 2 H), 1.69 - 1.79 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.77 (d, 1 H), 8.73 (t, 1 H), 7.29 (d, 1 H), 4.77 - 4.91 (m, 3 H), CPD- L 3.66 (m, 2 H), 3.60 (m, 2 H), 3.38 (m, 2 H), 104C-C 3.92 99 525 5232.86 - 2.99 (m, 5 H), 2.63 - 2.75 (m, 6 H), 2.38 (m, 2 H), 2.29 (s, 6 H), 1.65 - 1.81 (m, 7 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.77 - 8.80 (m, 2 H), 7.72 (s, 1 H), 7.30 (s, 1 H), 4.78 - 4.86 (m, CPD- 3 H), 3.42 (m, 2 H), 3.14 (m, 2 H), 3.00 (s 106LC-C 3.31 98.6 524 522, 2 H), 2.86 - 2.97 (m, 5 H), 2.62 (m, 2 H), 2.50 - 2.60 (m, 2 H), 2.38 (m, 2 H), 2.29 (s, 6 H), 1.68 - 1.80 (m, 5 H), 0.90 (d, 6 H)aThe reaction mixture was heated at 140°C for 18 h in step 3 Example 4: Preparation of 6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)pyridazine-4-carboxamide (CPD-008) CPD-008 Step 1: A mixture of methyl 6-chloropyridazine-4-carboxylate (1.00 g; 5.79 mmol), tert- butyl 4-(methylamino)piperidine-1-carboxylate (2.48 g; 11.6 mmol), DIPEA (2.87 mL; 17.4 mmol) and CsF (2.64 g; 17.4 mmol) in DMSO (10 mL) was heated at 120°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 7%) in CH2Cl2to afford 0.350 g (17%) of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyridazine-4- carboxylate. Solid NH4Cl was added to the aqueous phase until pH~6-7 and the aqueous phase was extracted with 10% MeOH in CH2Cl2(5 x 150 mL). The organic phases were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 5% AcOH in MeOH (0% to 30%) in CH2Cl2. The fractions containing 6-((1-(tert- butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxylic acid were combined and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with sat. Na2CO3(2 x 15 mL). The organic phase containing impurities was discarded. The aqueous phase was acidified with 3M HCl until pH~3-4 then extracted with EtOAc (3 x 20 mL) and 10% MeOH in CH2Cl2(3 x 20 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 0.258 g (10%) of 6-((1- (tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxylic acid as an orange solid. Methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxylate:1H NMR (DMSO-d6) δ 8.82 (d, 1 H), 7.36 (d, 1 H), 4.74 (m, 1 H), 4.07 (m, 2 H), 3.9 (s, 3 H), 2.83 - 2.95 (m, 5 H), 1.63 (m, 4 H), 1.42 (s, 9 H). 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxylic acid:1H NMR (DMSO-d6) δ 11.92 (s, 1 H), 8.80 (d, 1 H), 7.39 (d, 1 H), 4.72 (m, 1 H), 4.06 (m, 2 H), 2.81 - 2.93 (m, 5 H), 1.54 (m, 4 H), 1.41 (s, 9 H). Step 2: A mixture of 6-((1-(tert-butoxycarbonyl)piperidin-4- yl)(methyl)amino)pyridazine-4-carboxylic acid (0.216 g; 0.43 mmol), DIPEA (0.5 mL; 3.01 mmol), NH4Cl (0.115 g; 2.15 mmol) and HATU (0.326 g; 0.86 mmol) in DMF (1.4 mL) was stirred at room temperature for 64 h. The reaction mixture was diluted with sat. Na2CO3(15 mL) and extracted with EtOAc (3 x 20 mL). The organic phases were combined, washed with brine (3 x 15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2to afford 0.128 g (89%) of tert-butyl 4-((5-carbamoylpyridazin-3- yl)(methyl)amino)piperidine-1-carboxylate as an orange oil.1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, 1 H), 8.28 (s, 1 H), 7.81 (s, 1 H), 7.34 (d, 1 H), 4.72 (m, 1 H), 4.01 - 4.10 (m, 2 H), 2.94 (s, 3 H), 2.81 - 2.93 (m, 2 H), 1.61 - 1.67 (m, 4 H), 1.41 (s, 9 H). Step 3: To a solution of tert-butyl 4-((5-carbamoylpyridazin-3- yl)(methyl)amino)piperidine-1-carboxylate (0.128 g; 0.47 mmol) in dioxane (1.7 mL) cooled at 0°C was added 4N HCl in dioxane (2.34 mL; 9.36 mmol). The reaction mixture was stirred at room temperature for 1 h and was concentrated under reduced pressure. The residue was triturated with Et2O (10 mL). The solid was filtered and dried under high vacuum to afford quantitatively 6-(methyl(piperidin-4-yl)amino)pyridazine-4-carboxamide dihydrochloride as a beige solid. Step 4: A mixture of 6-(methyl(piperidin-4-yl)amino)pyridazine-4-carboxamide dihydrochloride (0.132 g; 0.43 mmol), 2-chloro-4,6-dimethyl-5-(2-methylpropyl)pyrimidine (0.071 g; 0.36 mmol) and Cs2CO3(0.467 g; 1.43 mmol) in CH3CN (5.1 mL) was heated at 130°C in a sealed tube for 44 h. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 30 mL). The organic phases were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2to afford 0.037 g (23%) of the desired compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, 1 H), 8.37 (s, 1 H), 7.88 (s, 1 H), 7.43 (d, 1 H), 4.79 - 4.95 (m, 3 H), 2.90 - 3.03 (m, 5 H), 2.45 (m, 2 H), 2.35 (s, 6 H), 1.71 - 1.88 (m, 5 H), 0.96 (d, 6 H). LCMS (method LC-C): Rt= 3.65 min (99.2%); m / z 398 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the section EXAMPLES OF THE PREPARATION OF INTERMEDIATES. Code LCMSLCMS RT [M+H]+[M-H]- methodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 mHz, DMSO-d6) 8.77 (m, 2 H), 7.32 (s, CPD- LC-C 3.83 99.8 412 41 H), 4.75 - 4.90 (m, 3 H), 2.86 - 2.97 (m, 5 00910H), 2.80 (d, 3 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.64 -1.82 (m, 5H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 9.37 (t, 1 H), 8.84 (d, 1 H), 7.33 - 7.41 (m, 5 H), 7.27 (m, 1 H), 4.85 CPD- 018LC-D 2.12 99.8 488(m, 3 H), 4.52 (d, 2 H), 2.85 - 2.97 (m, 5 H), 2.39 (d, 2 H), 2.29 (s, 6 H), 1.66 - 1.82 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.92 (t, 1 H), 8.81 (d, 1 H), 7.33 (d, 1 H), 4.80 - 4.91 (m, 3 H), 3.18 (t, CPD- 019LC-D 1.90 98.4 452 4502 H), 2.86 - 2.97 (m, 5 H), 2.40 (d, 2 H), 2.30 (s, 6 H), 1.67 - 1.82 (m, 5 H), 1.04 (m, 1 H), 0.91 (d, 6 H), 0.47 (m, 2 H), 0.25 (m, 2 H) (400 mHz, DMSO-d6) 8.91 (t, 1 H), 8.80 (d, 1 CPD- H), 7.35 (d, 1 H), 4.75 - 4.92 (m, 3 H), 3.41 - 020LC-D 1.33 100 456 4543.53 (m, 4 H), 3.28 (s, 3 H), 2.84 - 2.99 (m, 5 H), 2.39 (d, 2 H), 2.30 (s, 6 H), 1.66 - 1.82 (m, 5 H), 0.91 (d, 6 H) (400 mHz, DMSO-d6) 8.77 (d, 1 H), 8.57(d, 1 H), 7.28 (d, 1 H), 4.80 - 4.89 (m, 3 H), 3.73 CPD- LC-C 3.53 97.0 4(m, 1 H), 2.85 - 2.98 (m, 5 H), 2.79 (m, 2 H), 04895 4932.39 (d, 2 H), 2.30 (s, 6 H), 2.18 (s, 3 H), 1.97 (m, 2 H), 1.75 - 1.84 (m, 3 H), 1.66 - 1.74 (m, 4 H), 1.58 (m, 2 H), 0.91 (d, 6 H) (400 mHz, DMSO-d6) 8.88 (t, 1 H), 8.78 (d, 1 H), 7.30 (d, 1 H), 4.79 - 4.91 (m, 3 H), 3.59 - CPD- LC-C 4.03.82 (m, 3 H), 3.48 (m, 1 H), 3.20 - 3.28 (m, 3 0494 100 482 480H), 2.85 - 2.97 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.96 (m, 1 H), 1.69 - 1.82 (m, 5 H), 1.60 (m, 1 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.72 - 8.81 (m, 2 H), 7.29 (d, 1 H), 4.77 - 4.91 (m, 3 H), 3.57 (m, 4 CPD- 051LC-C 3.81 99.3 511 509H), 3.40 (m, 2 H), 2.86 - 2.96 (m, 5 H), 2.36 - 2.50 (m, 8 H), 2.29 (s, 6 H), 1.66 - 1.81 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.76 - 8.85 (m, 2 H), 7.30 (d, 1 H), 4.75 - 4.91 (m, 3 H), 3.40 (m, 2 CPD- 052LC-C 3.66 97.4 495 493H), 2.86 - 2.98 (m, 5 H), 2.57 (m, 2 H), 2.43 - 2.50 (m, 4 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.61 - 1.82 (m, 9 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.77 (d, 1 H), 8.74 (t, 1 H), 7.30 (d, 1 H), 4.78 - 4.89 (m, 3 H), 3.41 - CPD- LC-C3.47 (m, 1 H), 3.15 (m, 1 H), 2.86 - 2.96 (m, 6 0543.75 98.3 495 493H), 2.38 (d, 2 H), 2.32 - 2.36 (m, 1 H), 2.30 (s, 3 H), 2.29 (s, 6 H), 2.13 (m, 1 H), 1.52 - 1.87 (m, 9 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.72 - 8.82 (m, 2 H),7.32 (d, 1 H), 4.78 - 4.88 (m, 3 H), 3.20 - CPD-057aLC-C 3.29 98.3 441 4393.40 (m, 2H), 2.86 - 2.93 (m, 5 H), 2.74 (t, 2 H), 2.37 (d, 2 H), 2.29 (s, 6 H), 1.66 - 1.81 (m, 5 H), 0.90 (d, 6H) (400 mHz, DMSO-d6) 8.84 (d, 1 H), 8.78 (d, 1 H), 7.31 (d, 1 H), 4.83 - 4.86 (m, 3 H), 4.39 CPD- 58LC(m, 1 H), 2.86 - 2.93 (m, 5 H), 2.64 - 2.67 (m, 0-C 3.63 99.0 481 4792 H), 2.46 (m, 1 H), 2.32 - 2.39 (m, 3 H), 2.29 (s, 6 H), 2.26 (s, 3 H), 2.18 (m, 1 H), 1.68 - 1.78 (m, 6 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.86 (d, 1 H), 8.78 (d, 1 H), 7.30 (d, 1 H), 4.77 - 4.93 (m, 3 H), 4.46 CPD- LC-C 4.00 99.0 4(m, 1 H), 3.86 (m, 2 H), 3.71 (m, 1 H), 3.61 05968 466(m, 1 H), 2.86 - 2.95 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 2.19 (m, 1 H), 1.91 (m, 1 H), 1.68 - 1.84 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.88 (t, 1 H), 8.78 (d, 1 H), 7.30 (d, 1 H), 4.77 - 4.92 (m, 3 H), 3.74 (m, 1 H), 3.59 - 3.70 (m, 2 H), 3.47 (m, 1 H), CPD- 061LC-C 4.03 99.1 482 4803.20 - 3.30 (m, 2 H), 2.86 - 2.97 (m, 5 H), 2.44 - 2.48 (m, 1 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.96 (m, 1 H), 1.66 - 1.82 (m, 5 H), 1.60 (m, 1 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 9.46 (t, 1 H), 8.85 (d, 1 H), 8.52 (m, 1 H), 7.77 (m, 1 H), 7.41 (d, 1 H), CPD- LC-C 4.13 96.9 489 487.37 (m, 1 H), 7.29 (m, 1 H), 4.78 - 4.87 (m, 3 0627H), 4.58 (d, 2 H), 2.85 - 2.99 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.65 - 1.79 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 9.40 (t, 1 H), 8.82 (d, 1 H), 8.57 (d, 1 H), 8.48 (m, 1 H), 7.74 (m, 1 H), CPD- 063LC-C 3.98 97.5 489 4877.38 (m, 2 H), 4.77- 4.94 (m, 3 H), 4.53 (d, 2 H), 2.82 - 2.97 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.63 - 1.78 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.78 (m, 2 H), 7.30 (d, 1 H), 4.77 - 4.91 (m, 3 H), 3.16 (t, 2 H), 2.83 - CPD- LC-2.98 (m, 5 H), 2.69 - 2.79 (m, 2 H), 2.38 (d, 2 064C 3.56 99.4 509 507H), 2.29 (s, 6 H), 2.13 (s, 3 H), 1.57 - 1.85 (m, 9 H), 1.49 (m, 1 H), 1.17 (m, 2 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.76 - 8.85 (m, 2 H), 7.30 (d, 1 H), 4.78 - 4.91 (m, 3 H), 3.84 (m, 2 CPD- H), 3.26 (m, 2 H), 3.17 (t, 2 H), 2.83 - 2.97 065LC-D 1.48 98.4 496 494(m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.65 - 1.85 (m, 6 H), 1.60 (m, 2 H), 1.20 (m, 2 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 9.24 (t, 1 H), 8.80 (d, 1 H), 7.59 (d, 1 H), 7.36 (d, 1 H), 6.15 (d, 1 H), CPD- 066LC-D 1.27 100 492 4904.75 - 4.89 (m, 3 H), 4.42 (d, 2 H), 3.79 (s, 3 H), 2.85 - 2.97 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.63 - 1.82 (m, 5 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 9.45 (t, 1 H), 8.85 (d, 1 H), 8.52 (d, 2 H), 7.40 (s, 1 H), 7.33 (d, 2 H), CPD- 070LC-C 3.94 100 489 4874.77 - 4.93 (m, 3 H), 4.53 (d, 2 H), 2.84 - 2.99 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.66 - 1.82 (m, 5 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.78 (d, 1 H), 8.74 (br. s., 1 H), 7.32 (d, 1 H), 4.73 - 4.91 (m, 3 H), CPD- 073bLC-C 3.42 100 455 4533.31 - 3.38 (m, 3 H), 2.83 - 2.98 (m, 6 H), 2.65 (m, 4 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.64 - 1.79 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 9.15 (t, 1 H), 8.80 (s, 1 H), 7.67 (s, 1 H), 7.39 (s, 1 H), 7.34 (s, 1 H), CPD- LC-D 1.4.79 - 4.86 (m, 3 H), 4.32 (d, 2 H), 4.07 (q, 2 07433 100 506 504H), 2.86 - 2.96 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.65 - 1.82 (m, 5 H), 1.33 (t, 3 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.82 (t, 1 H), 8.77 (d, 1 CPD- H), 7.30 (d, 1 H), 4.78 - 4.89 (m, 3 H), 3.28 077LC-C 3.47 99.6 483 481(m, 2 H), 2.85 - 2.96 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 2.25 (m, 2 H), 2.12 (s, 6 H), 1.62 - 1.80 (m, 7 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.76 (d, 1 H), 8.73 (t, 1 H), 7.29 (d, 1 H), 4.75 - 4.89 (m, 3 H), 4.51 CPD- (d, 1 H), 3.34 - 3.47 (m, 4 H), 2.83 - 2.97 (m, 087LC-C 3.52 100 525 5235 H), 2.73 (m, 2 H), 2.44 (m, 2 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 2.07 (m, 2 H), 1.64 - 1.81 (m, 6 H), 1.37 (m, 2 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.78 (m, 2 H), 7.30 (s, 1 H), 4.75 - 4.90 (m, 3 H), 4.66 (d, 1 H), 4.18 (m, 1 H), 3.34 (m, 2 H), 2.86 - 2.96 (m, 5 H), CPD- 090LC-C 3.51 95.6 511 5092.74 (m, 1 H), 2.54 - 2.63 (m, 3 H), 2.44 - 2.47 (m, 1 H), 2.38 (d, 2 H), 2.33 (m, 1 H), 2.29 (s, 6 H), 1.96 (m, 1 H), 1.66 - 1.82 (m, 5 H), 1.53 (m, 1 H), 0.89 (d, 6 H) (400 mHz, DMSO-d6) 8.76 - 8.82 (m, 2 H), 7.30 (d, 1 H), 4.78 - 4.91 (m, 3 H), 3.41 (m, 2 CPD- LC-C 3.46 96.1 53H), 3.25 (m, 2 H), 3.05 (s, 2 H), 2.86 - 2.96 0978 536(m, 5 H), 2.81 (s, 3 H), 2.70 (m, 2 H), 2.52 - 2.56 (m, 2 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.65 - 1.82 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.77 (m, 2 H), 7.30 (d, 1 H), 4.75 - 4.91 (m, 3 H), 3.41 (m, 6 H), 2.84 CPD- 105LC-C 3.52 98.2 552 550- 2.97 (m, 5 H), 2.53 (m, 2 H), 2.44 (m, 2 H), 2.38 (m, 4 H), 2.29 (s, 6 H), 1.98 (s, 3 H), 1.68 - 1.80 (m, 5 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.77 (d, 1 H), 8.74 (t, 1 H), 7.29 (d, 1 H), 4.76 - 4.91 (m, 3 H), 4.57 - CPD- LC-D 1.54.75 (m, 1 H), 3.39 (m, 2 H), 2.83 - 2.97 (m, 5 1075 99.4 527 525H), 2.58 (m, 2 H), 2.46 - 2.48 (m, 2 H), 2.32 - 2.39 (m, 4 H), 2.29 (s, 6 H), 1.64 - 1.91 (m, 9 H), 0.90 (d, 6 H) (400 mHz, DMSO-d6) 8.73 - 8.80 (m, 2 H), 7.29 (d, 1 H), 4.78 - 4.86 (m, 3 H), 3.41 (m, 2 CPD- 108LC-D 1.84 98.8 545 543H), 2.85 - 2.97 (m, 5 H), 2.53 - 2.60 (m, 6 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.94 (m, 4 H), 1.68 - 1.80 (m, 5 H), 0.90 (d, 6 H)ausing N-BOC-ethylenediamine at first step;busing benzyl (2-aminoethyl)(methyl)carbamate hydrochloride at first step Example 5: Preparation of 6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)pyridazine-4-carboxylic acid (CPD-010) and 6-((1-(5-isobutyl-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N,N-dimethylpyridazine-4- Step 1: To a solution of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4- yl)(methyl)amino)pyridazine-4-carboxylate (0.352 g; 1.01 mmol) in dioxane (3.7 mL) cooled to 0°C was added 4N HCl in dioxane (5.0 mL; 20.0 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressureand was co-evaporated with MeOH. The residue was triturated with Et2O (10 mL) andcentrifuged. The supernatant was discarded. The solid was dissolved in water and freeze- dried to afford 0.303 g (93%) of methyl 6-(methyl(piperidin-4-yl)amino)pyridazine-4- carboxylate dihydrochloride as a brown solid. Step 2: A mixture of methyl 6-(methyl(piperidin-4-yl)amino)pyridazine-4-carboxylate dihydrochloride (0.255 g; 0.79 mmol), 2-chloro-4,6-dimethyl-5-(2-methylpropyl)pyrimidine (0.157 g; 0.79 mmol) and Cs2CO3(1.03 g; 3.16 mmol) in CH3CN (11 mL) was heated at 140°C in a sealed tube for 3.5 d. After cooling to room temperature, the reaction mixture was diluted with sat. NH4Cl (70 mL) and extracted with CH2Cl2(3 x 100 mL). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 5% AcOH in MeOH (0% to 20%) in CH2Cl2 to afford 0.082 g (31%) of 6-((1-(5- isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxylic acid CPD-010 as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 13.95 (br.s., 1 H), 8.79 (d, 1 H), 7.35 (d, 1 H), 4.76 - 4.85 (m, 3 H), 2.87 - 2.94 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.68 - 1.78 (m, 5 H), 0.90 (d, 6 H). Step 3: A mixture of 6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)pyridazine-4-carboxylic acid (0.077 g; 0.19 mmol), 2N Me2NH in THF (0.49 mL; 0.98 mmol), HATU (0.147 g; 0.39 mmol) and DIPEA (0.16 mL; 0.97 mmol) in DMF (0.4 mL) was stirred at room temperature for 18 h.2N Me2NH in THF (0.49 mL; 0.98 mmol), HATU (0.147 g; 0.39 mmol) and DIPEA (0.16 mL; 0.97 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with sat. NH4Cl (10 mL) and water (10 mL) and was extracted with EtOAc (3 x 20 mL). The organic phases were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2followed by a second purification by flash chromatography using a gradient of MeOH (3% to 10%) in CH2Cl2furnished 0.041 g (50%) of 6-((1-(5-isobutyl-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N,N-dimethylpyridazine-4-carboxamide CPD-011 as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1 H), 7.09 (s, 1 H), 4.84 (m, 2 H), 4.75 (m, 1 H), 2.99 (s, 3 H), 2.84 - 2.96 (m, 8 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.62 - 1.82 (m, 5 H), 0.90 (d, 6 H). LCMS (method LC-C): Rt= 3.96 min (99.3%); m / z 426 [M+H]+. The compound listed in the table below was prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the section EXAMPLES OF THE PREPARATION OF INTERMEDIATES. LCMSLCMS RT [M+H]+[M-H]-CodemethodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 mHz, DMSO-d6) 8.78 - 8.81 (m, 2 H), 7.31 (d, 1 H), 4.78 - 4.86 (m, 3 H), 3.27 - 3.34 CPD- 015LC-C 4.08 99.0 426 424(m, 2 H), 2.86 - 2.93 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.68 - 1.78 (m, 5 H), 1.14 (t, 3 H), 0.90 (d, 6 H) Example 6: Preparation of of (4,6-dimethyl-2-(4-(methyl(5-methylpyridazin-3- yl)amino)piperidin-1-yl)pyrimidin-5-yl)methanol (CPD-021) and N-(1-(4,6-dimethyl-5- (piperidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4-yl)-N,5-dimethylpyridazin-3-amine Step 1: Ethyl 4,6-dimethyl-2-(4-(methyl-(5-methylpyridazin-3-yl)amino)-1- piperidyl)pyrimidine-5-carboxylate was prepared according to the procedure described in Example 4 (Step 4) from N,5-dimethyl-N-(4-piperidyl)pyridazin-3-amine dihydrochloride (2.06 g; 7.16 mmol), ethyl 2-chloro-4,6-dimethyl-pyrimidine-5-carboxylate (1.78 g; 7.88 mmol), and Cs2CO3(7.00 g; 21.5 mmol) in CH3CN (200 mL). Purification by flash chromatography on silica gel using a gradient of EtOAc (60% to 100%) in heptane furnished 2.16 g (78%) of the desired compound as an orange oil.1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1 H), 6.50 (s, 1 H), 4.94 - 5.07 (m, 3 H), 4.27 (q, 2 H), 2.93 (m, 2 H), 2.79 (s, 3 H), 2.37 (s, 6 H), 2.20 (s, 3 H), 1.58 - 1.78 (m, 4 H), 1.31 (t, 3 H). Step 2: To a solution of ethyl 4,6-dimethyl-2-(4-(methyl-(5-methylpyridazin-3-yl)amino]- 1-piperidyl)pyrimidine-5-carboxylate (1.00 g; 2.60 mmol) in THF (32 mL) cooled at 0°C was added portionwise LiAlH4(0.197 g; 5.20 mmol). The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 4 h. After cooling to 0°C, the reaction was quenched by dropwise addition of water. Celite was added and the resulting mixture was filtered. The solids were washed with THF. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2and washed with sat. K2CO3. The phases were separated. The aqueous phase was extracted with CH2Cl2. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 6%) in CH2Cl2to afford 0.554 g (62%) of (4,6-dimethyl-2-(4-(methyl(5-methylpyridazin-3- yl)amino)piperidin-1-yl)pyrimidin-5-yl)methanol (CPD-021) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 6.93 (s, 1 H), 4.87 (m, 2 H), 4.78 (m, 1 H), 4.71 (t, 1 H), 4.40 (m, 2 H), 2.92 (m, 2 H), 2.83 (s, 3 H), 2.35 (s, 6 H), 2.22 (s, 3 H), 1.57 - 1.74 (m, 4 H). LCMS (method LC-C): Rt= 1.88 min (100%); m / z 343 [M+H]+. Step 3: To a solution of (4,6-dimethyl-2-(4-(methyl(5-methylpyridazin-3- yl)amino)piperidin-1-yl)pyrimidin-5-yl)methanol (0.410 g; 1.20 mmol) in THF (30 mL) was added MnO2(1.56 g; 18.0 mmol). After 20 h at room temperature, MnO2(1.56 g; 18.0 mmol) was added again and the reaction mixture was heated at 60°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with Et2O / pentane (1:2) and filtered. The solids were washed with pentane. The filtrate was concentrated under reduced pressure to afford 0.325 g of 4,6-dimethyl-2-(4-(methyl-(5-methylpyridazin-3-yl)amino)-1-piperidyl)pyrimidine-5- carbaldehyde as an orange solid which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1 H), 8.43 (d, 1 H), 6.57 (d, 1 H), 5.15 - 5.26 (m, 3 H), 3.06 (m, 2 H), 2.87 (s, 3 H), 2.64 (s, 6 H), 2.28 (s, 3 H), 1.89 (m, 2 H), 1.76 (m, 2 H). Step 4: A mixture of piperidine (0.041 mL; 0.41 mmol), 4,6-dimethyl-2-(4-(methyl-(5- methylpyridazin-3-yl)amino)-1-piperidyl)pyrimidine-5-carbaldehyde (0.070 g; 0.21 mmol) and 4Å molecular sieves in CH2Cl2(3 mL) was stirred at room temperature for 30 min. NaBH(OAc)3(0.131 g; 0.62 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with CH2Cl2and washed with 10% aq. NaHCO3. The phases were separated. The organic phase was washed with 10% aq. NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 3.5N NH3in MeOH (0% to 5%) in CH2Cl2to afford 0.013 g (15%) of N-(1-(4,6-dimethyl-5-(piperidin-1-ylmethyl)pyrimidin-2-yl)piperidin-4- yl)-N,5-dimethylpyridazin-3-amine (CPD-022) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 6.92 (s, 1 H), 4.86 (m, 2 H), 4.77 (m, 1 H), 3.26 - 3.30 (m, 2 H), 2.89 (m, 2 H), 2.85 (s, 3 H), 2.28 - 2.38 (m, 10 H), 2.21 (s, 3 H), 1.62 - 1.75 (m, 4 H), 1.34 - 1.54 (m, 6 H). LCMS (method LC-C): Rt= 3.19 min (100%); m / z 325 [M-C5H10N]+. The compound listed in the table below was prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the section EXAMPLES OF THE PREPARATION OF INTERMEDIATES. LCMS+Code LCMSRT [M+H] methodPurity1(min) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.37 (d, 1 H), 7.29 - 7.40 (m, 4 325 CPD- H), 7.23 (m, 1 H), 6.93 (d, 1 H), 4.85 (m, 2 H), 4. 045LC-C 3.51 10078 (m, [M- + 1 H), 3.75 (s, 2 H), 3.49 (s, 2 H), 2.90 (m, 2 H), 2.83 (s, C7H8N] 3 H), 2.29 (s, 6 H), 2.22 (s, 3 H), 1.55 - 1.73 (m, 4 H) Example 7: Preparation of N-(1-(5-(2-fluorophenyl)-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)-N,5-dimethylpyridazin-3-amine (CPD-023) Step 1: A mixture of 5-bromo-2-chloro-4,6-dimethyl-pyrimidine (2.50 g; 11.3 mmol), N,5-dimethyl-N-(4-piperidyl)pyridazin-3-amine dihydrochloride (2.87 g; 10.3 mmol), DIPEA (6.26 mL; 35.9 mmol) and CsF (5.46 g; 35.9 mmol) in CH3CN (50 mL) was heated at 120°C for 24 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was partitioned between EtOAc and water. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (70% to 100%) in heptane to afford 2.50 g (62%) of N-(1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N,5-dimethyl- pyridazin-3-amine as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, 1 H), 6.92 (d, 1 H), 4.72 - 4.83 (m, 3 H), 2.96 (m, 2 H), 2.83 (s, 3 H), 2.40 (s, 6 H), 2.21 (s, 3 H), 1.60 - 1.74 (m, 4 H). Step 2: A mixture of (2-fluorophenyl)boronic acid (0.039 g; 0.28 mmol), K3PO4(0.163 g; 0.77 mmol), XPhos (0.024 g; 0.05 mmol) in dioxane (2.7 mL) and H2O (0.3 mL) in a 10 mL- reaction tube was purged with N2for 5 min. Pd(Ph3)4(0.030 g; 0.03 mmol) was added and the reaction mixture was purged with N2for 5 min. After addition of N-(1-(5-bromo-4,6-dimethyl- pyrimidin-2-yl)-4-piperidyl)-N,5-dimethyl-pyridazin-3-amine (0.100 g; 0.26 mmol), the tube was sealed and the reaction mixture was heated at 90°C for 16 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and sat. NaHCO3. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2followed by a purification by preparative HPLC (method Prep-C) furnished 0.030 g (29%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1 H), 7.44 (m, 1 H), 7.25 - 7.38 (m, 3 H), 6.95 (d, 1 H), 4.88 - 4.98 (m, 2 H), 4.80 (m, 1 H), 2.99 (m, 2 H), 2.86 (s, 3 H), 2.22 (s, 3 H), 2.03 (s, 6 H), 1.61 - 1.76 (m, 4 H). LCMS (method LC- D): Rt= 1.76 min (100%); m / z 407 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. Code LCMSLCMS RT [M+H]+[M-H]- methodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.38 (s, 1 H), 7.49 (m, 1 H), 7.20 (m, 1 H), 7.15 (m, 1 H), 7.08 (m, CPD- 024LC-D 1.87 100 407 4051H), 6.94 (s, 1 H), 4.98 - 4.98 (m, 2 H), 4.81 (m, 1 H), 2.97 (m, 2 H), 3.11 (s, 3 H), 2.22 (s, 3 H), 2.05 (s, 6 H), 1.64 - 1.77 (m, 4 H) (400 MHz, DMSO-d6) 8.39 (d, 1 H), 7.28 (m, CPD- LC-D 1.83 100 44 H), 6.95 (d, 1 H), 4.88 - 4.98 (m, 2 H), 4.82 02807(m, 1 H), 2.97 (m, 2 H), 2.87 (s, 3 H), 2.23 (s, 3 H), 2.04 (s, 6 H), 1.66 - 1.75 (m, 4 H) (400 MHz, DMSO-d6) 8.39 (d, 1 H), 7.37 (m, 1 H), 6.92 - 6.98 (m, 2 H), 6.76 - 6.81 (m, 2 CPD- 029LC-D 1.68 100 419 417H), 4.87 - 4.97 (m, 2 H), 4.81 (m, 1 H), 3.78 (s, 3 H), 2.97 (m, 2 H), 2.87 (s, 3 H), 2.23 (s, 3 H), 2.06 (s, 6 H), 1.63 - 1.74 (m, 4 H) (400 MHz, DMSO-d6) 8.38 (d, 1 H), 7.41 - 7.52 (m, 2 H), 7.37 (m, 1 H), 7.20 - 7.27 (m, 2 CPD- 030LC-D 1.80 100 389 387H), 6.95 (d, 1 H), 4.88 - 4.98 (m, 2 H), 4.81 (m, 1 H), 2.96 (m, 2 H), 2.86 (s, 3 H), 2.22 (s, 3 H), 2.03 (s, 6 H), 1.64 - 1.76 (m, 4 H) (400 MHz, DMSO-d6) 8.38 (d, 1 H), 7.37 (m, 1 H), 7.07 - 7.13 (m, 2 H), 7.02 (m, 1 H), 6.94 CPD- LC-D 1.67 99.7(d, 1 H), 4.87 - 4.99 (m, 2 H), 4.79 (m, 1 H), 0334193.73 (s, 3 H), 2.95 (m, 2 H), 2.87 (s, 3 H), 2.22 (s, 3 H), 1.97 (s, 6 H), 1.66 - 1.79 (m, 4 H) (400 MHz, DMSO-d6) 8.38 (d, 1 H), 7.10 - 7.19 (m, 2 H), 6.98 - 7.05 (m, 2 H), 6.95 (d, 1 CPD- 034LC-D 1.68 100 419 417H), 4.87 - 4.98 (m, 2 H), 4.80 (m, 1 H), 3.80 (s, 3 H), 2.96 (m, 2 H), 2.87 (s, 3 H), 2.23 (s, 3 H), 2.04 (s, 6 H), 1.64 - 1.78 (m, 4 H) (400 MHz, DMSO-d6) 8.37 (s, 1 H), 6.92 (s, 1 CPD- H), 5.50 (s, 1 H), 4.85 (d, 2 H), 4.76 (m, 1 H), 035LC-D 2.55 100 3932.90 (m, 2 H), 2.84 (s, 3 H), 2.22 (s, 3 H), 2.19 (s, 6 H), 2.08 - 2.16 (m, 2 H), 1.95 - 2.06 (m, 2 H), 1.59 - 1.74 (m, 8 H) (400 MHz, DMSO-d6) 8.28 (d, 1 H), 7.42 - 7.48 (m, 2 H), 7.37 (m, 1 H), 7.20 - 7.27 (m, 2 CPD- 044LC-D 1.71 99.7 405H), 6.46 (d, 1 H), 4.85 - 5.01 (m, 3 H), 3.87 (s, 3 H), 2.97 (m, 2 H), 2.87 (s, 3 H), 2.04 (s, 6 H), 1.64 - 1.79 (m, 4 H) (400 MHz, DMSO-d6) 8.72 - 8.85 (m, 2 H), 7.42 - 7.51 (m, 2 H), 7.35 - 7.42 (m, 1 H), CPD- LC-C 37.33 (d, 1 H), 7.23 (m, 2 H), 4.80 - 5.00 (m, 3 047.51 96.1 489 487H), 3.38 (q, 2 H), 2.96 - 3.05 (m, 2 H), 2.94 (s, 3 H), 2.41 (t, 2 H), 2.19 (s, 6 H), 2.05 (s, 6 H), 1.66 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.72 - 8.83 (m, 2 H), 7.33 (d, 1 H), 7.28 (d, 4 H), 4.78 - 5.00 (m, 3 CPD- 050LC-C 3.51 95 507 505H), 3.36 (q, 2 H), 2.87 - 3.07 (m, 5 H), 2.42 (t, 2 H), 2.19 (s, 6 H), 2.04 (s, 6 H), 1.69 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.68 - 8.85 (m, 2 H), 7.34 - 7.41 (m, 1 H), 7.33 (d, 1 H), 6.94 (dd, 1 H), 6.74 - 6.83 (m, 2 H), 4.94 (m, 2 H), 4.81 - CPD- 053LC-C 3.4 98.6 519 5174.90 (m, 1 H), 3.78 (s, 3 H), 3.38 (q, 2 H), 2.96 - 3.05 (m, 2 H), 2.94 (s, 3 H), 2.41 (t, 2 H), 2.19 (s, 6 H), 2.06 (s, 6 H), 1.67 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.29 (d, 1 H), 7.36 (m, 1 H), 6.93 (m, 1 H), 6.75 - 6.82 (m, 2 H), 6.47 CPD- LC-C 3.84 100 4(d, 1 H), 4.82 - 5.03 (m, 4 H), 4.14 (t, 2 H), 072653.77 (s, 3 H), 3.74 (m, 2 H), 2.96 (m, 2 H), 2.86 (s, 3 H), 2.05 (s, 6 H), 1.63 - 1.75 (m, 4 H) (400 MHz, DMSO-d6) 8.76 - 8.87 (m, 2 H), 7.33 (d, 1 H), 7.28 (d, 4 H),4.95 (m, 2 H), 4.96 CPD- 075LC-C 3.7 100 533 531(m, 1 H), 3.40 (q, 2 H), 2.96 - 3.05 (m, 2 H), 2.94 (s, 3 H), 2.60 (m, 2 H), 2.43 - 2.50 (m, 4 H), 2.04 (s, 6 H), 1.61 - 1.82 (m, 8 H) (400 MHz, DMSO-d6) 8.76 - 8.87 (m, 2 H), 7.31 - 7.42 (m, 2 H), 6.94 (dd, 1 H), 6.75 - CPD- LC-C 36.84 (m, 2 H), 4.93 (m, 2 H), 4.80 - 4.91 (m, 1 076.59 100 545 543H), 3.78 (s, 3 H), 3.41 (q, 2 H), 2.96 - 3.05 (m, 2 H), 2.94 (s, 3 H), 2.43 - 2.50 (m, 4 H), 2.60 (m, 2 H), 2.06 (s, 6 H), 1.61 - 1.83 (m, 8 H) (400 MHz, DMSO-d6) 8.28 (d, 1 H), 7.23 - 7.32 (m, 4 H), 6.47 (d, 1 H), 4.83 - 5.00 (m, 4 CPD- 081LC-C 3.75 100 453H), 4.15 (t, 2 H), 3.75 (br. s., 2 H), 2.98 (m, 2 H), 2.86 (s, 3 H), 2.03 (s, 6 H), 1.64 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.78 - 8.85 (m, 2 H), 7.33 (d, 1 H), 7.25 - 7.30 (m, 4 H), 4.82 - 4.99 CPD- (m, 3 H), 3.85 (m, 2 H), 3.27 (m, 2 H), 3.19 (t, 093LC-C 4.02 99.3 534 5322 H), 2.91 - 3.03 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.83 (m, 5 H), 1.51 - 1.68 (m, 2 H), 1.20 (m 2 H) (400 MHz, DMSO-d6) 8.88 (t, 1 H), 8.80 (d, 1 H), 7.34 - 7.38 (m, 2 H), 6.94 (m, 1 H), 6.76 - CPD- 6.80 (m, 2 H), 4.834.90 (m, 3 H), 3.82 - 3.87 094LC-C 3.89 99.7 546 544(m, 2 H), 3.77 (s, 3 H), 3.27 (m, 2 H), 3.18 (t, 2H), 2.90 - 3.03 (m, 5 H), 2.05 (s, 6 H), 1.67 - 1.87 (m, 5 H), 1.56 - 1.63 (m, 2 H), 1.20 (m, 2 H) (400 MHz, DMSO-d6) 9.26 (t, 1 H), 8.82 (s, 1 H), 7.60 (s, 1 H), 7.39 (s, 1 H), 7.25 - 7.32 (m, CPD- 4 H), 6.16 (m, 1 H), 4.90 - 5.01 (m, 2 H), 4.86 095LC-C 3.85 96.5 530 528(m, 1 H), 4.43 (d, 2 H), 3.79 (s, 3 H), 2.86 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 9.26 (t, 1 H), 8.81 (d, 1 H), 7.60 (d, 1 H), 7.33 - 7.42 (m, 2 H), 6.94 CPD- LC-C 3(m, 1 H), 6.75 - 6.81 (m, 2 H), 6.15 (d, 1 H), 096.72 98.8 542 5404.89 - 4.99 (m, 2 H), 4.82 (m, 1 H), 4.43 (d, 2 H), 3.80 (s, 3 H), 3.78 (s, 3H), 2.89 - 3.05 (m, 5 H), 2.05 (s, 6 H), 1.67 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.84 (t, 1 H), 8.79 (d, 1 H), 7.37 (t, 1 H), 7.32 (d, 1 H), 6.94 (dd, 1 H), CPD- LC-D 1.45 98.2 56.73 - 6.82 (m, 2 H), 4.79 - 5.00 (m, 3 H), 13281 5793.78 (s, 3 H), 3.40 (q, 2 H), 2.89 - 3.05 (m, 7 H), 2.76 (t, 2 H), 2.63 (t, 2 H), 2.16 - 2.30 (m, 2 H), 2.06 (s, 6 H), 1.66 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.77 (m, 1 H), 7.35 (d, 1 H), 7.00 (d, 1 CPD- H), 6.79 (d, 1 H), 4.80 - 4.95 3LC-(m, 3 H), 3.83 (s, 20 aC 3.43 100 507 5053 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 3.00 (m, 2 H), 2.93 (s, 3 H), 2.13 (s, 6 H), 1.67 - 1.87 (m, 4 H)ausing tributyl-(6-methoxy-2-pyridyl)stannane (2 eq.) and Pd(Ph3)4 (0.1 eq.) in dioxane with heating at 140°C overnight Example 8: Preparation of 1-(4,6-dimethyl-2-(4-(methyl(5-methylpyridazin-3- yl)amino)piperidin-1-yl)pyrimidin-5-yl)-2-methylpropan-1-ol (CPD-025) and 1-(4,6- dimethyl-2-(4-(methyl(5-methylpyridazin-3-yl)amino)piperidin-1-yl)pyrimidin-5-yl)-2- methylpropan-1-one (CPD-026) Step 1: To a solution of 4,6-dimethyl-2-(4-(methyl-(5-methylpyridazin-3-yl)amino)-1- piperidyl)pyrimidine-5-carbaldehyde (0.040 g; 0.12 mmol) in THF (5 mL) cooled at -10°C was added 2M iPrMgCl in THF (0.088 mL; 0.18 mmol). The reaction mixture was stirred at 0 ºC for 1 h and at room temperature for 16 h. The reaction was quenched with water and the reaction mixture was extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (50% to 100%) in heptane to afford 0.020 g (43%) of 1- (4,6-dimethyl-2-(4-(methyl-(5-methylpyridazin-3-yl)amino)-1-piperidyl)pyrimidin-5-yl)-2- methyl-propan-1-ol (CPD-025) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 6.92 (s, 1 H), 5.01 (d, 1 H), 4.85 (m, 2 H), 4.74 (m, 1 H), 4.35 (m, 1 H), 2.79 - 2.97 (m, 5 H), 2.37 (s, 6 H), 2.21 (s, 3 H), 2.03 (m, 1 H), 1.57 - 1.77 (m, 4 H), 1.07 (d, 3 H), 0.63 (d, 3 H). LCMS (method LC-C): Rt= 3.23 min (100%); m / z 367 [M-OH]+. Step 2: To a solution of 1-(4,6-dimethyl-2-(4-(methyl-(5-methylpyridazin-3-yl)amino)-1- piperidyl)pyrimidin-5-yl)-2-methyl-propan-1-ol (0.080 g; 0.021 mol) in CH3CN (8 mL) was added MnO2(0.543 g; 6.24 mmol). The reaction mixture was heated at 60°C for 16 h. MnO2(0.543 g; 6.24 mmol) was added again and the reaction mixture was heated at 60°C for 16 h. MnO2 (0.543 g; 6.24 mmol) was added and the reaction mixture was heated at 60°C for 16 h. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 2%) in CH2Cl2to afford 0.034 g (41%) of 1-(4,6- dimethyl-2-(4-(methyl(5-methylpyridazin-3-yl)amino)piperidin-1-yl)pyrimidin-5-yl)-2- methylpropan-1-one (CPD-026) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 6.93 (s, 1 H), 4.88 - 4.95 (m, 2 H), 4.81 (m, 1 H), 3.09 (m, 1 H), 2.97 (m, 2 H), 2.84 (s, 3 H), 2.22 (s, 3 H), 2.21 (s, 6 H), 1.62 - 1.77 (m, 4 H), 1.08 (d, 6 H). LCMS (method LC-C): Rt= 3.73 min (97.6%); m / z 383 [M+H]+. Example 9: Preparation of N-(2-hydroxyethyl)-6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxamide (CPD-038) Step 1: To a solution of tert-butyl 4-((5-((2-hydroxyethyl)carbamoyl)pyridazin-3- yl)(methyl)amino)piperidine-1-carboxylate (0.120 g; 0.32 mmol; prepared similarly to tert-butyl 4-((5-carbamoylpyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate as described in Example 4 (step 2)) in anhydrous pyridine (0.4 mL) cooled at 0°C was added Ac2O (0.044 mL; 0.47 mmol). The reaction mixture was stirred at 0°C for 30 min and at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water (20 mL) and EtOAc (20 mL). The phases were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL). The organic phases were combined, washed with sat. NH4Cl (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 5%) in CH2Cl2to afford 0.067 g (50%) of tert-butyl 4-((5-((2-(acetyloxy)ethyl)carbamoyl)pyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate as a yellow solid.1H NMR (DMSO-d6) δ 8.94 (t, 1 H), 8.77 (s, 1 H), 7.30 (s, 1 H), 4.74 (m, 1 H), 4.07 - 4.16 (m, 4 H), 3.52 (m, 2 H), 2.80 - 2.95 (m, 5 H), 2.02 (s, 3 H), 1.58 - 1.72 (m, 4 H), 1.43 (s, 9 H). Step 2: To a solution of tert-butyl 4-((5-((2-(acetyloxy)ethyl)carbamoyl}pyridazin-3- yl)(methyl)amino)piperidine-1-carboxylate (0.078 g; 0.19 mmol) in dioxane (0.7 mL) cooled at 0°C was added 4N HCl in dioxane (0.93 mL; 3.72 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and coevaporated with CH2Cl2(2 x 5 mL) to afford 0.073 g (67%) of 2-((6-(methyl(piperidin-4- yl)amino)pyridazin-4-yl)formamido)ethyl acetate dihydrochloride as a beige solid. Step 3: A mixture of 2-((6-(methyl(piperidin-4-yl)amino)pyridazin-4-yl)formamido)ethyl acetate dihydrochloride (0.043 g; 0.09 mmol), 2-chloro-4,6-dimethyl-5-(2- methylpropyl)pyrimidine (0.017 g; 0.09 mmol) and DIPEA (0.060 mL; 0.35 mmol) in CH3CN (1.2 mL) was heated at 140°C in a sealed tube for 18 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 25 mL). The organic phases were combined, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 10%) in CH2Cl2to afford 0.014 g (32%) of 2-((6- ((1-(4,6-dimethyl-5-(2-methylpropyl)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)pyridazin-4- yl)formamido)ethyl acetate as a colourless oil.1H NMR (DMSO-d6) δ 8.94 (t, 1 H), 8.77 (d, 1 H), 7.30 (d, 1 H), 4.77 - 4.86 (m, 3 H), 4.14 (t, 2 H), 3.51 (m, 2 H), 2.92 (s, 3 H), 2.86 - 2.93 (m, 2 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 2.02 (s, 3 H), 1.69 - 1.77 (m, 5 H), 0.90 (d, 6 H). Step 4: To a solution of 2-((6-((1-(4,6-dimethyl-5-(2-methylpropyl)pyrimidin-2- yl)piperidin-4-yl)(methyl)amino)pyridazin-4-yl)formamido)ethyl acetate (0.018 g; 0.04 mmol) in MeOH (1.8 mL) was added Amberlyst® A26 (50 mg) and the reaction mixture was stirred on the rotary evaporator for 6 h. The reaction mixture was filtered and the solids were washed with MeOH (2 x 2 mL). The filtrate was concentrated under reduced pressure and the residue was dried under high vacuum to afford 0.014 g (86%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.81 (t, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.75 - 4.92 (m, 4 H), 3.52 (m, 2 H), 3.34 (m, 2 H), 2.84 - 2.99 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.65 - 1.84 (m, 5 H), 0.90 (d, 6 H). LCMS (method LC-C): Rt= 3.47 min (98.5%); m / z 442 [M+H]+. Example 10: Preparation of 3-((6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)pyridazin-4-yl)oxy)propan-1-ol (CPD-042) To a solution of 5-(3-benzyloxypropoxy)-N-(1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4- piperidyl)-N-methyl-pyridazin-3-amine (0.107 g; 0.21 mmol) in MeOH (5.8 mL) and TFA (0.2 mL) was added 10% Pd / C (0.024 g). The reaction mixture was stirred at room temperature for 3 h under H2atmosphere. The reaction mixture was filtered through celite and the solids were washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0.7N NH3in MeOH (0% to 5%) in CH2Cl2to afford 0.048 g (55%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, 1 H), 6.45 (d, 1 H), 4.76 - 4.93 (m, 3 H), 4.60 (t, 1 H), 4.17 (t, 2 H), 3.55 (m, 2 H), 2.78 - 2.95 (m, 5 H), 2.38 (m, 2 H), 2.28 (s, 6 H), 1.87 (m, 2 H), 1.75 (m, 1 H), 1.58 - 1.71 (m, 4 H), 0.89 (d, 6 H). LCMS (method LC-C): Rt= 3.97 min (99.8%); m / z 429 [M+H]+. Example 11: Preparation of N-(1-(5-((benzyl(methyl)amino)methyl)-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)-N,5-dimethylpyridazin-3-amine (CPD-046) A mixture of N-(1-(5-((benzylamino)methyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N,5- dimethyl-pyridazin-3-amine (0.021 g; 0.05 mmol), 37% formaldehyde in water (0.008 mL; 0.10 mmol) and 4Å molecular sieves in CH2Cl2(2 mL) was stirred at room temperature for 30 min. NaBH(OAc)3(0.052 g; 0.24 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2and washed with 10% aq. NaHCO3. The phases were separated. The organic phase was washed with 10% aq. NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 2%) in CH2Cl2to afford 0.009 g (41%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, 1 H), 7.17 - 7.37 (m, 5 H), 6.93 (d, 1 H), 4.83 - 4.91 (m, 2 H), 4.75 (m, 1 H), 3.47 (s, 2 H), 3.42 (s, 2 H), 2.90 (m, 2 H), 2.84 (s, 3 H), 2.36 (s, 6 H), 2.22 (s, 3 H), 2.01 (s, 3 H), 1.59 - 1.73 (m, 4 H). LCMS (method LC-D): Rt= 2.42 min (98.6%); m / z 446 [M+H]+. Example 12: Preparation of 5-(2-(dimethylamino)ethoxy)-N-(1-(5-isobutyl-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)-N-methylpyridazin-3-amine (CPD-055) Step 1: To a solution of 2-(6-((1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)- methyl-amino)pyridazin-4-yl)oxyethanol (0.150 g; 0.36 mmol) in CH2Cl2(3 mL) cooled at 0°C were added DMAP (0.004 g; 0.04 mmol), DIPEA (0.189 mL; 1.09 mmol) and MsCl (0.031 mL; 0.40 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2and was washed with water. The phases were separated. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 7%) in CH2Cl2to afford 0.091 g (51%) of 2-(6-((1-(5-isobutyl-4,6-dimethyl- pyrimidin-2-yl)-4-piperidyl)-methyl-amino)pyridazin-4-yl]oxyethyl methanesulfonate as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1 H), 6.12 (d, 1 H), 5.08 (m, 1 H), 4.92 - 5.04 (m, 2 H), 4.60 (m, 2 H), 4.34 (m, 2 H), 3.10 (s, 3 H), 2.87 - 3.02 (m, 5 H), 2.40 (d, 2 H), 2.36 (s, 6 H), 1.70 - 1.89 (m, 5 H), 0.94 (d, 6 H). Step 2: To a solution of 2-(6-((1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)- methyl-amino)pyridazin-4-yl)oxyethyl methanesulfonate (0.040 g; 0.08 mmol) in DMF (2 mL) was added 2M Me2NH in THF (3.0 mL; 6.00 mmol). The reaction mixture was heated at 100°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with sat. K2CO3. The phases were separated. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0.7N NH3in MeOH (0% to 5%) in CH2Cl2. Further purification by preparative HPLC (Prep-C) furnished 0.010 g (28%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, 1 H), 6.46 (d, 1 H), 4.76 - 4.91 (m, 3 H), 4.18 (t, 2 H), 2.81 - 2.94 (m, 5 H), 2.61 (m, 2 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 2.21 (s, 6 H), 1.76 (m, 1 H), 1.61 - 1.71 (m, 4 H), 0.90 (d, 6 H). LCMS (method LC-C): Rt= 3.83 min (99.9%); m / z 442 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCMS RT [M+Code LCMS+H] methodPurity1(min) ( H NMR (δ ppm) (%) m / z) (400 MHz, DMSO-d6) 8.25 (d,1 H), 6.42 (d, 1 H), 4.77 CPD- 056LC-C 3.73 99.1 456- 4.92 (m, 3 H), 4.12 (t, 2 H), 2.77 - 2.94 (m, 5 H), 2.37 (d, 2 H), 2.34 (m, 2 H), 2.29 (s, 6 H), 2.13 (s, 6 H), 1.85 (m, 2 H), 1.73 (m, 1 H), 1.61 - 1.69 (m, 4 H), 0.89 (d, 6 H) (400 MHz, DMSO-d6) 8.26 (d, 1 H), 6.44 (d, 1 H), 4.75 CPD- LC-C 3.- 4.92 (m, 3 H), 4.15 (t, 2 H), 2.78 - 2.96 (m, 5 H), 2.59 06051 98.6 442(t, 2 H), 2.38 (d, 2 H), 2.28 (s, 9 H), 1.85 (m, 2 H), 1.74 (m, 1 H), 1.61 - 1.70 (m, 4 H), 0.89 (d, 6 H) (400 MHz, DMSO-d6) 8.25 (d, 1 H), 6.43 (d, 1 H), 4.82 CPD- LC-D 2.18 96 44(m, 3 H), 4.14 (t, 2 H), 3.45 (t, 2 H), 3.24 (s, 3 H), 2.79 0713- 2.96 (m, 5 H), 2.37 (d, 2 H), 2.27 (s, 6 H), 1.96 (m, 2 H), 1.74 (m, 1 H), 1.57 - 1.70 (m, 4 H), 0.89 (d, 6 H) Example 13: Preparation of 5-(3-aminopropoxy)-N-(1-(5-isobutyl-4,6-dimethylpyrimidin- 2-yl)piperidin-4-yl)-N-methylpyridazin-3-amine (CPD-068) Step 1: 3-(6-((1-(5-Isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl- amino)pyridazin-4-yl)oxypropyl methanesulfonate was prepared according to the procedure described in Example 12 (Step 1) from 3-(6-((1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4- piperidyl)-methyl-amino)pyridazin-4-yl)oxypropan-1-ol (0.239 g; 0.56 mmol), DMAP (0.003 g; 0.03 mmol), DIPEA (0.291 mL; 1.67 mmol) and MsCl (0.048 mL; 0.61 mmol) in CH2Cl2(10 mL). Purification by flash chromatography on silica gel using a gradient of EtOAc (0% to 80%) in heptane furnished 0.200 g (67%) of the desired compound as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1 H), 6.47 (d, 1 H), 4.75 - 4.95 (m, 3 H), 4.36 (t, 2 H), 4.22 (t, 2 H), 3.19 (s, 3 H), 2.78 - 2.93 (m, 5 H), 2.28 (d, 2 H), 2.29 (s, 6 H), 2.16 (m, 2 H), 1.59 - 1.79 (m, 5 H), 0.90 (d, 6 H). Step 2: To a solution of 3-(6-((1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)- methyl-amino)pyridazin-4-yl)oxypropyl methanesulfonate (0.184 g; 0.36 mmol) in DMF (1.2 mL) was added NaN3(0.047 g; 0.72 mmol). The reaction mixture was heated at 60°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with sat. NaHCO3and extracted with EtOAc. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford quantitatively 0.156 g (67%) of 5-(3-azidopropoxy)-N-(1-(5- isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-pyridazin-3-amine as a brown oil which was used in the next step without further purification. Step 3: To a solution of (5-(3-azidopropoxy)-N-(1-(5-isobutyl-4,6-dimethyl-pyrimidin-2- yl)-4-piperidyl)-N-methyl-pyridazin-3-amine (0.144 g; 0.32 mmol) in THF (9 mL) and water (1 mL) was added PPh3(0.167 g; 0.64 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and co- evaporated with CH3CN. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 9%) in CH2Cl2to afford 0.050 g (35%) of the desired compound as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1 H), 6.45 (d, 1 H), 4.77 - 4.91 (m, 3 H), 4.18 (t, 2 H), 3.27 (m, 1 H), 2.81 - 2.96 (m, 5 H), 2.76 (m, 1 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.81 - 2.04 (m, 2 H), 1.58 - 1.76 (m, 5 H), 0.90 (d, 6 H). LCMS (method LC-C): Rt= 3.45 min (95.4%); m / z 428 [M+H]+. Example 14: Preparation of N-(1,3-dihydroxypropan-2-yl)-6-((1-(5-isobutyl-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxamide (CPD- Step 1: tert-Butyl 4-(methyl(5-(oxetan-3-ylcarbamoyl)pyridazin-3-yl)amino)piperidine- 1-carboxylate was prepared according to the procedure described in Example 4 (Step 2) from 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyridazine-4-carboxylic acid (0.090 g; 0.24 mmol), DIPEA (0.2 mL; 1.22 mmol), 3-oxetanamine (0.036 g; 0.49 mmol) and HATU (0.185 g; 0.49 mmol) in DMF (0.8 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 80%) in CH2Cl2furnished 0.090 g (90%) of the desired compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, 1 H), 8.79 (d, 1 H), 7.33 (d, 1 H), 5.01 (m, 1 H), 4.71 - 4.81 (m, 3 H), 4.59 (t, 2 H), 4.08 (m, 2 H), 2.83 - 2.93 (m, 5 H), 1.63 - 1.72 (m, 4 H), 1.42 (s, 9 H). Step 2: To a solution of tert-butyl 4-(methyl(5-(oxetan-3-ylcarbamoyl)pyridazin-3- yl)amino)piperidine-1-carboxylate (0.059 g; 0.15 mmol) in CH2Cl2(0.7 mL) cooled at 0°C was added TFA (0.17 mL; 2.26 mmol). The reaction mixture was stirred at room temperature for 1.5 h. NaHCO3(0.253 g; 3.01 mmol) and a few drops of water were added. The reaction mixture was concentrated under reduced pressure and coevaporated with CH2Cl2to afford quantitatively N-(1,3-dihydroxypropan-2-yl)-6-(methyl(piperidin-4-yl)amino)pyridazine-4- carboxamide. Step 3: A mixture of N-(1,3-dihydroxypropan-2-yl)-6-(methyl(piperidin-4- yl)amino)pyridazine-4-carboxamide (0.025 g; 0.08 mmol), 2-chloro-4,6-dimethyl-5-(2- methylpropyl)pyrimidine (0.016 g; 0.08 mmol) and Cs2CO3(0.130 g; 0.40 mmol) in CH3CN (1.1 mL) was heated at 140°C in a sealed tube for 23 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The organic phases were combined, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 5% NH4OH in MeOH (0% to 20%) in CH2Cl2to afford 0.004 g (11%) of N-(1,3-dihydroxypropan-2-yl)-6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin- 4-yl)(methyl)amino)pyridazine-4-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, 1 H), 8.39 (d, 1 H), 7.33 (d, 1 H), 4.80 - 4.91 (m, 3 H), 4.70 (m, 2 H), 3.97 (m, 1 H), 3.48 - 3.57 (m, 4 H), 2.84 - 2.96 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.62 - 1.81 (m, 5 H), 0.89 (d, 6 H). LCMS (method LC-C): Rt= 3.29 min (96.9%); m / z 472 [M+H]+. The compound listed in the table below was prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCMS odeRT [M+ -C LCMS+H] [M-H] methodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 mHz, DMSO-d6) 8.76 (d, 1 H), 8.65 (t, 1 H), 7.29 (d, 1 H), 4.85 (m, 3 H), 4.47 (t, 2 H), CPD- 078LC-C 3.63 98.1 500 4983.23 - 3.29 (m, 6 H), 2.82 - 3.03 (m, 5 H), 2.38 (d, 2 H), 2.29 (s, 6 H), 1.61 - 1.82 (m, 5 H), 0.90 (d, 6 H), 0.78 (s, 3H) Example 15: Preparation of 2-((6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)pyridazin-4-yl)amino)ethan-1-ol (CPD-079) Step 1: 5-(2-Azidoethoxy)-N-(1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N- methyl-pyridazin-3-amine was prepared according to the procedure described in Example 13 (Step 2) from 2-(6-((1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl- amino)pyridazin-4-yl)oxyethyl methanesulfonate (0.165 g; 0.17 mmol) and NaN3(0.022 g; 0.33 mmol) in DMF (5 mL). Purification by flash chromatography on silica gel using a gradient of EtOAc (0% to 55%) in heptane furnished 0.035 g (48%) of the desired compound as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1 H), 6.49 (d, 1 H), 4.75 - 4.95 (m, 3 H), 4.32 (m, 2 H), 3.72 (m, 2 H), 2.81 - 2.94 (m, 5 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.63 - 1.80 (m, 5 H), 0.90 (d, 6 H). Step 2: To a solution of 5-(2-azidoethoxy)-N-(1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)- 4-piperidyl)-N-methyl-pyridazin-3-amine (0.035 g; 0.08 mmol) in THF (3.2 mL) and water (0.3 mL) was added PPh3(0.042 g; 0.16 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water. The phases were separated. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0.07N NH3in MeOH (0% to 5%) in CH2Cl2followed by preparative HPLC (method Prep-C) to afford 0.010 g of 5-(2-azidoethoxy)-N-(1- (5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-pyridazin-3-amine.0.005 g of 5- (2-azidoethoxy)-N-(1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-pyridazin- 3-amine was dissolved in CH3CN (1 mL). The reaction mixture was heated at 80°C for 10 d in a sealed reaction tube and was concentrated under reduced pressure to afford 0.005 g (30%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, 1 H), 6.48 (t, 1 H), 5.82 (d, 1 H), 4.79 - 4.90 (m, 3 H), 4.76 (t, 1 H), 3.55 (m, 2 H), 3.15 (m, 2 H), 2.85 (m, 2 H), 2.75 (s, 3 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.75 (m, 1 H), 1.55 - 1.69 (m, 4 H), 0.89 (d, 6 H). LCMS (method LC-C): Rt= 3.48 min (100%); m / z 414 [M+H]+. Example 16: Preparation of 2-((6-((1-(5-isobutyl-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)pyridazin-4-yl)(methyl)amino)ethan-1-ol (CPD-080) A mixture of 2-(6-((1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl- amino)pyridazin-4-yl)oxyethyl methanesulfonate (0.060 g; 0.12 mmol) in 40% MeNH2in MeOH (6 mL) was heated at 50°C for 3 h. After cooling to room temperature, the reaction mixture was partitioned between sat. NaHCO3and EtOAc. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0.07N NH3in MeOH (0% to 5%) in CH2Cl2followed by preparative HPLC (method Prep-C) to afford 0.019 g of N-(1-(5-isobutyl-4,6- dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-5-(2-(methylamino)ethoxy)pyridazin-3-amine. 0.010 g of N-(1-(5-isobutyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-5-(2- (methylamino)ethoxy)pyridazin-3-amine was dissolved in CH3CN (1 mL). The reaction mixture was heated at 80°C for 8 d in a sealed reaction tube and was concentrated under reduced pressure to afford 0.016 g (31%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, 1 H), 5.81 (d, 1 H), 4.79 - 4.95 (m, 3 H), 4.72 (t, 1 H), 3.55 (m, 2 H), 3.46 (m, 2 H), 2.97 (s, 3 H), 2.86 (m, 2 H), 2.77 (s, 3 H), 2.38 (d, 2 H), 2.28 (s, 6 H), 1.75 (m, 1 H), 1.58 - 1.67 (m, 4 H), 0.89 (d, 6 H). LCMS (method LC-C): Rt= 3.72 min (98.4%); m / z 428 [M+H]+. Example 17: Preparation of N-(1-(5-(2,2-difluoroethyl)-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)-N,5-dimethylpyridazin-3-amine (CPD-082)

[0003] Step 1: To a suspension of NaH (0.299 g; 7.48 mmol) in THF (42.5 mL) was added dibenzyl propanedioate (1.87 mL; 7.48 mmol). The reaction mixture was stirred at room temperature for 30 min.2,2-Difluoroethyl trifluoromethanesulfonate (1.50 g; 6.80 mmol) was added and the reaction mixture was stirred at room temperature for 21 h. The reaction was quenched by addition of water and the reaction mixture was diluted with EtOAc. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0 to 10%) in heptane to afford 2.22 g (66%) of dibenzyl 2-(2,2-difluoroethyl)propanedioate as a colourless oil. Step 2: To a solution of dibenzyl 2-(2,2-difluoroethyl)propanedioate (2.00 g; 5.74 mmol) in EtOH (6 mL) were added urea (0.345 g; 5.74 mmol) and tBuOK (1.27 g; 13.2 mmol). The reaction mixture was heated at 60ºC for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up with Et2O. After 30 min stirring, the mixture was filtered. The filtrate was concentrated under reduced pressure to afford 1.5 g of 5-(2,2- difluoroethyl)hexahydropyrimidine-2,4,6-trione as a yellow solid which was used in next step without purification. Step 3: A mixture of 5-(2,2-difluoroethyl)hexahydropyrimidine-2,4,6-trione (1.5 g) and diethylaniline (3.73 mL; 23.4 mmol) in POCl3(44 mL) was heated at 140ºC for 1 h and at 120ºC for 22 h. The reaction mixture was concentrated under reduced pressure and coevaporated with toluene. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 10%) in heptane to afford 0.546 g (28% over two steps) of 2,4,6-trichloro-5-(2,2-difluoroethyl)pyrimidine as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ 6.15 - 6.55 (m, 1 H), 3.50 (m, 2 H). Step 4: To a solution of 2,4,6-trichloro-5-(2,2-difluoroethyl)pyrimidine (0.250 g; 1.01 mmol) and Fe(acac)2(0.071 g; 0.20 mmol) in THF (10 mL) cooled at -10°C was added 2M MeMgBr in hexane (1.11 mL; 2.22 mmol). The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. The reaction was quenched by addition of sat. NH4Cl and the reaction mixture was extracted with EtOAc. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 20%) in heptane to afford 0.140 g (67%) of 2-chloro-5-(2,2-difluoroethyl)-4,6-dimethyl-pyrimidine as a yellow oil.1H NMR (400 MHz, CDCl3) δ 5.82 - 6.19 (m, 1 H), 3.26 (m, 2 H), 2.56 (s, 6 H). Step 5: A mixture of 2-chloro-5-(2,2-difluoroethyl)-4,6-dimethyl-pyrimidine (0.080 g; 0.39 mmol), CsF (0.206 g; 1.36 mmol), DIPEA (0.236 mL; 1.36 mmol) and N,5-dimethyl-N-(4- piperidyl)pyridazin-3-amine dihydrochloride (0.108 g; 0.39 mmol) in CH3CN (3 mL) was heated at 120ºC for 5 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0 to 1.5%) in CH2Cl2to afford 0.048 g (33%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 6.92 (s, 1 H), 6.02 - 6.42 (m, 1 H), 4.87 (m, 2 H), 4.77 (m, 1 H), 3.14 (m, 2 H), 2.92 (m, 2 H), 2.84 (s, 3 H), 2.32 (s, 6 H), 2.21 (s, 3 H), 1.60 - 1.74 (m, 4 H). LCMS (method LC-C): Rt = 3.46 min (100%); m / z 377 [M+H]+. The compound listed in the table below was prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCMS odeRT [M+H+C LCMS] methodPurity1(min) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.36 (d, 1 H), 6.92 (d, 1 H), CPD- 4.87 (m, 2 H), 4.78 (m, 1 H), 3.63 (m, 2 H), 2.92 (m, 083LC-C 3.90 99.4 395 2 H), 2.83 (s, 3 H), 2.33 (s, 6 H), 2.21 (s, 3 H), 1.60 - 1.73 (m, 4 H) Example 18: Preparation of N-(1-(5-(4-fluorophenyl)-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)-N-methyl-5-(3-(methylamino)propoxy)pyridazin-3-amine (CPD-084) Step 1: tert-Butyl 4-((5-(3-benzyloxypropoxy)pyridazin-3-yl)-methyl-amino)piperidine- 1-carboxylate was prepared according to the procedure described in Example 3 (Step 1) from 5-(3-benzyloxypropoxy)-3-chloro-pyridazine (1.82 g; 6.53 mmol), DIPEA (3.41 mL; 19.6 mmol), CsF (2.98 g; 19.6 mmol) and tert-butyl 4-(methylamino)piperidine-1-carboxylate (2.80 g; 13.1 mmol) in DMSO (17 mL). Purification by flash chromatography on silica gel using a gradient of EtOAc (0% to 60%) in heptane furnished 1.66 g (55%) of the desired compound as an orange oil.1H NMR (300 MHz, CDCl3) δ 8.30 (d, 1 H), 7.26 - 7.35 (m, 5 H), 6.07 (d, 1 H), 5.05 (m, 1 H), 4.52 (s, 2 H), 4.09 - 4.29 (m, 4 H), 3.65 (t, 2 H), 2.85 - 2.91 (m, 5 H), 2.11 (m, 2 H), 1.69 - 1.79 (m, 4 H), 1.49 (s, 9 H). Step 2: To a solution of tert-butyl 4-((5-(3-benzyloxypropoxy)pyridazin-3-yl)-methyl- amino)piperidine-1-carboxylate (0.810 g; 1.77 mmol) in MeOH (5.9 mL) and TFA (0.3 mL) was added 10% Pd / C (0.162 g). The reaction mixture was stirred at room temperature for 23 h under H2(10 bars). The reaction mixture was filtered through celite and the solids were washed with MeOH. The residue was purified by flash chromatography on silica gel using a gradient of 0.7N NH3in MeOH (0% to 5%) in CH2Cl2to afford quantitatively tert-butyl 4-((5- (3-hydroxypropoxy)pyridazin-3-yl)-methyl-amino)piperidine-1-carboxylate as an orange foam.1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1 H), 6.69 (s, 1 H), 4.54 (m, 1 H), 4.36 (t, 2 H), 4.22 (m, 2 H), 3.79 (m, 2 H), 3.05 (s, 3 H), 2.88 (m, 2 H), 2.05 (m, 2 H), 1.64 - 1.84 (m, 4 H), 1.47 (s, 9 H). Step 3: To a solution of tert-butyl 4-((5-(3-hydroxypropoxy)pyridazin-3-yl)-methyl- amino)piperidine-1-carboxylate (0.950 g; 2.59 mmol) in CH2Cl2(24 mL) were added DMAP (0.032 g; 0.26 mmol), DIPEA (1.35 mL; 7.77 mmol) and MsCl (0.221 mL; 2.85 mmol). The reaction mixture was stirred at room temperature for 50 min. The reaction mixture was diluted with CH2Cl2and was washed with water. The phases were separated. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford quantitatively tert-butyl 4-(methyl-(5-(3- methylsulfonyloxypropoxy)pyridazin-3-yl)amino)piperidine-1-carboxylate as a brown oil. Step 4: A solution of tert-butyl 4-(methyl-(5-(3-methylsulfonyloxypropoxy)pyridazin-3- yl)amino)piperidine-1-carboxylate (1.15 g; 2.59 mmol) in 40% MeNH2in MeOH (94 mL) was heated at 50°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 3.5N NH3in MeOH (0% to 5%) in CH2Cl2to afford 0.665 g (64%) of tert-butyl 4-(methyl-(5-(3-(methylamino)propoxy]pyridazin-3-yl)amino)piperidine-1- carboxylate as a yellow oil. Step 5: To a solution of tert-butyl 4-(methyl-(5-(3-(methylamino)propoxy]pyridazin-3- yl)amino)piperidine-1-carboxylate (0.640 g; 1.69 mmol) in THF (6.3 mL) and 1M NaOH (1.6 mL) was added cBzCl (0.345 g; 2.02 mmol). The reaction mixture was stirred at room temperature for 1.5 h. cBzCl (0.345 g; 2.02 mmol) was added again and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and water. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 100%) in heptane to afford 0.347 g (39%) of tert-butyl 4-((5-(3- (benzyloxycarbonyl(methyl)amino)propoxy)pyridazin-3-yl)-methyl-amino)piperidine-1- carboxylate as a yellow oil.1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1 H), 7.32 (m, 5 H), 6.03 (m, 1 H), 5.00 - 5.13 (m, 3 H), 4.23 (m, 2 H), 4.04 (m, 2 H), 3.50 (t, 2 H), 2.97 (s, 3 H), 2.77 - 2.93 (m, 5 H), 2.08 (m, 2 H), 1.57 - 1.77 (m, 4 H), 1.49 (s, 9 H). Step 6: A solution of tert-butyl 4-((5-(- (benzyloxycarbonyl(methyl)amino)propoxy)pyridazin-3-yl)-methyl-amino)piperidine-1- carboxylate (0.320 g; 0.62 mmol) in CH2Cl2(10 mL) and TFA (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford quantitatively benzyl N-methyl-N-(3-(6-(methyl(4-piperidyl)amino)pyridazin-4- yl)oxypropyl)carbamate under its TFA salt form as a yellow oil. Step 7: Benzyl N-(3-(6-((1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl- amino)pyridazin-4-yl)oxypropyl)-N-methyl-carbamate was prepared according to the procedure described in Example 7 (Step 1) from 5-bromo-2-chloro-4,6-dimethyl-pyrimidine (0.222 g; 1.00 mmol), benzyl N-methyl-N-(3-(6-(methyl(4-piperidyl)amino)pyridazin-4- yl)oxypropyl)carbamate (0.480 g; 0.91 mmol; TFA salt), DIPEA (0.555 mL; 3.18 mmol) and CsF (0.484 g; 3.18 mmol) in CH3CN (7 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 4%) in CH2Cl2furnished 0.250 g (46%) of the desired compound as an orange oil. Step 8: Benzyl N-(3-(6-((1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)- methyl-amino)pyridazin-4-yl)oxypropyl)-N-methyl-carbamate was prepared according to the procedure described in Example 7 (Step 2) from (4-fluorophenyl)boronic acid (0.032 g; 0.23 mmol), K3PO4(0.149 g, 0.70 mmol), XPhos (0.017 g; 0.04 mmol), Pd(Ph3)4(0.020 g; 0.02 mmol) and benzyl N-(3-(6-((1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl- amino)pyridazin-4-yl)oxypropyl)-N-methyl-carbamate (0.105 g; 0.18 mmol) in dioxane (3.6mL) and H2O (0.4 mL). Purification by flash chromatography on silica gel using a gradient ofMeOH (0% to 5%) in CH2Cl2furnished 0.250 g (46%) of the desired compound as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 8.24 (m, 1 H), 7.83 (m, 1 H), 7.52 - 7.65 (m, 4 H), 7.24 - 7.36 (m, 5 H), 7.14 (m, 1 H), 6.41 (m, 1 H), 5.02 (m, 2 H), 4.91 (m, 3 H), 4.11 (m, 2 H), 2.81 - 3.02 (m, 8 H), 2.03 (s, 6 H), 1.96 (m, 2 H), 1.65 - 1.75 (m, 4 H). Step 9: To a solution of benzyl N-(3-(6-((1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin- 2-yl)-4-piperidyl)-methyl-amino)pyridazin-4-yl)oxypropyl)-N-methyl-carbamate (0.090 g; 0.15 mmol) in EtOAc (5 mL) and TFA (0.3 mL) was added 10% Pd / C (0.018 g). The reaction mixture was stirred at room temperature for 6 h under H2atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of 0.7N NH3in MeOH (0% to 10%) in CH2Cl2followed by purification by preparative HPLC (method Prep-D) furnished 0.024 g (34%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, 1 H), 7.26 - 7.30 (m, 4 H), 6.46 (d, 1 H), 4.85 - 4.97 (m, 3 H), 4.16 (t, 2 H), 2.97 (m, 2 H), 2.86 (s, 3 H), 2.59 (t, 2 H), 2.28 (s, 3 H), 2.04 (s, 6 H), 1.86 (m, 2 H), 1.67 - 1.76 (m, 4 H). LCMS (method LC-C): Rt= 3.56 min (99.6%); m / z 480 [M+H]+. The compound listed in the table below was prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCMS RT [M+H+Code LCMS] methodPurity1(min) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.26 (d,1 H), 7.35 (m, 1 H), 6.93 (m, 1 H), 6.75 - 6.79 (m, 2 H), 6.45 (d, 1 H), CPD- 085LC-C 3.41 98.9 4924.84 - 4.97 (m, 3 H), 4.15 (t, 2 H), 3.76 (s, 3 H), 2.96 (m, 2 H), 2.85 (s, 3 H), 2.57 (t, 2 H), 2.27 (s, 3 H), 2.04 (s, 6 H), 1.85 (m, 2 H), 1.63 - 1.74 (m, 4 H) Example 19: Preparation of 6-((1-(5-(4-fluorophenyl)-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4-carboxamide (CPD- 098) Step 1: A mixture of (4-fluorophenyl)boronic acid (0.345 g; 2.46 mmol), tert-butyl N-(1- (5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.507 g; 1.23 mmol), PEPPSI-IPr (0.043 g; 0.06 mmol) and 2N Na2CO3(1.8 mL; 3.60 mmol) in dioxane (10 mL) was degassed with Ar. The reaction mixture was heated under microwave irradiation at 130oC for 30 min and at 150°C for 30 min. PEPPSI-IPr (0.043 g; 0.06 mmol) was added. After degassing with Ar, the reaction mixture was heated under microwave irradiation at 150°C for 30 min. PEPPSI-IPr (0.043 g; 0.062 mmol) was added again. After degassing with Ar, the reaction mixture was heated under microwave irradiation at 150°C for 30 min. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water. The phases were separated. The organic layer was washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of EtOAc (2% to 30%) in heptane furnished 0.432 g (85%) of tert-butyl N-(1-(5-(4- fluorophenyl)-4,6-dimethyl-pyrimidin-2-y))-4-piperidy))-N-methyl-carbamate as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, 4 H), 4.87 (m, 2 H), 3.75 - 4.13 (m, 1 H), 2.83 (t, 2 H), 2.66 (s, 3 H), 2.02 (s, 6 H), 1.51 - 1.67 (m, 4 H), 1.41 (s, 9 H). LCMS (method LC-A): Rt= 1.97 min; m / z 415 [M+H]+. Step 2: To a solution of tert-butyl N-(1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)- 4-piperidyl)-N-methyl-carbamate (0.43 g; 1.04 mmol) in dioxane (5 mL) and MeOH (5 mL) was added 4N HCl in dioxane (5.2 mL; 20.8 mmol). The reaction mixture was stirred at room temperature for 3 h and was concentrated under reduced pressure to afford quantitatively 1- (5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-N-methyl-piperidin-4-amine dihydrochloride as a beige soild. LCMS (method LC-A): Rt= 1.24 min; m / z 315 [M+H]+. Step 3: Methyl 6-((1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)- methyl-amino)pyridazine-4-carboxylate was prepared according to the procedure described in Example 3 (Step 1) from methyl 6-chloropyridazine-4-carboxylate (0.080 g; 0.45 mmol), ), CsF (0.207 g; 1.36 mmol), DIPEA (0.31 mL; 1.82 mmol) and 1-(5-(4-fluorophenyl)-4,6-dimethyl- pyrimidin-2-yl)-N-methyl-piperidin-4-amine dihydrochloride (0.176 g; 0.45 mmol) in DMSO (2.2 mL). Purification by flash chromatography on silica gel using a gradient of EtOAc (5% to 50%) in heptane furnished 0.050 g (24%) of the desired compound as a beige oil. LCMS (method LC-A): Rt= 1.70 min; m / z 451 [M+H]+. Step 4: To a solution of methyl 6-((1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-4- piperidyl)-methyl-amino)pyridazine-4-carboxylate (0.035 g; 0.08 mmol) in THF (0.7 mL) and water (0.2 mL) was added LiOH (0.006 g; 0.14 mmol). The reaction mixture was stirred at room temperature for 1 h and was concentrated under reduced pressure. The residue was dissolved in water. The reaction mixture was acidified with 1N HCl until pH ~ 2 and was extracted several times with 5% MeOH in CH2Cl2. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 0.031 g (91%) of 6- ((1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl-amino)pyridazine-4- carboxylic acid as a beige solid. LCMS (method LC-A): Rt= 1.21 min; m / z 437 [M+H]+; 435 [M-H]-. Step 5: To a solution of 6-((1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-4- piperidyl)-methyl-amino]pyridazine-4-carboxylic acid (0.030 g; 0.067 mmol), 2- methoxyethanamine (0.012 mL; 0.13 mmol) and DIPEA (0.058 mL; 0.34 mmol) in CH2Cl2(0.5 mL) was added 50% T3P in EtOAc (0.048 mL; 0.081 mmol). The reaction mixture was stirred at room temperature overnight. Sat. NaHCO3was added and the phases were separated. The aqueous layer was extracted with CH2Cl2. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica using a gradient of MeOH (0% to 7%) in CH2Cl2furnished 0.023 g (69%) of the desired compound as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 8.87 - 8.97 (m, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 7.28 (d, 4 H), 4.95 (m, 2 H), 4.79 - 4.91 (m, 1 H), 3.41 - 3.53 (m, 4 H), 3.28 (s, 3 H), 2.96 - 3.05 (m, 2 H), 2.94 (s, 3 H), 2.04 (s, 6 H), 1.66 - 1.82 (m, 4 H). LCMS (method LC-D): Rt= 1.19 min (100%); m / z 494 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION.Code LCMSLCMS RT methodPurity [M+H]+1(min) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.55 (s, 1 H), 7.28 (d, 4 H), 7.17 (s, 1 H), 4.92 (m, 2 H), 4.74 - 4.89 (m, 1 H), 3.92 - 4.07 (m, 1 CPD- 099LC-D 1.28 99.8 520H), 3.54 - 3.68 (m, 2 H), 3.36 - 3.53 (m, 2 H), 3.20 - 3.27 (m, 3 H), 2.95 - 3.06 (m, 2 H), 2.92 (s, 3 H), 1.90 - 2.09 (m, 8 H), 1.65 - 1.83 (m, 4 H). (400 MHz, DMSO-d6) 8.56 (s, 1 H), 7.28 (m, 4 H), 7.17 (s, CPD- LC-D 1.1 H), 4.93 (d, 2 H), 4.75 - 4.87 (m, 1 H), 3.48 (m, 2 H), 11543 100 4903.39 (m, 2 H), 2.89 - 3.06 (m, 5 H), 2.04 (s, 6 H), 1.69 – 1.01 (m, 4 H), 1.73 (m, 4 H) (400 MHz, DMSO-d6) 9.11 (t, 1 H), 8.81 (d, 1 H), 7.36 (d, CPD- LC1 H), 7.28 (d, 4 H), 4,92 (m, 2 H), 4.80 - 4.91 (m, 1 H), 188-D 1.82 100 5484.22 (t, 2 H), 3.61 (q, 2 H), 2.91 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.81 (m; 4 H) Example 20: Preparation of 6-((1-(5-(4-fluorophenyl)-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)(methyl)amino)-N-(2-isopropoxyethyl)pyridazine-4-carboxamide (CPD- 100) Step 1: 6-Chloro-N-(2-isopropoxyethyl)pyridazine-4-carboxamide was prepared according to the procedure described in Example 19 (Step 5) from 6-chloropyridazine-4- carboxylic acid (0.100 g; 0.62 mmol), 2-aminoethyl isopropyl ether (0.065 g; 0.62 mmol), NEt3(0.345 mL; 2.47 mmol) and 50% T3P in EtOAc (0.441 mL; 0.74 mmol) in CH2Cl2(4 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 9%) in CH2Cl2furnished 0.120 g (79%) of the desired compound as an orange oil. LCMS (method LC-A): Rt= 0.96 min; m / z 244 [M+H]+; 242 [M-H]-. Step 2: 6-((1-(5-(4-Fluorophenyl)-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)-N-(2-isopropoxyethyl)pyridazine-4-carboxamide was prepared according to the procedure described in Example 3 (Step 1) from 6-chloro-N-(2-isopropoxyethyl)pyridazine- 4-carboxamide (0.060 g; 0.24 mmol), DIPEA (0.165 mL; 0.97 mmol), CsF (0.110 g; 0.72 mmol) and 1-(5-(4-fluorophenyl)-4,6-dimethyl-pyrimidin-2-yl)-N-methyl-piperidin-4-amine dihydrochloride (0.112 g; 0.29 mmol) in DMSO (1.2 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 9%) in CH2Cl2followed by a second purification by flash chromatography using a gradient of MeOH (0% to 6%) in EtOAc furnished 0.060 g (47% yield) of the desired compound as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, 1 H), 8.79 (d, 1 H), 7.35 (d, 1 H), 7.28 (m, 4 H), 4.94 (m, 2 H), 4.85 (m, 1 H), 3.58 (dt, 1 H), 3.45 - 3.53 (m, 2 H), 3.38 - 3.45 (m, 2 H), 2.90 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.80 (m, 4 H), 1.10 (d, 6 H). LCMS (method LC-E): Rt= 3.82 min (98.7%); m / z 522 [M+H]+; 520 [M-H]-. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCMS deRT [M+H]+[M -Co LCMS-H] methodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.98 (t, 1 H), 8.78 (d,1 H), 7.33 (d, 1H), 7.23 - 7.31 (m, 4 H), 6.97 (s, CPD- 102LC-C 3.51 100 543 5412 H), 4.94 (m, 2 H), 4.86 (m, 1 H), 3.66 (m, 2 H), 3.24 - 3.29 (m, 2 H), 2.91 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.75 (d, 1 H), 8.05 (s, 1 H), 7.28 (m, 4 H), 7.24 (d, 1 H), 4.84 – 4.99 CPD- 103LC-D 1.89 98.4 522 520(m, 3 H), 3.52 (s, 2 H), 3.29 (s, 3 H), 2.89 - 3.06 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.81 (m, 4 H), 1.35 (s, 6 H). (400 MHz, DMSO-d6) 8.91 (t, 1 H), 8.76 (d, 1 H), 8.52 (m, 1 H), 7.71 (m, 1 H), 7.20 - 7.35 CPD- 109LC-C 4.01 100 541 539(m, 7 H), 4.93 (m, 2 H), 4.85 (m, 1 H), 3.64 (m, 2 H), 2.89 - 3.08 (m, 7 H), 2.04 (s, 6 H), 1.66 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.89 (d, 1 H), 8.79 (d, 1 H), 7.33 (d, 1 H), 7.21 - 7.32 (m, 4 H), 4.84 - CPD- LC-C 35.01 (m, 3 H), 4.47 (m, 1 H), 3.86 (m, 2 H), 110.83 100 506 5043.73 (m, 1 H),3.63 (m, 1 H), 2.89 - 3.10 (m, 5 H), 2.19 (m, 1 H), 2.04 (s, 6 H), 1.91 (m, 1 H), 1.74 (m, 4 H) (400 MHz, DMSO-d6) 9.44 (t, 1 H), 9.11 (s, 1 H), 8.77 - 8.85 (m, 3 H), 7.38 (s, 1 H), 7.22 - CPD- 111LC-C 3.59 100 528 5267.35 (m, 4 H), 4.86 - 4.98 (m, 3 H), 4.54 (d, 2 H), 2.90 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.80 (d, 1 H), 8.60 (d, 1 H), 7.31 (d, 1 H), 7.28 (m, 4 H), 4.82 - 5.01 CPD- 112LC-C 4.11 98.2 508 506(m, 3 H), 4.20 (m, 1 H), 3.23 - 3.46 (m, 5 H), 2.91 - 3.06 (m, 5 H), 2.04 (s, 6 H), 1.66 - 1.81 (m, 4 H), 1.16 (d, 3 H) (400 MHz, DMSO-d6) 8.79 (d, 1 H), 8.66 (t, 1 CPD- H), 7.34 (d, 1 H), 7.22 - 7.32 (d, 4 H), 4.85 - 113LC-D 1.58 99.8 522 5204.98 (m, 3 H), 3.34 (m, 2 H), 3.15 (s, 3 H), 2.89 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.66 - 1.88 (m, 4 H), 1.12 (s, 6 H) (400 MHz, DMSO-d6) 8.78 (d, 1 H), 8.75 (t, 1 H), 7.32 (d, 1 H), 7.24 - 7.30 (m, 4 H), 4.93 CPD- LC-D 2.49 97.9 520 5(m, 2 H), 4.85 (m, 1 H), 3.27 - 3.30 (m, 2 H), 114182.98 (m, 2 H), 2.93 (s, 3 H), 2.04 (s, 6 H), 1.68 - 1.81 (m, 4 H), 1.47 (m, 2 H), 0.94 (s, 9 H) (400 MHz, DMSO-d6) 9.46 (s, 1 H), 8.82 (d, 1 CPD- LC-D 1H), 7.40 (d, 1 H), 7.23 - 7.35 (m, 4 H), 4.82 - 116.76 97.8 5185.03 (m, 3 H), 4.15 (m, 2 H), 2.90 - 3.07 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.85 (m, 4 H) (400 MHz, DMSO-d6) 9.51 (t, 1 H), 8.82 (d, 1 H), 7.40 (d, 1 H), 7.20 - 7.37 (m, 4 H), 4.80 - CPD- 117LC-C 3.90 99.6 532 5305.01 (m, 3 H), 4.59 (d, 2 H), 2.91 - 3.06 (m, 5 H), 2.58 (s, 3 H), 2.40 (s, 6 H), 1.67 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 9.09 (t, 1 H), 8.77 (d, 1 H), 7.33 (d, 1H), 7.21- 7.31 (m, 4 H), 4.78 - CPD- 118LC-C 3.65 100 542 5405.05 (m, 3 H), 3.69 (m, 2 H), 3.39 (m, 2 H), 3.04 (s, 3 H), 2.90 - 3.04 (m, 5 H), 2.03 (s, 6 H), 1.69 - 1.79 (m, 4 H) (400 MHz, DMSO-d6) 9.59 (t, 1 H), 8.83 (d, 1 H), 7.41 (d, 1 H), 7.22 - 7.37 (m, 4 H), 4.79 - CPD- 119LC-C 3.65 95.8 532 5305.02 (m, 3 H), 4.71 (m, 2 H), 2.90 - 3.07 (m, 5 H), 2.50 (s, 3 H), 2.04 (s, 6 H), 1.65 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.74 - 8.81 (m, 2 H), 7.33 (d, 1 H), 7.23 - 7.31 (m, 4 H), 4.94 (m, 2 CPD- LC-C 3.83 98H), 4.87 (m, 1 H), 4.51 (d, 1 H), 3.69 (m, 1 120.7 508 506H), 3.33 - 3.41 (m, 2 H), 2.91 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.69 - 1.83 (m, 4 H), 1.59 (m, 2 H), 1.09 (d, 3 H) (400 MHz, DMSO-d6) 8.75 - 8.81 (m, 2 H), CPD- 7.33 (d, 1 H), 7.23 - 7.31 (m, 4 H), 4.81 - 5.00 121LC-C 3.51 99.2 494 492(m, 3 H), 4.49 (t, 1 H), 3.47 (m, 2 H), 3.32 - 3.36 (m, 2 H), 2.90 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.65 - 1.82 (m, 6 H) (400 MHz, DMSO-d6) 8.86 (t, 1 H), 8.75 (s, 1 H), 7.31 (s, 1 H), 7.25 - 7.30 (m, 4 H), 6.30 (s, CPD- 122LC-C 3.44 100 548 5461 H), 4.93 (m, 2 H), 4.85 (m, 1 H), 3.36 - 3.42 (m, 4 H), 3.17 - 3.28 (m, 4 H), 2.91 - 3.07 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 9.13 (d, 1 H), 8.80 (s, 1 H), 7.32 (s, 1 H), 7.24 - 7.30 (m, 4 H), 4.84 - CPD- 123LC-D 1.76 99.6 526 5245.02 (m, 3 H), 4.27 (m, 1 H), 2.89 - 3.04 (m, 7 H), 2.75 (m, 2 H), 2.04 (s, 6 H), 1.68 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.80 (d, 1 H), 8.66 (t, 1 H), 7.32 (s, 1 H), 7.25 - 7.30 (m, 4 H), 4.86 - CPD- 124LC-D 2.16 97.6 506 5044.99 (m, 3 H), 3.12 (d, 2 H), 2.91- 3.04 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.82 (m 4 H), 0.91 (s, 9 H) (400 MHz, DMSO-d6) 8.77 - 8.81 (m, 2 H), 7.76 (t, 1 H), 7.37 (d 1 H), 7.18 - 7.23 (m, 4 CPD- 125LC-C 3.84 98.6 547 545H), 4.78 - 4.94 (m, 3 H), 4.67 (m, 1 H), 3.20 - 3.31 (m, 1 H), 3.11 (m, 1 H), 2.89 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.55 - 1.99 (m, 10 H) (400 MHz, DMSO-d6) 8.88 (t, 1 H), 8.80 (d, 1 H), 7.34 (d, 1 H), 7.24 - 7.32 (m, 4 H), 4.82 - CPD- 126LC-C 3.66 100 556 5544.97 (m, 3 H), 3.41 (m, 2 H), 3.19 (m, 2 H), 2.95 - 3.02 (m, 5 H), 2.94 (s, 3 H), 2.04 (s, 6 H), 1.96 (m, 2 H), 1.71 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.76 - 8.81 (m, 2 H), 7.34 (d, 1 H), 7.25 - 7.32 (m, 4 H), 4.82 - 5.01 CPD- 127LC-C 3.76 99.2 561 559(m, 3 H), 3.35 (m, 2 H), 3.20 - 3.29 (m, 4 H), 2.90 - 3.06 (m, 5 H), 2.21 (m, 2 H), 2.04 (s, 6 H), 1.93 (m, 2 H), 1.67 - 1.79 (m, 6 H) (400 MHz, DMSO-d6) 9.34 (t, 1 H), 8.82 (d, 1 H), 7.40 (d, 1 H), 7.26 - 7.34 (m, 4 H), 7.09 - CPD- LC-C 3.72 100 530 57.11 (m, 1 H), 6.81 (d, 1 H), 4.93 (m, 2 H), 128284.84 (m, 1 H), 4.55 (d, 2 H), 3.65 (s, 3 H), 2.93 - 3.03 (m, 5 H), 2.03 (s, 6 H), 1.70 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 9.45 (t, 1 H), 8.87 (d, 1 H), 8.83 (d, 1 H), 7.39 (d, 1 H), 7.24 - 7.32 CPD- 129LC-C 4.00 98.8 517 515(m, 4 H), 6.56 (d,1 H), 4.93 (m, 2 H), 4.85 (m, 1 H), 4.59 (d, 2 H), 2.91 - 3.06 (m, 5 H), 2.04 (s, 6 H), 1.69 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.76 - 8.84 (m, 2 H), 7.32 (d, 1 H), 7.23 - 7.31 (m, 4 H), 4.93 (m, 2 CPD- 130LC-C 4.02 95.3 508 506H), 4.85 (m, 1 H), 3.38 (t, 2 H), 3.32 - 3.35 (m, 2 H), 3.24 (s, 3 H), 2.90 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.84 (m, 6 H) (400 MHz, DMSO-d6) 9.45 (t, 1 H), 8.87 (d, 1 H), 8.75 - 8.82 (m, 2 H), 7.39 - 7.49 (m, 2 H), CPD- 131LC-C 3.63 95.1 528 5267.23 - 7.32 (m, 4 H), 4.94 (m, 2 H), 4.87 (m, 1 H), 4.70 (d, 2 H), 2.92 - 3.02 (m, 5 H), 2.04 (s, 6 H), 1.71 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 12.3 (br. s., 1 H), 8.90 (t, 1 H), 8.78 (d, 1 H), 7.68 (s, 1 H), 7.33 (d, CPD- LC-C 3.46 100 531H), 7.21 - 7.30 (m, 4 H), 6.90 (s, 1 H), 4.78 - 1330 5285.00 (m, 3 H), 3.50 (m, 2 H), 2.89 - 3.06 (m, 5 H), 2.78 (t, 2 H), 2.04 (s, 6 H), 1.70 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.78 (d, 1 H), 8.61 (d, 1 H), 7.21 - 7.37 (m, 5 H), 4.85 - 4.97 (m, 3 H), CPD- 134LC-D 1.92 96.5 5044.22 (m, 1 H), 2.91 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.86 - 1.96 (m, 2 H), 1.67 - 1.78 (m, 6 H), 1.50 - 1.59 (m, 4 H) (400 MHz, DMSO-d6) 9.01 (d, 1 H), 8.81 (d, 1 H), 7.71 (s, 1 H), 7.36 (d, 1 H), 7.22 - 7.33 (m, CPD- 135LC-C 3.48 98.6 533 5314 H), 4.80 - 5.03 (m, 3 H), 4.39 (m, 1 H), 3.18 (m, 2 H), 2.89 - 3.06 (m, 5 H), 1.96 - 2.09 (m, 7 H), 1.67 - 1.90 (m, 7 H) (400 MHz, DMSO-d6) 8.88 (t, 1 H), 8.77 (d, 1 H), 7.22 - 7.35 (m, 5 H), 4.93 (m, 2 H), 4.86 CPD- LC-C 3.52 99.0 547 5(m, 1 H), 3.69 (m, 1 H), 3.42 - 3.56 (m, 2 H), 136452.89 - 3.06 (m, 5 H), 2.76 (s, 3 H), 2.23 (m, 1 H), 1.97 - 2.18 (m, 8 H), 1.84 (m, 1 H), 1.65 - 1.77 (m, 4 H) (400 MHz, DMSO-d6) 9.08 (d, 1 H), 8.80 (d,1 H), 7.71 (s, 1 H), 7.34 (d, 1 H), 7.23 - 7.32 (m, CPD- LC-C4 H), 4.83 - 5.03 (m, 3 H), 4.61 (m, 1 H), 3.62 1373.31 98.0 519 517(m, 1 H), 3.18 (m, 1 H), 2.91 - 3.05 (m, 5 H), 2.59 (m, 1 H), 2.24 (m, 1 H), 2.04 (s, 6 H), 1.68 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.75 - 8.80 (m, 2 H), 7.31 (d, 1 H), 7.25 - 7.30 (m, 4 H), 4.82 - 4.98 CPD- LC-D 1.48 98.4(m, 3 H), 3.83 (m, 2 H), 3.22 - 3.28 (m, 4 H), 1395482.91 - 3.05 (m, 5 H), 2.00 - 2.07 (s, 6 H), 1.70 - 1.78 (m, 4 H), 1.44 - 1.67 (m, 4 H), 1.12 - 1.25 (m, 3 H) (400 MHz, DMSO-d6) 8.88 (t, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 7.28 (m, 4 H), 4.82 - 5.01 CPD- 146LC-E 3.42 99.9 508 506(m, 3 H), 3.44 - 3.54 (m, 1 H), 3.30 - 3.35 (m, 2 H), 3.28 (s, 3 H), 2.91 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.75 (m, 4 H), 1.10 (d, 3 H) (400 MHz, DMSO-d6) 9.54 (t, 1 H), 8.84 (d, 1 H), 8.70 (m, 1 H), 8.62 (m, 1 H), 8.57 (m, 1 CPD- 147LC-C 3.74 98.1 528 526H), 7.42 (d, 1 H), 7.22 - 7.33 (m, 4 H), 4.82 - 4.98 (m, 3 H), 4.65 (d, 2 H), 2.93 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.85 (m, 4 H) (400 MHz, DMSO-d6) 8.76 - 8.87 (m, 2 H), 7.37 (s, 1 H), 7.28 (d, 4 H), 4.83 - 5.01 (m, 3 CPD- LC-C 3H), 4.81 (d, 1 H), 3.80 (dt, 1 H), 3.12 - 3.29 155.62 98.9 494 492(m, 2 H), 2.94 (s, 3 H), 2.89 - 3.06 (m, 2 H), 2.04 (s, 6 H), 1.66 - 1.82 (m, 4 H), 1.08 (d, 3 H) (400 MHz, DMSO-d6) 11.5 (br. s., 1 H), 9.19 (t, 1 H), 8.81 (m, 1 H), 7.43 (m, 1 H), 7.36 (d, CPD- LC-C 3.38 81 H), 7.34 (s, 1 H), 7.24 - 7.31 (m, 4 H), 6.33 1576.3 543 541(d, 1 H), 4.82 - 4.98 (m, 3 H), 4.23 (d, 2 H), 2.91 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.78 (d, 1 H), 8.65 (t, 1 H), 7.32 (d, 1 H), 7.24 - 7.30 (m, 4 H), 4.83 - CPD- 161LC-D 1.59 98.2 5224.99 (m, 3 H), 4.57 (t, 1 H), 3.13 - 3.22 (m, 4 H), 2.91 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.82 (m, 4 H), 0.85 (s, 6 H) (400 MHz, DMSO-d6) 8.79 - 8.89 (m, 2 H), 7.39 (s, 1 H), 7.28 (m, 4 H), 5.46 (s, 1 H), CPD- 162LC-C 3.72 98.3 506 5044.82 - 5.00 (m, 3 H), 3.44 (d, 2 H), 2.91 - 3.06 (m, 5 H), 2.05 (s, 6 H), 1.75 (m, 4 H), 0.58 (s, 4 H) (400 MHz, DMSO-d6) 8.76 - 8.87 (m, 2 H), 7.37 (d, 1 H), 7.28 (m, 4 H), 4.82 - 5.01 (m, 3 CPD- 163LC-C 3.61 100 494 492H), 4.80 (d, 1 H), 3.80 (m, 1 H), 3.13 - 3.32 (m, 2 H), 2.89 - 3.04 (m, 5 H), 2.04 (s, 6 H), 1.75 (m, 4 H), 1.08 (d, 3 H) (400 MHz, DMSO-d6) 8.81 (d, 1 H), 8.66 (m, 1 H), 7.37 (d, 1 H), 7.25 - 7.32 (m, 4 H), 4.82 CPD- 167LC-C 3.77 100 508 506- 4.99 (m, 3 H), 4.57 (s, 1 H), 3.26 (m, 2 H), 2.92 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.68 - 1.83 (m, 4 H), 1.11 (s, 6 H) (400 MHz, DMSO-d6) 8.76 - 8.87 (m, 2 H), 7.37 (d, 1 H), 7.28 (d, 4 H), 4.82 - 5.01 (m, 3 CPD- 169LC-C 3.54 99.8 494 492H), 4.81 (d, 1 H), 3.80 (m, 1 H), 3.13 - 3.32 (m, 2 H), 2.89 - 3.06 (m, 5 H), 2.04 (s, 6 H), 1.75 (m, 4 H), 1.08 (d, 3 H) (400 MHz, DMSO-d6) 8.88 (t, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 7.28 (m, 4 H), 4.81 - 5.01 CPD- 170LC-C 4.04 99 508 506(m, 3 H), 3.48 (m, 1 H), 3.30 - 3.35 (m, 2 H), 3.28 (s, 3 H), 2.90 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1,75 (m, 4 H), 1.11 (d, 3 H) (400 MHz, DMSO-d6) 8.90 (t, 1 H), 8.82 (d, 1 H), 7.35 (d, 1 H), 7.28 (m, 4 H), 4.83 - 5.00 CPD- 171LC-D 1.41 98.9 520 518(m, 3 H), 3.54 (d, 2 H), 3.26 (s, 3 H), 2.90 - 3.06 (m, 5 H), 2.05 (s, 6 H), 1.75 (m, 4 H), 0.71 (m, 2 H), 0.65 (m, 2 H) (400 MHz, DMSO-d6) 8.86 (t, 1 H), 8.81 (d, 1 H), 7.44 (d, 1 H), 7.23 - 7.33 (m, 4 H), 4.95 CPD- 172LC-C 3.38 97.8 480 478(m, 2 H), 4.77 - 4.89 (m, 2 H), 3.50 - 3.55 (m, 2 H), 3.22 - 3.47 (m, 2 H), 2.90 - 3.07 (m, 5 H), 2.04 (s, 6 H), 1.67 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.88 (t, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 7.28 (m, 4 H), 4.81 - 5.01 CPD- 173LC-C 4.05 98.1 508 506(m, 3 H), 3.48 (m, 1 H), 3.30 - 3.35 (m, 2 H), 3.28 (s, 3 H), 2.90 - 3.05 (m, 5 H), 2.04 (s, 6 H), 1.75 (m, 4 H), 1.11 (d, 3 H) (400 MHz, DMSO-d6) 8.78 - 8.90 (m, 2 H), 7.59 (t, 1 H), 7.35 - 7.43 (m, 2 H), 7.24 - 7.33 CPD- 174LC-D 1.55 95.8 572 570(m, 2 H), 5.46 (s, 1 H), 4.82 - 5.02 (m, 3 H), 3.44 (d, 2 H), 2.89 - 3.08 (m, 5 H), 2.06 (s, 6 H), 1.75 (m, 4 H), 0.58 (s, 4 H) (400 MHz, DMSO-d6) 8.91 (d, 1 H), 8.78 (s, 1 H), 7.32 (s, 1 H), 7.23 - 7.31 (m, 4 H), 4.82 - CPD- LC-C 4.06 98.6 5205.01 (m, 3 H), 4.06 (m, 1 H), 3.64 (m, 1 H), 1755183.15 (s, 3 H), 2.90 - 3.06 (m, 5 H), 2.60 (m, 2 H), 2.04 (s, 6 H), 1.95 (m, 2 H), 1.65 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.87 - 8.98 (m, 1 H), 8.81 (s, 1 H), 7.49 - 7.52 (m, 1 H), 7.36 (s, 1 CPD- H), 7.31 (t, 1 H), 7.18 ( 76LCm, 1 H), 7.01 - 7.15 1-C 3.86 98.9 542 540(m, 2 H), 4.79 - 5.04 (m, 3 H), 3.42 - 3.51 (m, 4 H), 3.28 (s, 3 H), 2.89 - 3.07 (m, 5 H), 2.06 (s, 6 H), 1.75 (m, 4 H) (400 MHz, DMSO-d6) 9.00 (m, 1 H), 8.79 (s, 1 H), 7.22 - 7.36 (m, 5 H), 4.48 - 5.50 (m, 4 H), CPD- 177LC-D 1.53 97.8 508 5063.99 (m, 1 H), 2.90 - 3.08 (m, 5 H), 2.76 (m, 2 H), 2.29 (m, 2 H), 2.04 (s, 6 H), 1.66 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.90 (m, 1 H), 8.78 (d, 1 H), 7.22 - 7.37 (m, 5 H), 5.07 (d, 1 H), 4.84 CPD- 178LC-C 3.48 99.2 506 504- 5.00 (m, 3 H), 4.42 (m, 1 H), 4.35 (m, 1 H), 2.89 - 3.04 (m, 5 H), 2.28 (m, 2 H), 2.19 (m, 2 H), 2.04 (s, 6 H), 1.67 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.97 (m, 1 H), 8.79 (d, 1 H), 7.31 (d, 1 H), 7.26 - 7.30 (m, 4 H), 4.84 CPD- 179LC-C 4.02 97.4 520 518- 4.98 (m, 3 H), 4.42 (m, 1 H), 4.02 (m, 1 H), 3.17 (s, 3 H), 2.91 - 3.05 (m, 5 H), 2.24 - 2.32 (m, 4 H), 2.05 (s, 6 H), 1.68 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.89 (m, 1 H), 8.78 (d, 1 H), 7.32 (d, 1 H), 7.24 - 7.31 (m, 4 H), 5.18 CPD- 185LC-C 3.46 93.0 506 504(s, 1 H), 4.83 - 4.98 (m, 3 H), 3.90 (m, 2 H), 2.90 - 3.06 (m, 5 H), 2.57 (m, 2 H), 2.04 (s, 6 H), 1.92 (m, 2 H), 1.67 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.93 (m, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 7.02 (s, 1 H), 6.84 (s, 2 CPD- LC-C 3.04 99.1 53H), 4.75 - 5.01 (m, 3 H), 4.63 (t, 1 H), 3.62 1914 532(m, 2 H), 3.42 - 3.52 (m, 4 H), 3.28 (s, 3 H), 2.89 - 3.00 (m, 5 H), 2.72 (t, 2 H), 2.32 (s, 3 H), 2.05 (s, 6 H), 1.68 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (t, 1 H), 8.79 (d, 1 H), 7.35 (d, 1 H), 7.03 (s, 1 H), 6.85 (s, 2 H), CPD- LC-C 4.004.75 - 5.01 (m, 3 H), 3.55 (t, 2 H), 3.41 - 3.51 19397.0 548 546(m, 4 H), 3.27 (s, 3 H), 3.24 (s, 3 H), 2.90 - 3.04 (m, 5 H), 2.80 (t, 2 H), 2.31 (s, 3 H), 2.04 (s, 6 H), 1.70 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.39 (m, 1 H), 7.33 - 7.38 (m, 1H), 7.20 CPD- LC-D 1.21 10(m, 1 H), 6.92 (s, 1 H), 4.75 - 4.99 (m, 3 H), 1940 534 5324.03 (s, 2 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 3.15 (s, 3 H), 2.86 - 3.05 (m, 5 H), 2.33 (s, 3 H), 1.93 (s, 6 H), 1.63 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, CPD- LC-1 H), 7.35 (d, 1 H), 7.13 (s, 1 H), 6.92 - 6.98 197D 1.33 99.7 534 532(m, 2 H), 4.81 - 5.05 (m, 3 H), 4.41 (s, 2 H), 3.38 - 3.56 (m, 4 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 2.91 - 3.07 (m, 5 H), 2.35 (s, 3 H), 2.04 (s, 6 H), 1.68 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.76 - 8.83 (m, 2 H), 7.59 (t, 1 H), 7.36 - 7.41 (m, 2 H), 7.27 - 7.33 (m, 2 H), 4.95 (m, 2 H), 4.88 (m, 1 H), 4.78 CPD- 202LC-C 4.48 96.5 574 572(d, 1 H), 3.51 - 3.58 (m, 1 H), 3.13 - 3.21 (m, 1 H), 3.00 (m, 2 H), 2.94 (s, 3 H), 2.06 (s, 6 H), 1.75 (m, 4 H), 1.41 - 1.52 (m, 1 H), 1.27 - 1.38 (m, 2 H), 0.91 (t, 3 H) Example 21: Preparation of 6-((1-(5-bromo-4,6-dimethylpyrimidin-2-yl)piperidin-4- yl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4-carboxamide (CDP-187) and 6-((1- (4,6-dimethyl-5-(o-tolyl)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N-(2- methoxyethyl)pyridazine-4-carboxamide (CPD-138) Step 1: A solution of tert-butyl N-(1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)- N-methyl-carbamate (1.0 g; 2.50 mmol) in 4N HCl in dioxane (31 mL; 124 mL) was stirred at room temperature for 2 h and was concentrated under reduced pressure to afford quantitatively 1-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-N-methyl-piperidin-4-amine dihydrochloride as a white solid. Step 2: 6-((1-(5-Bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl-amino)-N-(2- methoxyethyl)pyridazine-4-carboxamide (CDP-187) was prepared according to the procedure described in Example 3 (Step 1) from 6-chloro-N-(2-methoxyethyl)pyridazine-4-carboxamide (2.20 g; 10.2 mmol), DIPEA (6.5 mL; 37.1 mmol), CsF (4.22 g; 27.8 mmol) and 1-(5-bromo- 4,6-dimethyl-pyrimidin-2-yl)-N-methyl-piperidin-4-amine dihydrochloride (3.45 g; 9.27 mmol) in DMSO (80 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 9%) in CH2Cl2followed by a second purification by flash chromatography using a gradient of EtOAc (80% to 100%) in heptane furnished 3.33 g (75% yield) of the desired compound as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.75 - 4.92 (m, 3 H), 3.39 - 3.55 (m, 4 H), 3.28 (s, 3 H), 2.88 (m, 2 H), 2.91 (s, 3 H), 2.41 (s, 6 H), 1.64 - 1.82 (m, 4 H). LCMS (method LC-C): Rt= 3.57 min (96.1%); m / z 478 [M+H]+. Step 3: 6-((1-(4,6-dimethyl-5-(o-tolyl)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N-(2- methoxyethyl)pyridazine-4-carboxamide (CPD-138) was prepared according to the procedure described in Example 7 (Step 2) from o-tolylboronic acid (0.071 g; 0.52 mmol), K3PO4(0.177 g; 0.84 mmol), XPhos (0.020 g; 0.04 mmol), Pd(Ph3)4(0.024 g; 0.02 mmol) and 6-((1-(5- bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl-amino)-N-(2-methoxyethyl)- pyridazine-4-carboxamide (0.100 g; 0.21 mmol) in dioxane (2.3 mL) and H2O (0.2 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 5%) in CH2Cl2furnished 0.068 g (66%) of the desired compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.93 (m, 1 H), 8.80 (d, 1 H), 7.33 - 7.39 (m, 2 H), 7.24 - 7.32 (m, 2 H), 7.06 (m, 1 H), 4.95 (m, 2 H), 4.86 (m, 1 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.88 - 3.04 (m, 5 H), 2.00 (s, 3 H), 1.94 (s, 6 H), 1.69 - 1.83 (m, 4 H). LCMS (method LC-D): Rt= 1.30 min (100%); m / z 490 [M+H]+. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCLCMS RT [M+H]+[M-H]-Code MSmethodPurity1(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (d, 1 H), 7.61 (m, 1 H), 7.41 - 7.49 (m, 2 H), CPD- L 7.36 (d, 1 H), 7.33 (m, 1 H), 4.95 (m, 2 H), 140C-D 1.33 98.7 510 x4.87 (m, 1 H), 3.37 - 3.54 (m, 4 H), 3.27 (s, 3 H), 2.93 - 3.06 (m, 5 H), 1.96 (s, 6 H), 1.68 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.31 - 7.37 (m, 2 H), 7.18 (m, 1 H), CPD- LC-D 1.7.03 (s, 1 H), 7.00 (m, 1 H), 4.93 (m, 2 H), 14149 100 490 4884.86 (m, 1 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.01 (m, 5 H), 2.35 (s, 3 H), 2.04 (s, 6 H), 1.68 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (d, 1 H), 7.35 (d, 1 H), 7.32 (m, 1 H), 7.03 (d, 1 H), 6.97 (d, 1 H), 6.92 (m, 1 H), 4.93 (m, 2 CPD- 142LC-D 1.77 97.2 516 514H), 4.85 (m, 1 H), 3.42 - 3.51 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.10 (m, 5 H), 2.03 (s, 6 H), 1.94 (m, 1 H), 1.65 - 1.82 (m, 4 H), 0.97 (m, 2 H), 0.71 (m, 2 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.59 (t, 1 H), 7.34 - 7.42 (m, 2 H), 7.25 CPD- LC-D 1.80 99.8 560 5- 7.33 (m, 2 H), 4.94 (m, 2 H), 4.85 (m, 1 H), 143583.42 - 3.50 (m, 4 H), 3.28 (s, 3 H), 3.00 (m, 2 H), 2.94 (s, 3 H), 2.05 (s, 6 H), 1.69 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (d, 1 H), 7.36 (d, 1 H), 7.25 (d, 2 H), 7.10 (d, 2 CPD- 144LC-D 1.51 99.6 490 488H), 4.81 - 4.97 (m, 3 H), 3.43 - 3.49 (m, 4 H), 3.28 (s, 3 H), 2.89 - 3.03 (m, 5 H), 2.36 (s, 3 H), 2.03 (s, 6 H), 1.66 - 1.85 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, CPD- 145LC-D 1.32 99.3 512 5101 H), 7.36 (d, 1 H), 7.25 (m, 1 H), 7.01 - 7.09 (m, 2 H), 4.94 (m, 2 H), 4.84 (m, 1 H), 3.41 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.99 (m, 2 H), 2.93 (s, 3 H), 2.07 (s, 6 H), 1.68 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.31 - 7.40 (m, 2 H), 7.21 (d, 1 H), 7.01 - 7.09 (m, 2 H), 4.94 (m, 2 H), 4.86 (m, CPD- 148LC-C 2.85 100 520 5181 H), 4.64 (t, 1 H), 3.63 (m, 2 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91- 3.01 (m, 5 H), 2.76 (t, 2 H), 2.05 (s, 6 H), 1.68 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.85 (d, 1 H), 7.78 (s, 1 H), 7.59 - 7.69 CPD- 9LC-(m, 2 H), 7.36 (d, 1 H), 4.93 (m, 2 H), 4.86 14C 3.39 100 501 499(m, 1 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.06 (m, 5 H), 2.04 (s, 6 H), 1.69 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (m, 1 H), 7.33 - 7.39 (m, 2 H), 6.94 (m, 1 H), CPD- LC-C6.76 - 6.80 (m, 2 H), 4.93 (m, 2 H), 4.86 (m, 1503.77 99.5 506 5041 H), 3.77 (s, 3 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.04 (m, 5 H), 2.05 (s, 6 H), 1.67 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.80 (d, 1 H), 7.89 (m, 1 H), 7.71 - 7.78 (m, 2 H), 7.65 (m, 1 H), 7.36 (d, 1 H), 4.95 (m, 2 H), CPD- 151LC-C 2.97 97.5 568 5664.86 (m, 1 H), 3.41 - 3.50 (m, 4 H), 3.36 (q, 2 H), 3.28 (s, 3 H), 3.01 (m, 2 H), 2.94 (s, 3 H), 2.05 (s, 6 H), 1.67 - 1.84 (m, 4 H), 1.11 (t, 3 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.80 (d,1 H), 7.44 (m, 1 H), 7.36 (d, 1 H), 6.99 (d, CPD- LC-C 3.721 H), 6.92 (t, 1 H), 4.94 (m, 2 H), 4.87 (m, 1 152100 524 522H), 3.77 (s, 3 H), 3.42 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.06 (m, 5 H), 1.98 (s, 6 H), 1.71 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 7.21 (m, 1 H), 7.12 (m, 1 CPD- LC-C 3.77 98.8 52H), 7.02 (m, 1 H), 4.93 (m, 2 H), 4.86 (m, 1 1534 522H), 3.71 (s, 3 H), 3.40 - 3.53 (m, 4 H), 3.28 (s, 3 H), 2.88 - 3.05 (m, 5 H), 1.99 (s, 6 H), 1.68 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (d, 1 H), 7.36 (d, 1 H), 6.50 (t, 1 H), 6.36 (d, 2 CPD- LC-C 3.H), 4.92 (m, 2 H), 4.85 (m, 1 H), 3.76 (s, 6 15462 100 536 534H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.05 (m, 5 H), 2.07 (s, 6 H), 1.67 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.35 (d, 1 H), 7.26 (m, 1 H), 7.03 (m, 1 CPD- LC-C 3.78H), 6.78 (m, 1 H), 4.93 (m, 2 H), 4.85 (m, 1 15697.2 524 522H), 3.84 (s, 3 H), 3.41 - 3.51 (m, 4 H), 3.28 (s, 3 H), 2.90 - 3.05 (m, 5 H), 2.07 (s, 6 H), 1.67 - 1.80 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.80 (d, 1 H), 7.40 - 7.52 (m, 2 H), 7.34 - 7.36 (m, 2 CPD- H), 7.21 (d, 1 H), 4.94 (m, 2 H), 4.85 (m, 1 158LC-D 1.77 99.9 510 508H), 3.41 - 3.52 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.07 (m, 5 H), 2.05 (s, 6 H), 1.66 - 1.84 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.80 (d, 1 H), 7.35 (d, 1 H), 7.03 (t, 1 H), 6.89 (t, 1 CPD- LC-C 4.31H), 6.78 (m, 1 H), 4.93 (m, 2 H), 4.85 (m, 1 159100 540 538H), 3.80 (s, 3 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.05 (m, 5 H), 2.06 (s, 6 H), 1.67 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 8.22 (d, 1 H), 7.35 (d, 1 H), 6.89 (m, 1 CPD- LC-C 3.16 100 5H), 6.73 (s, 1 H), 4.94 (m, 2 H), 4.87 (m, 1 16007 505H), 3.89 (s, 3 H), 3.39 - 3.54 (m, 4 H), 3.27 (s, 3 H), 3.00 (m, 2 H), 2.94 (s, 3 H), 2.07 (s, 6 H), 1.68 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.88 (d, 1 H), 7.78 (t, 1 H), 7.64 (t, 1 CPD- LC-C 4.13H), 7.33 - 7.42 (m, 2 H), 4.94 (m, 2 H), 4.87 16498.8 544 542(m, 1 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.08 (m, 5 H), 1.91 (s, 6 H), 1.69 - 1.85 (m, 4 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.36 (d, 1 H), 6.84 (m, 1 H), 6.63 - CPD- 6.71 (m, 2 H), 4.93 (m, 2 H) 5LC-C, 4.84 (m, 1 H), 163.96 95.7 524 5223.80 (s, 3 H), 3.43 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.91 - 3.05 (m, 5 H), 2.07 (s, 6 H), 1.67 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.80 (d, 1 H), 8.31 (d, 1 H), 8.05 (d, 1 H), 7.36 (d, 1 CPD- LC-C 2.65 9H), 7.32 (m, 1 H), 4.95 (m, 2 H), 4.85 (m, 1 1667.4 507 505H), 3.86 (s, 3 H), 3.42 - 3.51 (m, 4 H), 3.28 (s, 3 H), 3.01 (m, 2 H), 2.94 (s, 3 H), 2.07 (s, 6 H), 1.68 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.80 (d, 1 H), 7.75 (m, 1 H), 7.70 (t, 1 H), 7.63 (s, 1 CPD- LC-D 1H), 7.58 (m, 1 H), 7.36 (d, 1 H), 4.95 (m, 2 168.55 99.9 544 542H), 4.87 (m, 1 H), 3.44 - 3.49 (m, 4 H), 3.28 (s, 3 H), 3.00 (m, 2 H), 2.94 (s, 3 H), 2.04 (s, 6 H), 1.69 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.73 - 8.85 (m, 2 H), 7.59 (t, 1 H), 7.27 - 7.42 (m, 4 H), 4.95 (m, 2 CPD- LC-H), 4.88 (m, 1 H), 4.80 (d, 1 H), 3.80 (m, 1 180D 1.40 100 560 558H), 3.13 - 3.29 (m, 2 H), 2.89 - 3.06 (m, 5 H), 2.05 (s, 6 H), 1.64 - 1.82 (m, 4 H), 1.07 (d, 3 H) (400 MHz, DMSO-d6) 9.14 (d, 1 H), 8.80 (d, 1 H), 7.60 (t, 1 H), 7.38 (m, 1 H), 7.25 - 7.35 CPD- 181LC-D 2.30 98.9 592 590(m, 3 H), 4.83 - 4.99 (m, 3 H), 4.28 (m, 1 H), 2.90 - 3.07 (m, 7 H), 2.78 (m, 2 H), 2.06 (s, 6 H), 1.68 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 9.46 (t, 1 H), 8.88 (d, 1 H), 8.83 (m, 1 H), 7.59 (t, 1 H), 7.34 - 7.44 CPD- LC-D 1.84 98.0 5(m, 2 H), 7.24 - 7.35 (m, 2 H), 6.57 (d, 1 H), 18283 5814.94 (m, 2 H), 4.87 (m, 1 H), 4.59 (d, 2 H), 2.89 - 3.05 (m, 5 H), 2.06 (s, 6 H), 1.68 - 1.82 (m, 4 H) (400 MHz, DMSO-d6) 9.45 (t, 1 H), 8.87 (d, 1 H), 8.82 (d, 1 H), 7.39 (d, 1 H), 7.31 (t, 1 H), 7.03 (d, 1 H), 6.97 (d, 1 H), 6.92 (s, 1 CPD- 183LC-D 1.82 95.4 539 537H), 6.56 (d, 1 H), 4.81 - 4.99 (m, 3 H), 4.59 (d, 2 H), 2.88 - 3.07 (m, 5 H), 2.03 (s, 6 H), 1.94 (m, 1 H), 1.65 - 1.83 (m, 4 H), 0.97 (m, 2 H), 0.71 (m, 2 H) (400 MHz, DMSO-d6) 8.78 - 8.82 (m, 2 H), 7.36 (d, 1 H), 7.32 (m, 1 H), 7.03 (d, 1 H), 6.97 (m, 1 H), 6.93 (m, 1 H), 4.94 (m, 2 H), CPD- LC-D 1.37 954.87 (m, 1 H), 4.80 (d, 1 H), 3.80 (m, 1 H), 184.2 516 5143.14 - 3.30 (m, 2 H), 2.88 - 3.06 (m, 5 H), 2.03 (s, 6 H), 1.94 (m, 1 H), 1.67 - 1.82 (m, 4 H), 1.07 (d, 3 H), 0.96 (m, 2 H), 0.71 (m, 2 H) (400 MHz, DMSO-d6) 9.13 (d, 1 H), 8.79 (d, 1 H), 7.28 - 7.35 (m, 2 H), 7.04 (m, 1 H), 6.97 (m, 1 H), 6.92 (s, 1 H), 4.83 - 4.98 (m, CPD- 186LC-D 2.30 99.3 548 5463 H), 4.26 (m, 1 H), 2.89 - 3.06 (m, 7 H), 2.78 (m, 2 H), 2.03 (s, 6 H), 1.94 (m, 1 H), 1.67 - 1.83 (m, 4 H), 0.96 (m, 2 H), 0.70 (m, 2 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (d, 1 H), 7.37 (d, 1 H), 7.13 (m, 1 H), 6.93 (s, 1 CPD- LC-C 2.81 99.5 520 51H), 6.89 (s, 1 H), 5.17 (t, 1 H), 4.80 - 5.01 1898(m, 3 H), 4.51 (d, 2 H), 3.42 - 3.55 (m, 4 H), 3.28 (s, 3 H), 2.90 - 3.053 (m, 5 H), 2.34 (s, 3 H), 2.05 (s, 6 H), 1.69 - 1.81 (m, 4 H) (400 MHz, DMSO-d6) 8.93 (m, 1 H), 8.80 (d, 1 H), 7.35 (d, 1 H), 7.27 (s, 1 H), 7.06 (s, 1 CPD- LC-C 3.30 9H), 6.85 (s, 1 H), 4.82 - 5.00 (m, 4 H), 3.41 - 1929.1 548 5463.52 (m, 4 H), 3.28 (s, 3 H), 2.90 - 3.05 (m, 5 H), 2.34 (s, 3 H), 2.05 (s, 6 H), 1.67 - 1.80 (m, 4 H), 1.43 (s, 6 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.80 (d, 1 H), 7.35 (d, 1 H), 7.18 (s, 1 H), 6.98 (s, 1 CPD- LC-C 4.26 100 56H), 6.92 (s, 1 H), 4.79 - 4.99 (m, 3 H), 3.37 - 1952 5603.55 (m, 4 H), 3.28 (s, 3 H), 2.90 - 3.07 (m, 8 H), 2.36 (s, 3 H), 2.05 (s, 6 H), 1.66 - 1.82 (m, 4 H), 1.46 (s, 6 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (m, 1 H), 7.36 (d, 1 H), 7.28 (m, 1 H), 7.14 (m, 1 H), 6.86 (m, 1 H), 4.94 (m, 2 H), 4.86 CPD- 198LC-D 1.52 100 548 546(m, 1 H), 3.42 - 3.51 (m, 4 H), 3.35 (t, 2 H), 3.28 (s, 3 H), 3.13 (s, 3 H), 2.93 - 3.02 (m, 5 H), 2.45 - 2.48 (m, 2 H), 2.30 (s, 3 H), 1.96 (m, 6 H), 1.71 - 1.84 (m, 4 H) Example 22: Preparation 6-((1-(5-(2-(hydroxymethyl)-5-methylphenyl)-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4- carboxamide (CPD-190)

[0004] Step 1: A mixture of 2-(2-(methoxymethoxymethyl)-5-methyl-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.168 g; 0.40 mmol), K3PO4(0.171 g; 0.80 mmol), 6-((1-(5- bromo-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl-amino)-N-(2-methoxyethyl)pyridazine- 4-carboxamide (0.128 g; 0.27 mmol), XPhos PdG4 (0.023 g; 0.03 mmol) and XPhos (0.026 g; 0.05 mmol) in dioxane (0.6 mL) and H2O (0.2 mL) was purged with N2for 1 min. The reaction mixture was heated at 140°C for 30 min under microwave irradiation. After cooling to room temperature, the reaction mixture was filtered through celite and the solids were washed withEtOAc. The filtrate was washed with sat. NaHCO3. The phases were separated. The aqueousphase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (0% to 1.5%) in CH2Cl2to afford 0.082 g (37%) of N-(2-methoxyethyl)-6-((1-(5-(2-(methoxymethoxymethyl)-5-methyl-phenyl)-4,6- dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl-amino)pyridazine-4-carboxamide as a yellow solid. Step 2: A solution of N-(2-methoxyethyl)-6-((1-(5-(2-(methoxymethoxymethyl)-5- methyl-phenyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-methyl-amino)pyridazine-4- carboxamide (0.080 g; 0.10 mmol) in 4N HCl in dioxane (2 mL) was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure and was coevaporated with heptane. The residue was purified by flash chromatography on silica gel using a gradient of 3N NH3in MeOH (0 to 1.5%) in CH2Cl2to afford 0.020 g (39%) of the desired compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.92 (m, 1 H), 8.79 (s, 1 H), 7.43 (d, 1 H), 7.35 (s, 1 H), 7.19 (d, 1 H), 6.86 (s, 1 H), 4.92 - 4.98 (m, 3 H), 4.85 (m, 1 H), 4.10 (d, 2 H), 3.39 - 3.54 (m, 4 H), 3.28 (s, 3 H), 2.87 - 3.11 (m, 5 H), 2.32 (s, 3 H), 1.94 (s, 6 H), 1.66 - 1.85 (m, 4 H). LCMS (method LC-C): Rt= 2.93 min (99.9%); m / z 520 [M+H]+. The compound listed in the table below was prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. LCMS RT [M+H]+[M- -Code LCMSH] Purity1method(min) (m / z) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.95 (m, 1 H), 8.80 (d, 1 H), 7.37 (d, 1 H), 7.25 (m, 1 H), 7.12 (m, 1 H), 6.86 CPD- LC-C 3.27(d, 1 H), 4.95 (m, 2 H), 4.86 (m, 1 H), 4.56 (t, 1 20499.5 534 532H), 3.44 - 3.53 (m, 4 H), 3.40 (m, 2 H), 3.28 (s, 3 H), 2.91 - 3.04 (m, 5 H), 2.41 (t, 2 H), 2.29 (s, 3 H), 1.96 (s, 6 H), 1.69 - 1.84 (m, 4 H) Example 23: Preparation of 6-((1-(5-((3,3-dimethylpyrrolidin-1-yl)methyl)-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4- carboxamide (CPD-196) Step 1: Ethyl 2-(4-(tert-butoxycarbonyl(methyl)amino)-1-piperidyl)-4,6-dimethyl- pyrimidine-5-carboxylate was prepared according to the procedure described in Example 6 (Step 1) from ethyl 2-chloro-4,6-dimethyl-pyrimidine-5-carboxylate (0.500 g; 2.33 mmol), tert- butyl N-methyl-N-(4-piperidyl)carbamate (0.549 g; 2.56 mmol) and Cs2CO3(3.04 mL; 9.32 mmol) in CH3CN (32 mL) with 92% yield.1H NMR (400 MHz, CDCl3) δ 5.02 (m, 2 H), 4.34 (q, , 2 H), 2.86 (m, 2 H), 2.70 (s, 3 H), 2.43 (s, 6 H), 1.72 (m, 2 H), 1.53 - 1.67 (m, 3 H), 1.48 (s, 9 H), 1.37 (t, 3 H). Step 2: tert-Butyl N-(1-(5-(hydroxymethyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N- methyl-carbamate was prepared with 90% yield according to the procedure described in Example 6 (Step 2) from ethyl 2-(4-(tert-butoxycarbonyl(methyl)amino)-1-piperidyl)-4,6- dimethyl-pyrimidine-5-carboxylate (0.840 g; 2.14 mmol) and LiAlH4(0.106 g; 2.78 mmol) in THF (21 mL) with heating at 80°C for 2 h.1H NMR (400 MHz, CDCl3) δ 5.02 (m, 2 H), 4.34 (q, , 2 H), 2.86 (m, 2 H), 2.70 (s, 3 H), 2.43 (s, 6 H), 1.72 (m, 2 H), 1.53 - 1.67 (m, 3 H), 1.48 (s, 9 H), 1.37 (t, 3 H).1H NMR (400 MHz, CDCl3) δ 4.88 (m, 2 H), 4.55 (s, 2 H), 2.76 (m, 2 H), 2.63 (s, 3 H), 2.35 (s, 6 H), 1.63 (m, 2 H), 1.49 - 1.59 (m, 3 H), 1.41 (s, 9 H). Step 3: To a solution of tert-butyl N-(1-(5-(hydroxymethyl)-4,6-dimethyl-pyrimidin-2-yl)- 4-piperidyl)-N-methyl-carbamate (0.675 g; 1.93 mmol) in THF (60 mL) was added MnO2(2.51 g; 28.9 mmol). The reaction mixture was heated at 75°C for 18 h. MnO2(2.51 g; 28.9 mmol) was added again and the reaction mixture was heated at 75°C for 6 h. After cooling to room temperature, the reaction mixture was filtered through celite. The solids were washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 15%) in heptane to afford 0.470 g (69%) of tert-butyl N-(1-(5-formyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl- carbamate as a white solid.1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1 H), 5.14 (m, 2 H), 2.92 (m, 2 H), 2.71 (s, 3 H), 2.62 (s, 6 H), 1.77 (m, 2 H), 1.59 - 1.69 (m, 3 H), 1.49 (s, 9 H). Step 4: tert-butyl N-(1-(5-((3,3-dimethylpyrrolidin-1-yl)methyl)-4,6-dimethyl-pyrimidin- 2-yl)-4-piperidyl)-N-methyl-carbamate was prepared according to the procedure described in Example 6 (Step 4) from 3,3-dimethylpyrrolidine hydrochloride (0.127 g; 0.93 mmol), tert-butyl N-(1-(5-formyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.250 g; 0.72 mmol), 4Å molecular sieves and NaBH(OAc)3(0.608 g; 2.87 mmol) in CH2Cl2(10 mL). Purification by flash chromatography on silica gel using a gradient of EtOAc (0% to 20%) in heptane furnished 0.234 g (76%) of the desired compound as a colourless oil.1H NMR (400 MHz, CDCl3) δ 4.94 (m, 2 H), 4.24 (m, 1 H), 3.43 (s, 2 H), 2.82 (m, 2 H), 2.72 (s, 3 H), 2.54 (m, 2 H), 2.41 (s, 6 H), 2.24 (s, 2 H), 1.58 - 1.75 (m, 4 H), 1.52 (m, 2 H), 1.48 (m, 9 H), 1.03 (s, 6 H). Step 5: A solution of tert-butyl N-(1-(5-((3,3-dimethylpyrrolidin-1-yl)methyl)-4,6- dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.230 g; 0.53 mmol) in 4N HCl in dioxane (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and was coevaporated with heptane to afford quantitatively 1-(5-((3,3- dimethylpyrrolidin-1-yl)methyl)-4,6-dimethyl-pyrimidin-2-yl)-N-methyl-piperidin-4-amine trihydrochloride as a white solid. Step 6: 6-((1-(5-((3,3-Dimethylpyrrolidin-1-yl)methyl)-4,6-dimethylpyrimidin-2- yl)piperidin-4-yl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4-carboxamide was prepared according to the procedure described in Example 3 (Step 1) from 6-chloro-N-(2- methoxyethyl)pyridazine-4-carboxamide (0.111 g; 0.52 mmol), DIPEA (0.315 mL; 1.81 mmol), CsF (0.275 g; 1.81 mmol), 1-(5-((3,3-dimethylpyrrolidin-1-yl)methyl)-4,6-dimethyl-pyrimidin-2- yl)-N-methyl-piperidin-4-amine trihydrochloride (0.53 mmol) in DMSO (5 mL). Purification by flash chromatography on silica gel using a gradient of MeOH (0% to 5%) in CH2Cl2followed by purification by preparative HPLC (method Prep-C) furnished 0.099 g (37%) of the desired compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.92 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.73 - 5.00 (m, 3 H), 3.38 - 3.52 (m, 6 H), 3.27 (s, 3 H), 2.85 - 2.98 (m, 5 H), 2.51 - 2.58 (m, 2 H), 2.36 (s, 6 H), 2.22 (s, 2 H), 1.54 - 1.86 (m, 4 H), 1.49 (t, 2 H), 1.02 (s, 6 H). LCMS (method LC-C): Rt= 3.80 min (96.1%); m / z 509 [M-H]-. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. Code LCMSLCMS RT [M-H]- methodPurity1(min) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 CPD- (d, 1 H), 4.76 - 4.91 (m, 3 H), 3.41 - 3.52 (m, 4 00LC-CH), 3.25 - 23.65 99.1 4953.30 (m, 5 H), 2.86 - 2.97 (m, 5 H), 2.34 (m, 10 H), 1.63 - 1.79 (m, 4 H), 1.31 - 1.51 (m, 6 H) (400 MHz, DMSO-d6) 8.79 (d, 1 H), 8.66 (t, 1 H), 7.21 - CPD- 7.37 (m, 6 H), 4.78 - 4.87 (m, 3 H), 4.56 (s, 1 H), 3.44 - 205LC-C 3.96 98.6 5453.48 (m, 4 H), 3.25 (d, 2 H), 2.85 - 2.97 (m, 5 H), 2.36 (s, 6 H), 2.01 (s, 3 H), 1.62 - 1.78 (m, 4 H), 1.11 (s, 6 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.79 - 4.92 (m, 3 H), 3.41 - 3.50 (m, 4 H), 3.30 CPD- 206LC-C 4.35 98.5 523(m, 2 H), 3.28 (s, 3 H), 2.87 - 2.97 (m, 5 H), 2.34 (s, 6 H), 2.18 (m, 2 H), 2.03 - 2.13 (m, 4 H), 1.60 - 1.78 (m, 6 H), 1.43 - 1.53 (m, 4 H), 1.10 (m, 2 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.76 - 4.92 (m, 3 H), 3.42 - 3.50 (m, 4 H), 3.30 CPD- 209LC-C 2.63 97.0 483(m, 2 H), 3.27 (s, 3 H), 2.85 - 2.98 (m, 5 H), 2.35 (s, 6 H), 2.27 (t, 2 H), 2.05 (s, 3 H), 1.61 - 1.80 (m, 4 H), 1.45 (m, 2 H), 0.83 (t, 3 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.73 - 4.92 (m, 3 H), 3.40 - 3.49 (m, 6 H), 3.34 - CPD- 210LC-C 2.35 99.3 4993.38 (m, 2 H), 3.30 (m, 2H), 3.28 (s, 3 H), 3.22 (s, 3 H), 2.87 - 2.96 (m, 5 H), 2.34 (s, 6 H), 2.11 (s, 3 H), 1.63 - 1.79 (m, 4 H) (400 MHz, DMSO-d6) 8.90 (m, 1 H), 8.78 (d, 1 H), 7.29 - CPD- LC-D 1.7.42 (m, 5 H), 7.25 (m, 1 H), 4.75 - 4.90 (m, 3 H), 3.41 - 21287 98.9 5573.50 (m, 4 H), 3.18 - 3.39 (m, 6 H), 2.81 - 2.97 (m, 5 H), 2.29 (m, 1 H), 2.13 - 2.24 (m, 7 H), 1.59 - 1.87 (m, 8 H) (400 MHz, DMSO-d6) 8.90 (m, 1 H), 8.79 (d, 1 H), 7.34 (m, 1 H), 4.76 - 4.91 (m, 3 H), 3.80 (m, 2 H), 3.40 - 3.51 CPD- LC-C 2.88 9(m, 6 H), 3.28 - 3.30 (m, 2 H), 3.26 (s, 3 H), 3.20 (t, 1 2139.2 525H), 2.86 - 2.96 (m, 5 H), 2.46 (m, 1 H), 2.33 (s, 6 H), 2.07 (s, 3 H), 1.96 (m, 1 H), 1.66 - 1.74 (m, 4 H), 1.51 (m, 2 H) (400 MHz, DMSO-d6) 8.89 (m, 1 H), 8.78 (d, 1 H), 7.34 (d, 1 H), 7.23 - 7.30 (m, 4 H), 7.16 (m, 1 H), 4.76 - 4.93 CPD- 215LC-C 4.03 92.9 557(m, 3 H), 3.55 (m, 2 H), 3.42 - 3.48 (m, 4 H), 3.30 (m, 2 H), 3.28 (s, 3 H), 2.84 - 2.96 (m, 6 H), 2.59 - 2.82 (m, 2 H), 2.39 (s, 6 H), 2.25 (m, 1 H), 1.66 - 1.78 (m, 5 H) (400 MHz, DMSO-d6) 8.92 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.72 - 4.97 (m, 3 H), 3.41 - 3.51 (m, 4 H), 3.30 CPD- 216LC-D 2.45 100 523(m, 2 H), 3.27 (s, 3 H), 3.25 (s, 2 H), 2.82 - 3.00 (m, 5 H), 2.34 (s, 6 H), 2.20 (m, 2 H), 2.01 (m, 2 H), 1.65- 1.74 (m, 4 H), 1.47 (m, 2 H), 1.21 (m, 2 H), 0.87 (s, 6 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.77 - 4.93 (m, 3 H), 3.42 - 3.52 (m, 4 H), 3.26 - CPD- 217LC-D 1.53 100 5353.28 (m, 5 H), 2.87 - 2.95 (m, 5 H), 2.34 (s, 6 H), 2.26 (m, 4 H), 1.83 (m, 2 H), 1.66 - 1.74 (m, 8 H), 1.45 - 1.51 (m, 4 H) (400 MHz, DMSO-d6) 8.90 (m, 1 H), 8.78 (d, 1 H), 7.30 - 7.37 (m, 5 H), 7.26 (m, 1 H), 4.74 - 4.96 (m, 3 H), 3.83 (t, CPD- 219LC-C 2.84 95.5 5881 H), 3.38 - 3.60 (m, 5 H), 3.21 - 3.30 (m, 4 H), 2.84 - 2.97 (m, 5 H), 2.75 (m, 2 H), 2.27 (s, 6 H), 2.15 (s, 6 H), 1.90 (s, 3 H), 1.62 - 1.80 (m, 4 H) Example 24: Preparation of 6-((1-(5-(((cyclopropylmethyl)(methyl)amino)methyl)-4,6- dimethylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4- carboxamide (CPD-208) Step 1: A solution of cyclopropylmethylamine (0.195 mL; 2.25 mmol) and tert-butyl N- (1-(5-formyl-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.156 g; 0.45 mmol) in CH2Cl2(6.3 mL) was stirred at room temperature for 16 h. NaBH(OAc)3(0.381 g; 1.80 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with CH2Cl2and washed with 10% aq. NaHCO3. The phases were separated. The organic phase was washed with 10% aq. NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 20%) in CH2Cl2to afford 0.110 g (58%) of tert- butyl N-(1-(5-((cyclopropylmethylamino)methyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N- methyl-carbamate as a white solid.1H NMR (400 MHz, CDCl3) δ 4.94 (m, 2 H), 4.25 (m, 1 H), 3.75 (s, 2 H), 2.84 (m, 2 H), 2.72 (s, 3 H), 2.56 (m, 2 H), 2.43 (s, 6 H), 1.54 - 1.73 (m, 6 H), 1.48 (s, 9 H), 1.03 (m, 1 H), 0.52 (m, 2 H), 0.16 (m, 2 H). Step 2: A solution of tert-butyl N-(1-(5-((cyclopropylmethylamino)methyl)-4,6-dimethyl- pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.107 g; 0.26 mmol) and 37% formaldehyde solution in water (0.198 mL; 2.64 mmol) in CH2Cl2(3.6 mL) was stirred at room temperature for 16 h. NaBH(OAc)3(0.224 g; 1.06 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with CH2Cl2and washed with 10% aq. NaHCO3. The phases were separated. The organic phase was washed with 10% aq. NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0 to 40%) in heptane to afford 0.065 g (59%) of tert-butyl N-(1-(5- ((cyclopropylmethyl(methyl)amino)methyl)-4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl- carbamate as a white solid.1H NMR (400 MHz, CDCl3) δ 4.94 (m, 2 H), 4.25 (m, 1 H), 3.37 (s, 2 H), 2.83 (m, 2 H), 2.72 (m, 3 H), 2.41 (s, 6 H), 2.24 (d, 2 H), 2.18 (s, 3 H), 1.67 - 1.76 (m, 3 H), 1.63 (m, 2 H), 1.49 (s, 9 H), 0.51 (m, 2 H), 0.10 (m, 2 H). Step 3: To a solution of tert-butyl N-(1-(5-((cyclopropylmethyl(methyl)amino)methyl)- 4,6-dimethyl-pyrimidin-2-yl)-4-piperidyl)-N-methyl-carbamate (0.058 g; 0.14 mmol) in dioxane (0.7 mL) was added 4N HCl in dioxane (2.3 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and was coevaporated with heptane. The residue was taken up with CH2Cl2(1 mL). NEt3(0.300 mL; 2.15 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 3N NH3in MeOH (0% to 8%) in CH2Cl2to afford 0.039 g (80%) of 1-(5-((cyclopropylmethyl(methyl)amino)methyl)-4,6-dimethyl- pyrimidin-2-yl)-N-methyl-piperidin-4-amine as a white solid. Step 4: 6-((1-(5-((Cyclopropylmethyl(methyl)amino)methyl)-4,6-dimethyl-pyrimidin-2- yl)-4-piperidyl)(methyl)amino)-N-(2-methoxyethyl)pyridazine-4-carboxamide was prepared according to the procedure described in Example 3 (Step 1) from 6-chloro-N-(2- methoxyethyl)pyridazine-4-carboxamide (0.026 g; 0.122 mmol), DIPEA (0.064 mL; 0.367 mmol), CsF (0.056 g; 0.367 mmol) and 1-(5-((cyclopropylmethyl(methyl)amino)methyl)-4,6- dimethyl-pyrimidin-2-yl)-N-methyl-piperidin-4-amine (0.039 g; 0.122 mmol) in DMSO (0.8 mL). Purification by flash chromatography on silica gel using a gradient of 10% MeOH in CH2Cl2(0% to 60%) in CH2Cl2furnished 0.018 g (30%) of the desired compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.79 - 4.92 (m, 3 H), 3.42 - 3.51 (m, 4 H), 3.37 (s, 2 H), 3.27 (s, 3 H), 2.88 - 2.96 (m, 5 H), 2.36 (s, 6 H), 2.21 (d, 2 H), 2.13 (s, 3 H), 1.64 - 1.81 (m, 4 H), 0.88 (m, 1 H), 0.49 (m, 2 H), 0.10 (m, 2 H). LCMS (method LC-C): Rt= 2.47 min (94.4%); m / z 495 [M-H]-. The compounds listed in the table below were prepared following a similar procedure to the one described above (use of appropriate reagents and purification methods known to the skilled in the art). The intermediates are commercially available or synthesized as described in the sections EXAMPLES OF THE PREPARATION OF INTERMEDIATES and PREPARATION OF COMPOUNDS OF THE INVENTION. Code LCMSLCMS RT methodPurity [M-H]-1(min) (m / z) H NMR (δ ppm) (%) (400 MHz, DMSO-d6) 8.90 (m, 1 H), 8.78 (d, 1 H), 7.22 - CPD- LC-C 4.37 937.36 (m, 6 H), 4.75 - 4.92 (m, 3 H), 3.39 - 3.49 (m, 8 H), 199.4 5313.27 (s, 3 H), 2.86 - 3.01 (m, 5 H), 2.36 (s, 6 H), 2.01 (s, 3 H), 1.65 - 1.75 (m, 4 H) (400 MHz, DMSO-d6) 8.90 (br s, 1 H), 8.79 (d, 1 H), 7.34 (d, CPD- LC-D 2.42 981 H), 4.75 - 4.92 (m, 3 H), 3.42 - 3.51 (m, 4 H), 3.39 (s, 2 201.5 511H), 3.27 (s, 3 H), 2.86 - 2.99 (m, 5 H), 2.38 (s, 6 H), 2.19 (s, 3 H), 2.10 (s, 2 H), 1.62 - 1.76 (m, 4 H), 0.78 (s, 9 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 CPD- LC-C 3.H), 4.77 - 4.93 (m, 3 H), 3.59 (s, 2 H), 3.40 - 3.51 (m, 4 H), 20767 100 5233.27 (s, 3 H), 3.19 (q, 2 H), 2.86 - 2.99 (m, 5 H), 2.34 (s, 6 H), 2.26 (s, 3 H), 1.62 - 1.83 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.78 (d, 1 H), 7.34 (d, 1 CPD- H), 4.77 - 4.92 (m, 3 H), 3.50 - 3.57 (m, 3 H), 3.41 - 3 11LC-C 3.49 (m, 2.48 98.7 4814 H), 3.27 (s, 3 H), 2.85 - 2.99 (m, 5 H), 2.32 (s, 6 H), 2.17 (s, 3 H), 1.63 - 1.78 (m, 4 H), 0.41 (m, 2 H), 0.22 (m, 2 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 7.25 (m, 2 H), 7.14 - 7.21 (m, 3 H), 4.77 - 4.96 (m, 3 H), CPD- 214LC-C 4.11 94.8 5453.40 - 3.52 (m, 4 H), 3.37 (s, 2 H), 3.27 (s, 3 H), 2.85 - 2.97 (m, 5 H), 2.76 (t, 2 H), 2.60 (m, 2 H), 2.26 (s, 6 H), 2.14 (s, 3 H), 1.60 - 1.79 (m, 4 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 CPD- LC-C 3.0H), 4.75 - 4.91 (m, 3 H), 3.41 - 3.49 (m, 6 H), 3.27 (s, 3 H), 2189 100 5232.86 - 2.97 (m, 5 H), 2.34 (s, 6 H), 2.05 (s, 3 H), 1.66 - 1.81 (m, 8 H), 1.59 (m, 1 H), 1.02 - 1.35 (m, 6 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.72 (d, 1 H), 7.34 (d, 1 H), 4.74 - 4.94 (m, 3 H), 3.41 - 3.52 (m, 4 H), 3.29 (s, 2 H), CPD- 220LC-D 2.56 99.3 5373.27 (s, 3 H), 2.80 - 2.96 (m, 5 H), 2.34 (s, 6 H), 2.09 (d, 2 H), 2.04 (s, 3 H), 1.66 - 1.74 (m, 6 H), 1.58 - 1.65 (m, 3 H), 1.46 (m, 1 H), 1.12 - 1.25 (m, 3 H), 0.74 (m, 2 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.35 - CPD- 221LC-D 2.06 99.1 5577.41 (m, 4 H), 7.28 - 7.35 (m, 2 H), 4.75 - 4.90 (m, 3 H), 3.37 - 3.53 (m, 6 H), 3.27 (s, 3 H), 2.80 - 3.00 (m, 5 H), 2.20 (s, 6 H), 1.96 (s, 3 H), 1.62 - 1.75 (m, 4 H), 0.97 (m, 2 H), 0.84 (m, 2 H) (400 MHz, DMSO-d6) 8.90 (m, 1 H), 8.78 (d, 1 H), 7.34 (d, 1 CPD- LC-D 2.34 100 55H), 7.12 - 7.32 (m, 5 H), 4.74 - 4.94 (m, 3 H), 3.37 - 3.53 (m, 22298 H), 3.27 (s, 3 H), 2.82 - 2.97 (m, 5 H), 2.78 (m, 1 H), 2.31 (s, 6 H), 1.61 - 1.79 (m, 4 H), 1.06 (d, 6 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.31 - 7.41 (m, 5 H), 7.27 (m, 1 H), 4.78 - 4.96 (m, 3 H), 3.70 (m, 1 CPD- 223LC-C 4.34 95.5 545H), 3.30 - 3.51 (m, 6 H), 3.29 (s, 3 H), 2.87 - 2.96 (m, 5 H), 2.33 (s, 6 H), 1.92 (s, 3 H), 1.66 - 1.80 (m, 4 H), 1.42 (d, 3 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.79 (d, 1 H), 7.34 (d, 1 H), 4.74 - 4.97 (m, 3 H), 3.42 - 3.55 (m, 4 H), 3.39 (s, 2 H), CPD- 224LC-D 3.09 100 5513.27 (s, 3 H), 2.84 - 2.99 (m, 5 H), 2.38 (s, 6 H), 2.19 (s, 3 H), 2.14 (s, 2 H), 1.60 - 1.75 (m, 4 H), 1.04 - 1.46 (m, 10 H), 0.78 (s, 3 H) (400 MHz, DMSO-d6) 8.89 (m, 1 H), 8.78 (d, 1 H), 7.20 - 7.35 (m, 6 H), 4.75 - 4.89 (m, 3 H), 3.66 (s, 2 H), 3.54 (s, 2 CPD- 225LC-D 2.12 100 557H), 3.40 - 3.49 (m, 4 H), 3.27 (s, 3 H), 2.84 - 2.95 (m, 5 H), 2.24 (s, 6 H), 1.80 (m, 1 H), 1.62 - 1.77 (m, 4 H), 0.27 (m, 2 H), 0.00 (m, 2 H) (400 MHz, DMSO-d6) 8.91 (m, 1 H), 8.78 (d, 1 H), 7.51 (d, 2 CPD- LC-C 4.56 97.9H), 7.29 - 7.36 (m, 3 H), 7.22 (m, 1 H), 4.80 - 4.92 (m, 3 H), 2265593.53 (s, 2 H), 3.41 - 3.50 (m, 4 H), 3.28 (s, 3 H), 2.85 - 2.97 (m, 5 H), 2.37 (s, 6 H), 1.67 - 1.78 (m, 7 H), 1.46 (s, 6 H) Part B Example 25: In vitro antiviral activity of the compounds of the invention SARS-Cov-2 B.1.1.7 infection model in A549-dual_ACE2_TMPRSS2 cells The A549-dual_ACE2_TMPRSS2 cells (InvivoGen Cat #a–49-cov2r) were propagated in the growth medium which was prepared by supplementing DMEM (gibco cat no 41965-039) with 10% v / v heat-inactivated FCS and 10 µg / mL blasticidin (InvivoGen ant-bl-05), 100 µg / mL hygromycin (InvivoGen ant-hg-1), 0.5 µg / mL puromycin (InvivoGen ant-pr-1) and 100 µg / mL zeocin (InvivoGen ant-zn-05) in a humidified 5% CO2incubator at 37°C. The assay medium was prepared by supplementing DMEM (gibco cat no 41965-039) with 2% v / v heat-inactivated FCS. The SARS-Cov-2 virus isolate used is from the B.1.1.7 lineage (derived from hCoV- 19 / Belgium / rega-12211513 / 2020; EPI_ISL_791333,2020-12-21; see Abdelnabi et al., “Comparing infectivity and virulence of emerging SARS-CoV-2 variants in Syrian hamsters” EBioMedicine (2021) Jun;68:103403. doi: 10.1016 / j.ebiom.2021.103403). For antiviral testing, cells were seeded in 96-well plates (Falcon) at a density of 15,000 cells per well in assay medium. After overnight growth, cells were treated with the indicated compound concentrations and infected with a MOI of 0.001 TCID50 / cell (final volume 200 μL / well in assay medium). On day 4 p.i. differences in cell viability caused by virus-induced CPE or by compound-specific side effects are analyzed using MTS as described previously (PMID: 22575574). For cytotoxicity testing, the same experimental setup was used except that assay medium without virus was added to the cells and that an additional control of well without cells was added to the plate. Table 2 shows the activity against B.1.1.7 and the cytotoxicity of some example compounds of the invention. EC50ranges are reported as follows: A < 0.1 µM; B 0.1 - 1 µM; C 1 - 10 µM; D > 10 µM. For cytotoxicity, CC50ranges are reported as follows: A > 10 µM; B 1 - 10 µM. CodeB.1.1.7MTS B.1.1.7 MTS B.1.1.7 MTS EC50 CC50CodeEC50 CC50CodeEC50CC50CPD-001 B A CPD-079 C A CPD-153 B A CPD-002 B B CPD-080 B A CPD-154 B A CPD-003 B B CPD-081 B A CPD-155 B A CPD-004 B A CPD-082 C A CPD-156 B A CPD-005 B A CPD-083 C A CPD-157 C A CPD-008 B A CPD-084 B B CPD-158 B A CPD-009 B A CPD-085 B B CPD-159 A B CPD-011 C A CPD-086 A B CPD-160 B A CPD-012 A B CPD-087 B B CPD-161 B A CPD-013 A B CPD-088 A B CPD-162 B A CPD-014 B A CPD-089 A A CPD-163 B A CPD-015 B A CPD-090 A A CPD-164 B A CPD-016 B B CPD-091 B A CPD-165 B A CPD-017 A B CPD-092 A A CPD-166 C A CPD-018 A A CPD-093 B B CPD-167 B A CPD-019 B A CPD-094 B B CPD-168 B A CPD-020 B A CPD-095 B A CPD-169 B A CPD-021 D A CPD-096 B A CPD-170 B A CPD-022 C A CPD-097 C A CPD-171 B A CPD-023 B A CPD-098 B A CPD-172 B A CPD-024 B A CPD-099 C A CPD-173 B A CPD-025 D A CPD-100 A B CPD-174 A B CPD-026 C A CPD-101 A A CPD-175 B A CPD-027 B B CPD-102 C A CPD-176 B A CPD-028 B B CPD-103 B B CPD-177 B B CPD-029 B A CPD-104 A A CPD-178 C B CPD-030 B B CPD-105 B A CPD-179 B A CPD-031 A B CPD-106 C A CPD-180 B B CPD-032 C A CPD-107 A A CPD-181 A B CPD-033 B A CPD-108 A A CPD-182 A B CPD-034 C A CPD-109 B A CPD-183 A B CPD-035 B B CPD-110 B A CPD-184 B B CPD-036 B A CPD-111 B A CPD-185 C A CPD-037 B B CPD-112 B A CPD-186 B B CPD-038 B A CPD-113 B A CPD-187 C A CPD-039 C B CPD-114 A A CPD-188 A B CPD-040 B A CPD-115 C A CPD-189 C A CPD-041 B A CPD-116 B A CPD-190 C A CPD-042 B A CPD-117 B A CPD-191 C A CPD-044 B B CPD-118 B A CPD-192 C A CPD-045 D A CPD-119 C A CPD-193 B A CPD-046 B A CPD-120 B A CPD-194 B A CPD-047 B B CPD-121 C A CPD-195 A A CPD-048 B B CPD-122 C A CPD-196 C A CPD-049 B A CPD-123 B B CPD-197 B A CPD-050 B B CPD-124 B A CPD-198 B A CPD-051 B A CPD-125 B B CPD-199 B A CPD-052 A B CPD-126 B A CPD-200 C A CPD-053 B B CPD-127 B A CPD-201 B A CPD-054 A B CPD-128 B A CPD-202 A B CPD-055 B B CPD-129 B A CPD-203 B A CPD-056 B B CPD-130 B A CPD-204 C A CPD-057 C A CPD-131 B A CPD-205 B A CPD-058 B B CPD-132 B A CPD-206 B A CPD-059 A A CPD-133 C B CPD-207 B A CPD-060 A B CPD-134 B A CPD-208 C A CPD-061 B A CPD-135 C A CPD-209 C A CPD-062 A A CPD-136 B A CPD-210 C A CPD-063 A A CPD-137 C A CPD-211 C A CPD-064 B B CPD-138 B A CPD-212 B A CPD-065 B A CPD-139 B A CPD-213 C A CPD-066 B A CPD-140 B A CPD-214 B A CPD-067 B A CPD-141 A A CPD-215 B A CPD-068 C B CPD-142 A B CPD-216 B A CPD-069 C A CPD-143 A A CPD-217 B A CPD-070 B B CPD-144 B A CPD-218 C A CPD-071 B A CPD-145 B A CPD-219 C A CPD-072 B A CPD-146 B A CPD-220 A A CPD-073 B B CPD-147 B A CPD-221 A B CPD-074 B A CPD-148 C A CPD-222 A B CPD-075 B B CPD-149 C A CPD-223 B A CPD-076 B B CPD-150 B A CPD-225 B B CPD-077 B B CPD-151 C A CPD-226 B A CPD-078 C A CPD-152 B A SARS-CoV-2 and SARS-CoV infection models in VeroE6 cells In these assays, fluorescence of VeroE6-GFP cells declines after infection with SARS-CoV-2 or SARS-CoV due to the cytopathogenic effect of the virus. In the presence of an antiviral compound, the cytopathogenicity is inhibited and the fluorescent signal rescued. SARS-CoV-2 variants were all recovered from nasopharyngeal swabs of RT-qPCR-confirmed human cases. Virus stocks were generated by passaging the virus on Calu-3 cells followed by production of a screening virus stock on A549+hACE2+hTMPRSS2 cells. For antiviral testing, VeroE6-GFP cells were seeded at a density of 25000 cells / well in 96-well plates (Greiner Bio One, catalogue no. 655090) and P-gp MDR1-inhibitor CP-100356 (final concentration 0.5 μM). On the next day, cells were infected with the SARS-CoV-2 (SARS2_B.1.617.2_EPI_ISL_2425097, SARS2_B.1.1.529_EPI_ISL_6794907, BA.5.2.1_EPI_ISL_14782497 or XBB.1.5_EPI_ISL_17273054) or SARS-CoV (SARS1_Vietnam_strain-200300592) inoculum at a MOI of 0.001 TCID50 / per cell. The number of fluorescent pixels of GFP signal determined by High-Content Imaging on day 4 p. i. was used as a read-out. Percentage of inhibition was calculated by subtracting background (number of fluorescent pixels in the untreated-infected control wells) and normalizing to the untreated-uninfected control wells (also background subtracted). The 50% effective concentration (EC50, the concentration of compound required for fifty percent recovery of cell- induced fluorescence) was determined using logarithmic interpolation. Potential cytotoxicity of compounds was assessed in a similar set-up in treated-uninfected cultures where metabolic activity was quantified at day 5 using the MTS assay. The 50% cytotoxic concentration (CC50, the concentration at which cell viability reduced to 50%) was calculated by logarithmic interpolation Table 3 shows the activity against several SARS-CoV-2 variants and SARS-CoV and the cytotoxicity of some exemplary compounds of formula (I). EC50ranges are reported as follows: A < 0.1 µM; B 0.1 - 1 µM; C 1 - 10 µM; D > 10 µM. For cytotoxicity, CC50ranges are reported as follows: A > 10 µM; B 1 - 10 µM; ND means not determined. Table 3 CodeB.1.617.2B.1.1.529 BA.5 XBB.1.5 SARS-CoV MTS EC50EC50EC50EC50EC50CC50CPD-005 B B B ND B A CPD-018 A A A ND B A CPD-052 A A A B B B CPD-065 ND B B ND B A CPD-066 ND B ND ND C A CPD-098 ND ND B ND B A CPD-108 ND ND A ND A A CPD-143 ND ND B ND B A CPD-146 ND ND B ND ND A CPD-158 ND ND B ND ND A CPD-159 ND ND B ND ND A CPD-162 ND ND B ND ND A CPD-165 ND ND B ND ND A CPD-174 ND ND A ND B B CPD-181 ND ND A ND ND A CPD-183 ND ND A ND B B CPD-199 ND ND ND B B A Example 26: antiviral activity of the compounds of the invention in a mouse model of SARS-CoV-2 infection Male SCID mice (n = 6 mice per group) were treated by oral gavage with either vehicle (14% propylene glycol, 1% Tween 80 and 85% pH 5 citrate buffer) BID, Nirmatrelvir at 300 mg / kg BID or CPD-052 (at 50 or 100 mg / kg, QD or BID) starting from day 0, just before the infection with 105TCID50SARS-CoV-2 beta variant (hCoV-19 / Belgium / rega-1920 / 2021; EPI_ISL_896474, 2021-01-11). CPD-052 was formulated in 14% propylene glycol, 1% Tween 80 and 85% pH 5 citrate buffer. All treatments were continued for 3 consecutive days. At day 3 p.i., mice were euthanized and lungs were collected and viral RNA and infectious virus were quantified by RT-qPCR and end-point virus titration, respectively. The results are shown in Figure 1. Treatment of SARS-CoV-2 infected SCID mice with CPD-052 (at 100 mg / kg QD and BID or at 50 mg / kg BID) significantly reduced viral RNA loads and infectious virus titers in the lungs compared to the vehicle control group. CPD- 052 is able to exert a potent antiviral efficacy in SARS-CoV-2 infected SCID mice.

Claims

CLAIMS 1. A compound having formula (I)or a pharmaceutically acceptable salt thereof, wherein: R1is according to -X1-R4, X1is selected from a bond, -O-, -S-, -NR5-, -CO-, -CO-NR5- and -CO-O-, R4is selected from: - hydrogen provided X1is not a bond, - alkyl, alkenyl or alkynyl, each optionally substituted by one or more groups independently selected from o halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, o cycloalkyl , cycloalkenyl or cycloalkynyl, each optionally further substituted by one or more group selected from halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, alkyl, haloalkyl, alkenyl, alkynyl, o heterocyclyl optionally further substituted by one or more groups independently selected from halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, - CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, =O, =S, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl , o aryl and heteroaryl each optionally further substituted by halogen, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, - CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - heterocyclyl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - C3-6-cycloalkyl optionally substituted by one or more groups independently selected from halogen, alkyl, alkenyl, alkynyl, =O, =S, -OR6, -SR6-NR7R8, -SO2-R6, -CO-R6, -CO- OR6, -CO-NR7R8, -SO2-NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,- aryl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and, - heteroaryl optionally substituted by one or more groups independently selected from halogen, =O, =S, -OR6, -SR6, -NR7R8, -SO2-R6, -CO-R6, -CO-OR6, -CO-NR7R8, -SO2- NR7R8, -SO(NR5)-NR7R8, -CN, -NO2, -SF5, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, R2is selected from alkyl optionally substituted by one or more group independently selected from halogen and – OR9, -SR9and -NR10R11, and, R3is selected from - halogen, - alkyl, alkenyl or alkynyl, each optionally substituted by one or more group independently selected from halogen, =O, =S, -OR12, -SR12, -NR13R14, -SO2-R12, -CO- R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, cycloalkyl or heterocyclyl wherein each cycloalkyl and heterocyclyl is optionally further substituted with one or more groups independently selected from halogen, - OR12, alkyl, alkenyl, alkynyl, haloalkyl, aryl and heteroaryl, and, aryl or heteroaryl wherein each aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, -OR12, -SR12, -CN, - NO2, -SF5, -NR13R14, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, cycloalkyl, heterocyclyl, aryl and heteroaryl, - cycloalkyl, heterocyclyl, aryl or heteroaryl, each optionally further substituted with one or more groups independently selected from halogen, -OR12, -SR12, -CN, -SO2-R12, -NR13R14, -SF5, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14, -SO(NR5)-NR13R14, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally further substituted with one or more groups independently selected from halogen, alkyl, - OR12, -SR12, -NR13R14, -SF5, -CO-R12, -CO-OR12, -CO-NR13R14, -SO2-NR13R14and - SO(NR5)-NR13R14, and, each R5, R6, R9, R10, R11, R12, R13and R17are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more groups independently selected from halogen, -OR15, -SR15, -NR15R16, =O, =S, cycloalkyl, heterocyclyl, aryl and heteroaryl, each R7, R8and R14are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one ormore groups independently selected from halogen, -OR15, -SR15, -NR15R16, -CN, -SF5, -CO- R12, -CO-OR12, -CO-NR13R17, -SO2-NR13R17and -SO(NR5)-NR13R17, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, and, each R15and R16are independently selected from hydrogen alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl.

2. A compound according to claim 1 wherein R4is selected from - C1-6-alkyl optionally substituted by one or more groups independently selected from C5-9-heterocyclyl optionally further substituted by one or more groups independently selected from halogen (such asfluorine) and -OR6, - C5-9-heterocyclyl optionally substituted with halogen or C1-4-alkyl, and, - C3-6-cycloalkyl, optionally substituted with one or more groups selected from halogen, such asfluorine or chloride, and -OR6, such as hydroxy or methoxy, and, R3is selected from - C1-6-alkyl optionally substituted by one or more group independently selected from o C6-10-aryl optionally further substituted with one or more groups selected from halogen and -OR12, o -NR13R14, whereby at least one of the independently selected R13and R14is C1-6-alkyl and C3-6-cycloalkyl, and, o C5-9-heterocyclyl optionally further substituted with one or more groups independently selected from C1-4-alkyl and aryl, - C6-10-aryl, such as phenyl, optionally further substituted with one or more group selected from halogen, -OR12, C3-6-cycloalkyl, C1-4-haloalkyl and C1-4-alkyl, and, - C5-9-heteroaryl, such as pyridine, optionally substituted by one or more -OR12, such as alkoxy, e.g. methoxy.

3. A pharmaceutical composition comprising at least one compound according to claim 1 or 2 and a pharmaceutically acceptable carrier.

4. A method of inhibiting or preventing infection by or diseases caused by an infection by a coronavirus, in particular a beta-coronavirus, more in particular SARS- CoV-1 or SARS-CoV-2 virus, comprising the step of administering a subject (mammalian or human) a therapeutically effective amount of the compound or composition according to any of the preceding claims.

5. A compound or composition according to claims 1 to 3 for use in a method according to claim 4.

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