Imidazo[1,2-b]pyridazine compounds, preparation and therapeutic uses thereof

Abstract

Compounds are provided which can inhibit ERK5. Also provided are pharmaceutical compositions and medical uses of the same, including the use in treating or preventing conditions such as cancers.

Description

[0001] IMIDAZ0[1 ,2-B]PYRIDAZINE COMPOUNDS, PREPARATION AND THERAPEUTIC USES THEREOF

[0002] Compounds are provided which can inhibit ERK5. Also provided are pharmaceutical compositions and medical uses of the same, including the use in treating or preventing conditions such as cancers.

[0003] The mitogen-activated protein kinase (MAPK) cascade is a highly -conserved cellular pathway which transmits signals from the cell surface to the nucleus. The pathway plays an important role in cell proliferation, differentiation, and migration and it is well known to be involved in the development of cancer. Proteins in the pathway include the extracellular signal-regulated kinase (ERK) proteins; among those, ERK5 (expressed from the MAPK7 gene) plays an important role in cell proliferation, as well as epithelial development and neural differentiation. ERK5 is unique among the ERK proteins, having a large C-terminal domain which contains a transcriptional activation domain (TAD) as well as a nuclear localization signal and two proline-rich regions. Autophosphorylation of the TAD is required for transcriptional activation.

[0004] ERK5 plays an important role in controlling cell proliferation and cell cycle progression, for example via direct or indirect phosphorylation of MEF2C, cMYC, SGK1, RSK, FOS, and FRA1 among others. The involvement of ERK5 in numerous biological pathways means that its activity is associated with many aspects of cancer progression, including tumour angiogenesis, metastasis, inflammation, sustained proliferation, and evasion of growth suppression. It therefore presents an attractive target for modulating disease pathology and treatment in a wide range of conditions. In previous studies, ERK5 inhibition or downregulation has been shown to block tumorigenesis in murine leukaemia cells, reduce growth of chronic myeloid leukaemia cells, inhibit growth of breast cancer and multiple myeloma cells, suppress colon cancer cell proliferation, and have to have an impact on renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma and hepatocellular carcinoma cell growth or survival, among others.

[0005] ERK5 inhibition thus represents a promising approach to tackle a broad range of cancers. Despite recent progress in cancer treatment with the development of targeted therapies and immunotherapies, not all cancer patients can be offered an efficient therapeutic solution. There is therefore a need to identify and develop new drugs. The present disclosure seeks to address this need by providing novel compounds, which comprise a 5-5 bicyclic piperidine core, for use as ERK5 inhibitors and for the treatment of ERK5 related diseases and conditions.

[0006] Accordingly, herein is provided a compound of Formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] R1 represents a hydrogen atom, a fluorine atom or a -NH2 group;

[0010] R2 represents a hydrogen atom or a fluorine atom;

[0011] R3 is selected from the groups -OCF3, -CF2CF3, -O-cycloalkyl and -SFs; and R4 represents a (Cl-C4)alkyl group or a (C4-C6)cycloalkyl group, optionally substituted by a hydroxy or methoxy group, or R4 represents a 5 or 6-membered heterocycloalkyl group.

[0012] In an embodiment of formula (I), R1 represents a hydrogen atom or a -NH2 group.

[0013] In another embodiment of formula (I), R2 represents a hydrogen atom.

[0014] In another embodiment of formula (I), R3 represents a group -OCF3.

[0015] In another embodiment of formula (I), R4 is selected from:

[0016] . an isopropyl, cyclobutyl, cyclopentyl or bicyclo[l.l.l]pentanyl, said groups being optionally substituted by a hydroxy or methoxy group; and

[0017] . a tetrahydrofuranyl, tetrahydropyranyl or morpholinyl group. A further aspect provides a compound selected from the group consisting of:

[0018] [4-[2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l- piperidyl] - [4-(trifluoromethoxy)phenyl] methanone

[0019] (trans)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3- methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone

[0020] (cis)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone

[0021] (trans)-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone

[0022] (cis)-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone

[0023] [4- [2-[(2R)-morpholin-2-yl] imidazo [ 1 ,2-b] pyridazin-8-yl] - 1 -piperidyl] - [4- (trifluoromethoxy)phenyl]methanone

[0024] [4- [2-[(2S)-morpholin-2-yl] imidazo [ 1 ,2-b] py ridazin-8-yl] - 1 -piperidyl] - [4- (trifluoromethoxy)phenyl]methanone

[0025] [2-amino-4-(trifluoromethoxy)pheny 1] - [4- [2- [(2S)-morpholin-2-yl] imidazo [1,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone

[0026] [2-amino-4-(trifluoromethoxy)pheny 1] - [4- [2- [(2R)-morpholin-2-yl] imidazo [1,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone

[0027] [2-amino-4-(trifluoromethoxy)phenyl]- [4- [2-(3 -methoxy- 1- bicy clo[ 1.1.1 ]pentanyl)imidazo[ 1 ,2-b]pyridazin-8-yl]- 1 -piperidyl] methanone

[0028] [2-amino-3-fluoro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4- ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone

[0029] [4-[2-(l-hydroxy-l-methyl-ethyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone

[0030] [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(l-hydroxy-l-methyl-ethyl)imidazo[l,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone

[0031] [4-(l,l,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0032] [4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l- piperidyl]methanone

[0033] (rac)-[4-(2-morpholin-2-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0034] [2-fluoro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0035] [4-(2-cyclopentylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone

[0036] [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclopentylimidazo[l,2-b]pyridazin-8- yl)- 1 -piperidyl] methanone

[0037] (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-morpholin-2-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0038] (rac)-[4-(2-tetrahydrofuran-3-ylimidazo[l,2-b]pyridazin-8-yl)-l -piperidyl] -[4- (trifluoromethoxy)phenyl]methanone

[0039] (rac)-[2-arruno-4-(trifluoromethoxy )phenyl] - [4-(2-tetrahy drofuran-3 -y limidazo [ 1 ,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0040] [4-(pentafluoro-X6-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0041] [2-amino-4-(pentafluoro-X6-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone,

[0042] and the pharmaceutically acceptable salts thereof.

[0043] Definitions

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety.

[0045] All numerical designations, e.g., pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations which are varied ( + ) or ( - ) by increments of, e.g., 0.1 or 1.0, where appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”, which is used to denote a conventional level of variability. For example, a numerical designation which is “about” a given value may vary by ± 10% of said value; alternatively, the variation may be ± 5%, ± 2%, or ± 1% of the value. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0046] As used in the specification and claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.

[0047] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, without excluding other elements. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass, and to disclose, the corresponding statements in which the term “comprising” is replaced by “consisting essentially of’ or “consisting of’.

[0048] A “subject,” “individual”, or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, sport animals, pets, and primates; for example murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans. In a particular embodiment, the mammal is a human.

[0049] “Administering” is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being contacted with (e.g., being inside) the subject’s body. Such an administration can be by any route including, without limitation, oral, transdermal (e.g., by the vagina, rectum, or oral mucosa), by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g., oral or nasal). Administration may also involve providing a substance or composition to a part of the surface of the subject’s body, for example by topical administration to the skin. Pharmaceutical preparations are, of course, given by forms suitable for each administration route.

[0050] “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and / or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms. The term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with or is predisposed to the disease. A patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.

[0051] An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, the severity of the particular disorder being treated and the form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and / or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with the condition. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

[0052] As used herein, the terms "increased" and "elevated" are used interchangeably and encompass any measurable increase in a biological function and / or a biological activity and / or a concentration. For example, an increase can be by at least about 10%, e.g. at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, an increase can be by at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as at least about 20-fold, 25-fold, 50-fold, 100-fold, or higher, relative to a control or baseline amount or function, or activity, or concentration.

[0053] As used herein, the terms "increased expression" and / or "increased activity" of a substance, such as ERK5, in a sample or cancer or patient, typically refers to an increase in the amount of the substance (e.g., of the MAPK7 gene product or ERK5 protein), although it may also denote an increase in the biological activity of the substance (e.g., constitutive activation of phosphorylation and / or reduced discrimination of phosphorylation sites of ERK5). For example, an increase can be by an amount of about 5%, e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as about 96%, 97%, 98%, 99%, or 100%. Thus, the increase can be about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as about 20-fold, 25-fold, 50-fold, 100-fold, or higher, relative to the amount (or activity) of the substance, such as ERK5, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g. cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an "increased expression” or "increased activity" of ERK5 if the expression and / or activity of ERK5 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of ERK5 in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples. As used herein, the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, for example as described in Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000). Such excipients include carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil / water or water / oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like.

[0054] As used herein, the term “(Cl-C4)alkyl” group means a linear or branched saturated hydrocarbon group comprising from 1 to 4 carbon atoms, such as isopropyl.

[0055] As used herein, the term “(C4-C6)cycloalkyl” group means a saturated cyclic group, which may contain a single ring or bicyclic bridged rings, such as a cyclobutyl, cyclopentyl or bi cyclofl.1.1 ]pentanyl group.

[0056] As used herein, the term “5 or 6-membered heterocycloalkyl” group means a saturated cyclic group comprising one or two heteroatoms selected from oxygen and nitrogen atoms, such as a tetrahydrofuranyl, tetrahydropyranyl or morpholinyl group.

[0057] The compounds of the present disclosure are described, inter alia, by way of structural formulae. It will be appreciated that these formulae typically show only one form (e.g., resonance form, tautomeric form, etc.) of the compound, whereas certain compounds may exist in more than one such form. This will be readily apparent to the skilled reader. The present disclosure includes all possible tautomers of the compounds characterised by the structural formulae hereinbefore and below, including as single tautomers, or as any mixture of tautomers in any ratio.

[0058] It will also be appreciated that certain of the present compounds may exist in one or more isomeric (e.g., stereoisomeric) forms. The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc. of the compounds described hereinbefore and below, as well as cis- and trans- forms and conformers of the same. The purification and the separation of isomers may be accomplished by methods described hereinafter, as well as by techniques known in the art. For example, optical isomers of the compounds can be obtained by resolution of the racemic mixture of diastereoisomeric salts thereof (e.g., using an optically active acid or base, or by the formation of covalent diastereomers). A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation, with or without derivatisation, may also be useful, and optically active compounds of the present disclosure can likewise be obtained by chiral syntheses utilizing optically active starting materials. The present disclosure includes all possible stereoisomers of the compounds described herein as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.

[0059] The compounds of the disclosure may exist in the form of free acids or bases, or may exist as addition salts with suitable acids or bases.

[0060] As used herein, the term “pharmaceutically acceptable” when used in connection with salts means a salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0061] Compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein.

[0062] The following abbreviations and empirical formulae are used herein:

[0063] °C degree Celsius

[0064] pm micrometer

[0065] Ac acetyl

[0066] DCM dichloromethane

[0067] DiPEA diisopropylethylamine

[0068] DMF dimethylformamide

[0069] DMSO dimethylsulfoxide

[0070] Dppf (diphenylphosphino)ferrocene

[0071] Et ethyl

[0072] G gram

[0073] i-Pr iso-propyl

[0074] LC / MS liquid chromatography / mass spectrometry

[0075] LDA lithium diisopropylamide Mg milligram

[0076] Min minute

[0077] mL milliliter

[0078] mm millimeter

[0079] mmol millimoles

[0080] MW microwave

[0081] NBS N-bromosuccinimide

[0082] NMR Nuclear Magnetic Resonance

[0083] Pd palladium

[0084] Pd / C palladium on charcoal

[0085] Ph phenyl

[0086] SCX strong cation exchange

[0087] TBTU O-(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TEA triethylamine

[0088] TFA trifluoroacetic acid

[0089] THF tetrahydrofuran

[0090] UV ultra-violet

[0091] General synthetic schemes

[0092] The following scheme, Scheme 1, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples: STEP 1

[0093] Base, EtOH MW, 100 °C 6 hrs Compound 1A Compound 1C Compound 1E Pd / C 10% H2 or Ammonium STEP 3 formate 80 °C, 2.5 hrs

[0094]

[0095] Compound I

[0096] SCHEME 1

[0097] According to Scheme 1 (in which R4may be, e.g., defined as described in formula (I); R1is -H or -NH2 ; R2 is -H or -F, R3 is -OCF3, -O-cPr, -CF2CF3, -SFs), Compound 1C can be obtained in STEP 1 by condensation of Compound 1 A with Compound IB using a base such as sodium bicarbonate for example. Compound IE can be obtained by Suzuki coupling in STEP 2 between Compound 1C and Compound ID using, for example, a catalyst such as [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water and in the presence of a base, such as sodium carbonate, by heating to reflux.

[0098] Compound I can be obtained by hydrogenation of compound IE in STEP 3 using Pd / C with ammonium formate for example.

[0099] The preparation of compound I (in which R4may be, e.g., defined as described in formula (I); R1is -H or -NH2; R2 is -H or -F; R3 is -OCF3, -O-c-Pr, -CF2CF3, -SFs), may be also effected according to the alternative following scheme, Scheme 2: STEP 2

[0100] Pd / C 10% H2 or Ammonium Compound 1F formate Base, Pd Catalyst 80 °C, 2.5 hrs solvent, 80 °C, 1 hr Compound 1C

[0101] STEP 4

[0102] R1 O H Compound 1J TBTU, base, solvent

[0103]

[0104] Compound I room temperature, 1 h Compound 11

[0105] SCHEME 2

[0106] According to Scheme 2 (in which R4may be, e.g., defined as described in formula (I); R1is -H or -NH2; R2 is -H or -F; R3 is -OCF3, -O-cPr, -CF2CF3, -SFs), Compound 1G can be obtained by Suzuki coupling in STEP 1 between Compound 1C and Compound IF using, for example, a catalyst such as [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water and in the presence of a base, such as sodium carbonate, by heating to reflux. Compound 1H can be obtained by hydrogenation of compound 1G in STEP 2 using Pd / C with ammonium formate for example. Compound 1H can then be converted to Compound II in STEP 3 by deprotection using TFA or HC1 in DCM. Compound I can then be prepared from Compound II in STEP 4 with carboxylic acid Compound 1J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. STEP 4 may optionally further comprise cis / trans mixture separation, for example, with compounds in which R4is 3-methoxy-cyclobutyl substituent. The preparation of compound I (in which R4may be, e.g., defined as described in formula (I); R1is -H or -NH2; R2 is -H or -F; R3 is -OCF3, -O-c-Pr, -CF2CF3, -SFs), may be also effected according to the alternative following scheme, Scheme 3: STEP 2

[0107] Pd / C 10% H2 or Ammonium Compound 1F formate Base, Pd Catalyst 80 °C, 1 hr solvent, 90 °C, 12 hrs Compound 1A Compound 1K Compound 1L HCI or TFA STEP 3 solvent STEP 5 STEP 4 room temperature O

[0108] Compound 1B R1 OH Base, EtOH Compound 1J MW, 100 °C TBTU, base, solvent 6 hrs room temperature, 1 h

[0109]

[0110] Compound I

[0111] SCHEME 3

[0112] According to Scheme 3 (in which R4may be, e.g., defined as described in formula (I); R1is -H or -NH2; R2 is -H or -F; R3 is -OCF3, -O-cPr, -CF2CF3, -SFs), Compound IK can be obtained by Suzuki coupling in STEP 1 between Compound 1A and Compound IF using, for example, a catalyst such as [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixture of dioxane and water and in the presence of a base, such as sodium carbonate, by heating to reflux. Compound IL can be obtained by hydrogenation of compound IK in STEP 2 using Pd / C with ammonium formate for example. Compound IL can then be converted to Compound IM in STEP 3 by deprotection using TFA or HCI in DCM. Compound IN can then be prepared from Compound IM in STEP 4 with carboxylic acid Compound 1J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. Compound I can be obtained in STEP 5 by condensation of Compound IN with Compound IB using a base such as sodium bicarbonate for example. STEP 5 may optionally further comprise NH-BOC deprotection under acidic conditions and / or chiral separation of isomers, for example, with compounds in which R4is a racemic, N-BOC-protected 2-morpholinyl substituent. Pharmaceutical compositions, uses

[0113] A further aspect provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable excipient or carrier.

[0114] The pharmaceutical compositions of the disclosure may be formulated for administration in solid or liquid form, e.g., using conventional carriers or excipients. Compositions may be adapted for, e.g., oral administration (e.g., as a solution, suspension, tablet, or capsule), parenteral administration (e.g., as a solution, dispersion, suspension, or emulsion, or as a dry powder for reconstitution), or topical application (e.g., as a cream, ointment, patch, or spray to be applied to the skin) using techniques known in the art.

[0115] Compounds of the present disclosure act as inhibitors of ERK5, which gives them utility in the treatment of ERK5 -associated disorders and conditions. In particular, compounds of the disclosure are useful in the treatment of cancers.

[0116] Viewed from this aspect, the disclosure provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy.

[0117] Compounds of the present disclosure are useful for treating or preventing: diseases or deleterious conditions in which ERK5, or a variant or mutant thereof, is known to play a role; diseases or disorders associated with increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity; and diseases or disorders in which inhibition or antagonism of ERK5 activity is beneficial.

[0118] In one aspect, the present disclosure provides a method of treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder in which ERK5 is implicated, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereol) in the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by ERK5, or a disease or disorder in which ERK5 is implicated. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereol) for use in the treatment or prevention of a disease or disorder mediated by ERK5, or a disease or disorder in which ERK5 is implicated.

[0119] In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder associated with ERK5 (e.g., cancer) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with ERK5 (e.g., cancer). In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a disease or disorder associated with ERK5 (e.g., cancer).

[0120] In another aspect, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of cancer. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of cancer.

[0121] In embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., in part or completely), reduces evasion of growth suppression, reduces or inhibits growth of cancerous or pre-cancerous cells, supresses proliferation of cancerous or pre-cancerous cells, and / or reduces the survival of cancerous or pre-cancerous cells. In embodiments, the cancer is characterized by increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity. In embodiments, the cancer has elevated ERK5 activity. In embodiments, the cancer overexpresses ERK5. In embodiments, the cancer is characterised by MAPK7 genomic amplification and / or constitutively active ERK5 signalling. In embodiments, the cancer has genomically amplified ERK5. In embodiments, the cancer has constitutively active ERK5 signalling.

[0122] In embodiments, the cancer is a solid tumour (e.g., a melanoma, carcinoma, or blastoma). In other embodiments, the cancer is leukaemia (e.g., chronic lymphocytic leukaemia, CLL; acute myelogenous leukaemia, AML; or chronic myelogenous leukaemia, CML).

[0123] In embodiments, the cancer is a primary tumour. In other embodiments, the cancer is a secondary tumour (e.g., a metastatic tumour).

[0124] In embodiments, the cancer is selected from breast cancer (e.g., ductal breast carcinoma, or breast adenocarcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, colorectal cancer (CRC), lung cancer (e.g., non-small cell lung cancer, NSCLC; lung adenocarcinoma; or lung squamous cell carcinoma), pancreatic cancer (e.g., adenocarcinoma), ovarian cancer, brain cancer (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer (e.g., melanoma), bile duct cancer (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

[0125] In embodiments, the cancer is selected from leukaemia (e.g., acute leukaemia, acute lymphocytic leukaemia, acute myelocytic leukaemia, acute myeloblastic leukaemia, acute promyelocytic leukaemia, acute myelomonocytic leukaemia, acute monocytic leukaemia, acute erythroleukemia, chronic leukaemia, chronic myelocytic leukaemia, or chronic lymphocytic leukaemia), polycythaemia vera, lymphoma (e.g., Hodgkin's disease or nonHodgkin's disease), Waldenstrom macroglobulinemia, and multiple myeloma.

[0126] In embodiments, the cancer is selected from leukaemia (e.g., chronic myeloid leukaemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

[0127] In embodiments, the cancer is selected from leukaemia (e.g., chronic myeloid leukaemia), breast cancer, multiple myeloma, colon cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma. In another aspect, the disclosure provides a method of inhibiting ERK5 activity, the method comprising contacting ERK5 (e.g., a cell comprising ERK5) with a compound of the present disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is an in vitro or ex vivo method. In other embodiments the method is an in vivo method. In a related aspect, the disclosure provides an in vitro method of inhibiting ERK5 activity in a cell, the method comprising contacting the cell with a compound of the present disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof).

[0128] The compounds of the disclosure may be used alone (e.g., as a monotherapy) or in combination with one or more cancer therapies.

[0129] Having been generally described herein, the follow non-limiting examples are provided to further illustrate this disclosure.

[0130] Although specific embodiments of the present disclosure will now be described with reference to the description and examples, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0131] EXAMPLES

[0132] Examples 1 to 25 - Compounds

[0133] All synthetic reactions were performed under an inert atmosphere, unless otherwise stated. In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds (e.g., commercially available compounds from suppliers such as Sigma- Aldrich).

[0134] Analytical data have been obtained as follows:

[0135] Proton NMR: 'H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (8 in ppm) in the solvent dimethyl sulfoxide-de (DMSO-de) referenced at 2.5 ppm at the quoted temperatures. Coupling constants (J) are given in Hertz.

[0136] LC-MS: The liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210<l<400 nm and column Acquity UPLC CSH Cl 8, 1.7 pm, dimension 2.1x50 mm, mobile phase H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H.

[0137] Table 1 below lists the compounds of formula (I) synthesized as in the previous general schemes or in the following synthetic examples.

[0138] Table 1:

[0139] Example Structure Name

[0140] No.

[0141] 9

[0142] [4-[2-(3-methoxy-l- bicyclofl .1. l]pentanyl)imidazo[l ,2- 1

[0143] b] py ridazin-8-y 1] - 1 -piperidyl] -[4- (trifluoromethoxy)pheny 1] methanone Q

[0144] F"T

[0145] (trans)-[2-amino-4- vXp (trifluoromethoxy)phenyl]-[4-[2-(3- 2

[0146] methoxycyclobutyl)imidazo[l ,2- .NH b]pyridazin-8-yl]-l-piperidyl]methanone 9

[0147]

[0148] Example Structure Name No.

[0149] p

[0150] b

[0151] (cis)-[2-amino-4-(trifluoromethoxy)phenyl]- 3 p [4-[2-(3-methoxycyclobutyl)imidazo[l,2- b]pyridazin-8-yl]-l-piperidyl]methanone F3

[0152] f—\

[0153] (trans)-[4-[2-(3- 'rp methoxycyclobutyl)imidazo[l ,2- 4

[0154] b] py ridazin-8-y 1] - 1 -piperidy 1] -[4- (trifluoromethoxy)pheny 1] methanone 9

[0155] p

[0156] (cis)-[4-[2-(3- methoxycyclobutyl)imidazo[l ,2- 5a

[0157] b] py ridazin-8-y 1] - 1 -piperidy 1] -[4- (trifluoromethoxy)pheny 1] methanone V FP

[0158] N / X PN

[0159] [4- [2- [(2R)-morpholin-2- y 1] imidazo[ 1 ,2-b] py ridazin-8-yl] - 1 - 6 ^3

[0160] piperidyl] -[4- (trifluoromethoxy)pheny 1] methanone o

[0161]

[0162] Example Structure Name No.

[0163] Q \|H

[0164] \ _ /

[0165] Y

[0166] [4-[2-[(2S)-morpholin-2-yl]imidazo[l,2- 7 ' Oy b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)pheny 1] methanone ff

[0167] T

[0168] >T'°

[0169] F

[0170] o \1H

[0171] 2

[0172] N' J V N

[0173] Il I [2-amino-4-(trifluoromethoxy)phenyl] - [4- 8 T 1

[0174] \ zY / z0[2-[(2S)-morpholin-2-yl]imidazo[l,2- b]pyridazin-8-yl]-l-piperidyl]methanone 9

[0175] Y ,0

[0176] F-T F

[0177] -ZR

[0178] ^NH

[0179] N' V

[0180] [2-amino-4-(trifluoromethoxy)phenyl] - [4- 9 Y'Z [2-[(2R)-morpholin-2-yl]imidazo[l,2- 1 / NH b]pyridazin-8-yl]-l-piperidyl]methanone

[0181] Fv,0

[0182] a

[0183] F

[0184] /

[0185] Y PA YI / -^ [2-amino-4-(trifluoromethoxy)phenyl]-[4- [2-(3-methoxy-l- 10 l^N

[0186] bicyclo[l .1. l]pentanyl)imidazo[l ,2- b]pyridazin-8-yl]-l-piperidyl]methanone 6 "’

[0187] R n

[0188] F4 F

[0189]

[0190] Example Structure Name No.

[0191] o

[0192] ,NC I

[0193] [2-amino-3 -fluoro-4- (trifluoromethoxy)phenyl]-[4-(2- 11

[0194] tetrahy dropyran-4-ylimidazo[ 1 ,2- b]pyridazin-8-yl)-l-piperidyl]methanone A

[0195] A

[0196] [

[0197] [4-[2-(l-hydroxy-l-methyl- ethyl)imidazo[l ,2-b]pyridazin-8-yl]-l - 12 ^ VVY

[0198] A J piperidyl] -[4- x (trifluoromethoxy)pheny 1] methanone FY

[0199] A

[0200] Alp [2-amino-4-(trifluoromethoxy)phenyl] - [4- 13 [2 - ( 1 -hydroxy- 1 -methy 1-ethy l)imidazo [1,2- b]pyridazin-8-yl]-l-piperidyl]methanone r

[0201] FA

[0202] [4 - ( 1 , 1 ,2,2,2-pentafluoroethyl)phenyl] - [4- 14 (2-tetrahy dropy ran-4-ylimidazo [ 1 ,2- b]pyridazin-8-yl)-l-piperidyl]methanone

[0203]

[0204] Example Structure Name No.

[0205] f )

[0206] [4-(cyclopropoxy)phenyl]-[4-(2- 15 tetrahy dropyran-4-ylimidazo[ 1 ,2- b]pyridazin-8-yl)-l-piperidyl]methanone V

[0207] / '

[0208] Un(rac)- [4-(2-morpholin-2-ylimidazo [1,2- 16 b] py ridazin-8-y 1)- 1 -piperidy 1] -[4- (trifluoromethoxy)pheny 1] methanonecr

[0209] [2-amino-4-(trifluoromethoxy)phenyl]-[4- 17 (2-tetrahy dropy ran-4-ylimidazo [ 1 ,2- b]pyridazin-8-yl)-l-piperidyl]methanone ,AY'NH!

[0210] V

[0211] C)

[0212] f:=\ r

[0213] [2-fluoro-4-(trifluoromethoxy)phenyl]-[4- 18 (2-tetrahy dropy ran-4-ylimidazo [ 1 ,2- b]pyridazin-8-yl)- 1 -piperidyl] methanone 9

[0214]

[0215] Example Structure Name No.

[0216] ,N, ,,N

[0217] N V

[0218] U p [4-(2-cyclopentylimidazo[ 1 ,2-b]pyridazin-8- 19 yl)- 1 -piperidyl] -[4- T<0(trifluoromethoxy)pheny 1] methanone

[0219] 0

[0220] F^

[0221] F

[0222] o

[0223] J N J

[0224] [2-amino-4-(trifluoromethoxy)phenyl] - [4- 20 ,o (2-cyclopentylimidazo[l,2-b]pyridazin-8- y 1)- 1 -piperidyl] methanoner^LL V-==J Mk° '

[0225] ( \ X :

[0226] Fx ,0

[0227] rT

[0228] F

[0229] C)L

[0230] (rac)-[2-amino-4- (trifluoromethoxy)phenyl]-[4-(2-morpholin- 21 ,0

[0231] 2-ylimidazo[l,2-b]pyridazin-8-yl)-l- x / N4 piperidyl] methanone

[0232] ZO

[0233] \J

[0234] ,Nx ,'>N

[0235] N V

[0236] (rac)-[4-(2-tetrahydrofuran-3-ylimidazo[l,2-a. - 22 b]pyridazin-8-yl)-l-piperidyl]-[4- (trifluoromethoxy)pheny 1] methanone

[0237] Fx,O

[0238] F"T

[0239] F

[0240]

[0241] Example Structure Name No.

[0242] ox

[0243] o

[0244] /

[0245] / — . ~ < \

[0246] FT A <N

[0247] (rac)-[2-amino-4- (trifluoromethoxy)phenyl]-[4-(2- 23

[0248] tetrahy drofuran-3-ylimidazo[ 1 ,2- 1 ,NHl b]pyridazin-8-yl)-l-piperidyl]methanoneF\

[0249] FA

[0250] F

[0251] / 0\

[0252] \ / 0

[0253] [4-(pentafluoro-X6-sulfanyl)phenyl]-[4-(2- Y A ...

[0254] 24 A r' TT X X tetrahy dropyran-4-ylimidazo[ 1 ,2- < 1 1 J I I J 1F

[0255] N" >- Y b]pyridazin-8-yl)-l-piperidyl]methanone 1 1 F I F

[0256] YY F

[0257] 0—

[0258] / \

[0259] \ / 0 |2-amino-4-(pentafluoro-Z6- X . JI , sulfanyl)phenyl]-[4-(2-tetrahydropyran-4- 25

[0260] « 4. . J j! J. 4 , ylimidazof 1 ,2-b]pyridazin-8-yl)- 1 - N" Y H.N Y

[0261] i d F"- A piperidyl] methanone

[0262] F

[0263]

[0264] Example 1: [4-[2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl] - [4-(trifluoromethoxy)phenyl] methanone

[0265]

[0266] METHOD A STEP 1: l-(3-methoxy-l-bicyclo[l.l.l]pentanyl)vinyloxy-trimethyl-silane

[0267] \ /

[0268] — Si

[0269]

[0270] At -70 °C, to a solution of LDA (2 M solution in THF, 1.96 mL, 3.92 mmol) in THF 4 mL, was added dropwise chlorotrimethylsilane (852 mg, 7.85 mmol) and the resulting reaction mixture was stirred for 10 minutes at -70 °C, and then, was added dropwise a solution of l-(3-methoxybicyclo[l.l.l]pentan-l-yl)ethan-l-one (500 mg, 3.57 mmol) in THF (1 mL). The resulting mixture was stirred for 10 minutes at -70 °C then warmed up to room temperature and stirred for one additional hour. After one hour, 20 mL of cyclohexane and 20 mL of 10% aqueous solution of NaHCCh were added to the mixture. The aqueous layer was separated and extracted with cyclohexane. The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo to give 500 mg (66% yield) of crude l-(3-methoxy-l-bicyclo[l.l.l]pentanyl)vinyloxy-trimethyl-silane as an orange wax which was engaged in the next step without further purification.

[0271] STEP 2: 2-bromo-l-(3-methoxy-l-bicyclo[l.l.l]pentanyl)ethanone

[0272] Br

[0273]

[0274] To a solution of l-(3-methoxy-l-bicyclo[l.l.l]pentanyl)vinyloxy-trimethyl-silane (500 mg, 2.35 mmol) in DCM (3 mL), at 5 °C was added portionwise, NBS (419 mg, 2.35 mmol) and the whole mixture was stirred at this temperature for 1 hour. After one hour, 30 mL of DCM and 20 mL of 10% aqueous solution of NaHCCL were added to the mixture. The aqueous layer was separated and the organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (SiCh 40 g) eluting with cyclohexane / AcOEt 100 / 0 to 80 / 20 to give 390 mg (75% yield) of 2-bromo-l-(3-methoxy-l-bicyclo[l.l.l]pentanyl)ethanone as a yellow oil. LC / MS (m / z, M+H): calc. 220.1, found 220.9.

[0275] STEP 3: 8-bromo-6-chloro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazine

[0276] Br

[0277]

[0278] In 10-20 mL microwave vial, were placed 2-bromo-l-(3-methoxy-l-bicyclo[l.l.l]pentanyl)ethenone (399 mg, 1.82 mmol), 4-bromo-6-chloro-pyridazin-3-amine (380 mg, 1.82 mmol), sodium bicarbonate (184 mg, 2.19 mmol) in 15 mL of ethanol. The vial was sealed and submitted to irradiation at 100 °C for 11 hours. After 11 hours, the reaction mixture was cooled down to room temperature, the vial was opened and the whole mixture was concentrated to dryness. The resulting residue was diluted with water and DCM. The aqueous layer was separated, extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (SiO224 g) eluting with cyclohexane / AcOEt 90 / 10 to 60 / 40 to give 429 mg (68% yield) of 8-bromo-6-chloro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazine as a white powder. LC / MS (m / z, M+H): calc. 329.6, found 329.9.

[0279] STEP 4: [4-[6-chloro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-3,6-dihydro-2H-pyridin-l-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0280] F. O

[0281] FF

[0282]

[0283] Under argon atmosphere, to a solution of 8-bromo-6-chloro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazine (200 mg, 0.61 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL) was added potassium carbonate (126 mg, 0.91 mmol) and the resulting mixture was bubbled with argon for 10 minutes. Then, [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-l-yl]-[4-(trifluoromethoxy)phenyl]methanone (290 mg, 0.73 mmol) was added followed by Pd(PPh3)4 (35 mg, 0.03 mmol) and the whole mixture was then stirred at 90 °C for 1.5 hours. After 1.5 hours, the resulting mixture was diluted with water and AcOEt. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (SiCh 40 g) eluting with cyclohexane / AcOEt 80 / 20 to 50 / 50 to give 293 mg (93% yield) of [4-[6-chloro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-3,6-dihydro-2H-pyridin-l-yl]-[4-(trifluoromethoxy)phenyl]methanone as a yellow oil. LC / MS (m / z, M+H): calc. 519.1, found 519.1.

[0284] STEP 5: [4-[2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0285]

[0286] Under argon atmosphere, to a solution of [4-[6-chloro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-3,6-dihydro-2H-pyridin-l-yl]-[4-(trifluoromethoxy)phenyl]methanone (292 mg, 0.56 mmol) in ethanol (15 mL) was added ammonium formate (710 mg, 11.25 mmol) followed by Pd / C 10% (50% wet) (60 mg, .56 mmol) and the resulting mixture was stirred at 80 °C for 2.5 hours. After 2.5 hours, the reaction mixture was cooled down to room temperature, filtered, washed with EtOH and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel (SiCh 12 g) eluting with DCM / MeOH 95 / 5 to 92 / 8 to give 96 mg (35% yield) of 4-[2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a pale brown solid. LC / MS (m / z, M+H): calc. 487.5, found 487.4. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.77-1.91 (m, 2 H), 2.01 (br d, .7=12.0 Hz, 2 H), 2.20 (s, 6 H), 3.06-3.22 (m partially hidden, 2 H), 3.27 (s, 3 H), 3.55 (tt, .7=11.9, 3.7 Hz, 1 H), 4.05-4.28 (m, 2 H), 7.05 (d, .7=4,8 Hz, 1 H), 7.38 (br d, J=8.5 Hz, 2 H), 7.56 (br d, J=8.5 Hz, 2 H), 7.99 (s, 1 H), 8.34 (d, .7=4,8 Hz, 1 H).

[0287] Examples 2 & 3: (trans)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxy cyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone & (cis)-[2-amino- 4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl] methanone

[0288]

[0289] METHOD B STEP 1: cis / trans mixture of 8-bromo-6-chloro-2-(3-methoxycyclobutyl)imidazo[l,2-b]py ridazine Br

[0290]

[0291] In microwave vial, to a solution of commercially available 4-bromo-6-chloro-pyridazin-3-amine (500 mg, 2.4 mmol) in ethanol (12 mL) was added NaHCCh (403 mg, 4.8 mmol) followed by commercially available cis / trans mixture of 2-bromo-l-(3-methoxycyclobutyl)ethenone (546 mg, 2.64 mmol). The vial was sealed and submitted to microwave irradiation at 100 °C for 1 hour. After one hour, 2-bromo-l-(3-methoxycyclobutyl)ethenone (100 mg, 0.48 mmol) was added, and the resulting reaction was submitted to micro wave irradiations at 100 °C for one additional hour. Then, the reaction mixture was concentrated to dryness, diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated and the resulting residue was purified twice by flash chromatography on silica gel (SiCh 24 g) eluting with AcOEt / heptane 3 / 7 to give 599 mg (79% yield) of a cis / trans mixture of 8-bromo-6-chloro-2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazine as ayellow oil. LC / MS (m / z, M+H): calc. 317.5, found 317.9.

[0292] STEP 2: cis / trans mixture of tert-butyl 4-[6-chloro-2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-3,6-dihydro-2H-pyridine-l -carboxylate

[0293]

[0294] To a solution of a cis / trans mixture of 8-bromo-6-chloro-2-(3-methoxycyclobutyl)imidazo[l ,2-b]pyridazine (529 mg, 1.67 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL), was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (542 mg, 1.75 mmol) and K3PO4 (780 mg, 3.68 mmol) and the resulting mixture was bubbled with argon for 10 minutes. Then, PdC12(dppf).DCM (136 mg, 0.17 mmol) was added and the resulting mixture was stirred at 80 °C for 1 hour. After one hour, the resulting mixture was diluted with AcOEt, washed with an aqueous saturated solution of NaHCOs. The aqueous layer was extracted with AcOEt and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (SiO224 g) eluting with AcOEt / heptane 4 / 6 to give 474 mg (61% yield) of a cis / trans mixture of tert-butyl 4-[6-chloro-2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-3,6-dihydro-2H-pyridine-l-carboxylate as a yellow oil. LC / MS (m / z, M+H): calc. 419.2, found 419.2.

[0295] STEP 3: cis / trans mixture of tert-butyl 4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]piperidine-l -carboxylate

[0296] N

[0297]

[0298] To a solution of a cis / trans mixture of tert-butyl 4-[6-chloro-2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (474 mg, 1.13 mmol) in ethanol (10 mL) was added ammonium formate (1426 mg, 22.6 mmol) followed by Pd / C 10% (50% wet) (150 mg) and the resulting mixture was stirred at 80 °C for 1 hour. After one hour, the reaction mixture was cooled down to room temperature, filtered, washed with ethanol and concentrated in vacuo. The resulting residue was diluted with AcOEt, washed with an aqueous saturated solution of NaHCCb. dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (SiCh 12 g) eluting with AcOEt / heptane 6 / 4 to give 325 mg (74% yield) of a cis / trans mixture of tert-butyl 4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]piperidine-l-carboxylate as a yellow oil. LC / MS (m / z, M+H): calc. 387.2, found 387.2.

[0299] STEP 4: cis / trans mixture of 2-(3-methoxycyclobutyl)-8-(4-piperidyl)imidazo[l,2-b] py ridazine; dihydrochloride

[0300]

[0301] To a solution of a cis / trans mixture of tert-butyl 4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]piperidine-l-carboxylate (322 mg, 0.83 mmol) in MeOH (4 mL), was added a 4N solution of HC1 in 1,4-dioxane (3.12 mL, 12.49 mmol) and the resulting mixture was stirred at room temperature for 2 hours. After 2 hours, the whole mixture was concentrated in vacuo to give 299 mg (100% yield) of a cis / trans mixture of 2-(3-methoxycyclobutyl)-8-(4- piperidyl)imidazo[l,2-b]pyridazine;dihydrochloride as a white solid which was engaged in the next step without further purification.

[0302] STEP 5: cis / trans mixture of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxy cyclobutyl)imidazo[ 1 ,2-b]pyridazin-8-yl] - 1 -piperidyl] methanone

[0303]

[0304] To a solution of a cis / trans mixture of 2-(3-methoxycyclobutyl)-8-(4-piperidyl)imidazo[l,2-b]pyridazine; dihydrochloride (150 mg, 0.42 mmol) in DMF (2.8 mL) was added DiPEA (0.29 mL, 1.67 mmol) and the resulting reaction mixture was stirred for 10 minutes. Then, 2-amino-4-(trifluoromethoxy)benzoic acid (101 mg, 0.46 mmol) and TBTU (160 mg, 0.5 mmol) were successively added. The whole mixture was then stirred at room temperature for 1 hour. After one hour, the resulting mixture was diluted with AcOEt, washed with an aqueous saturated solution of NaHCCE, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (SiCh 12 g) eluting with DCM / MeOH 94 / 6 to give 185 mg (90% yield) of a cis / trans mixture of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone as pale brown foam. LC / MS (m / z, M+H): calc. 490.2, found 490.2.

[0305] STEP 6: (trans)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo [l,2-b]pyridazin-8-yl]-l-piperidyl]methanone & (cis)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone

[0306]

[0307] Separation of the cis / trans mixture of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxy cyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone (182 mg, 0.37 mmol) was performed using a Chiralpak AY column (20 pm, 100x230 mm), eluting with (EtOH 90 / MeOH 10)+0.1% TEA (flow rate 400 mL / min, UV detection at 254 nm) to give: 73 mg (40% yield) of (trans)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 490.2, found 490.1. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.80-1.95 (m, 2 H), 1.98-2.07 (m, 2 H), 2.26-2.41 (m, 2 H), 2.41-2.51 (m partially hidden, 2 H), 3.06-3.17 (m, 2 H), 3.18 (s, 3 H), 3.49 (tt, J=11.8, 3.7 Hz, 1 H), 3.54-3.63 (m, 1 H), 4.10-4.22 (m, 3 H), 5.34 (br s, 2 H), 6.45-6.50 (m, 1 H), 6.68 (br s, 1 H), 6.97 (d, .7=4,8 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 7.99 (s, 1 H) 8.29 (d, .7=4,8 Hz, 1 H).

[0308] And 95 mg (52% yield) of (cis)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 490.1, found 490.2. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.80-1.94 (m, 2 H), 1.96-2.05 (m, 2 H), 2.08-2.18 (m, 2 H), 2.57-2.67 (m, 2 H), 3.07-3.18 (m, 3 H), 3.19 (s, 3 H), 3.50 (tt, J=11.8, 3.7 Hz, 1 H), 3.83-3.92 (m, 1 H), 4.16 (br d, J=12.9 Hz, 2 H), 5.34 (br s, 2H), 6.44-6.51 (m, 1 H), 6.68 (br s, 1 H), 6.96 (d, .7=4,8 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 7.95 (s, 1 H), 8.28 (d, .7=4,8 Hz, 1 H).

[0309] Examples 4 & 5: (trans)-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone and (cis)-[4-[2-(3-methoxy cy clobutyl)imidazo [ 1 ,2-b]py ridazin-8-yl] - 1 -piperidyl] - [4-(trifluoromethoxy)phenyl]methanone

[0310]

[0311] Examples 4 & 5 were prepared following Method B (examples 2 & 3) using 4-(trifluoromethoxy)benzoic acid in step 5, to give 65 mg (37% yield) of (trans)-[4-[2-(3-methoxy cy clobutyl)imidazo [ 1 ,2-b]py ridazin-8-yl] - 1 -piperidyl] - [4- (trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 475.2, found 475.1. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.82-1.96 (m, 2 H), 1.99-2.06 (m, 2 H), 2.30-2.41 (m, 2H), 2.42-2.51 (m partially hidden, 2 H), 3.09-3.19 (m, 2H), 3.18 (s, 3 H), 3.46- 3.63 (m, 2 H), 4.08-4.29 (m, 3 H), 6.99 (d, .7=4,8 Hz, 1 H), 7.38 (br d, J=8.5 Hz, 2 H), 7.56 (br d, .7=8.5 Hz, 2 H), 8.00 (s, 1 H), 8.30 (d, .7=4,8 Hz, 1 H);

[0312] and 95 mg (54% yield) of (cis)-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): calc.

[0313] 475.2, found 475.1. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.82-1.94 (m, 2 H), 1.96-2.06 (m, 2 H), 2.08-2.20 (m, 2 H), 2.57-2.70 (m, 2 H), 3.09-3.21 (m, 3 H), 3.19 (s, 3 H), 3.53 (tt, J=11.8, 3.8 Hz, 1 H), 3.82-3.92 (m, 1 H), 4.07-4.32 (m, 2 H), 6.98 (d, .7=4,8 Hz, 1 H), 7.38 (br d, .7=8.5 Hz, 2 H), 7.56 (br d, J=8.5 Hz, 2 H), 7.95 (s, 1 H), 8.29 (d, .7=4,8 Hz, 1 H) Examples 16 and 6 & 7: (rac)-[4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl] methanone, [4-[2-[(2R)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone and [4-[2-[(2S)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0314]

[0315] METHOD C STEP 1: tert-butyl 4-(3-amino-6-chloro-pyridazin-4-yl)-3,6-dihydro-2H-pyridine-l-carboxylate

[0316]

[0317] Under argon atmosphere, to a solution of 3-amino-4-bromo-6-chloropyridazine (2 g, 9.59 mmol) in a mixture of 1,4-di oxane (80 mL) and water (20 mL) wad added potassium carbonate (2 g, 14.47 mmol). The resulting reaction mixture was bubbled with argon for 2 minutes and then N-BOC-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.6 g, 12 mmol) and Pd(PPhs)4 (5.6 g, 4.85 mmol) were successively added and the reaction mixture was stirred at 85 °C for 3.5 hours. After 3.5 hours, the whole mixture was cooled down to room temperature, diluted with 150 mL of AcOEt and 150 mL of water. The aqueous layer was then extracted with 100 mL of AcOEt and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (SiO2220 g) eluting with cyclohexane / AcOEt 5 / 5 to 3 / 7 to give 2.73 g (91% yield) of tert-butyl 4-(3-amino-6-chloro-pyridazin-4-yl)-3,6-dihydro-2H-pyridine-l-carboxylate as a pink solid. LC / MS (m / z, M+H): calc. 311.1, found 311.1.

[0318] STEP 2: tert-butyl 4-(3-aminopyridazin-4-yl)piperidine-l -carboxylate

[0319]

[0320] To a solution of tert-butyl 4-(3-amino-6-chloro-pyridazin-4-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (2.72 g, 8.75 mmol) in ethanol (40 mL) was added ammonium formate (11 g, 174.45 mmol) and the resulting reaction mixture was bubbled with argon for 2 minutes. Then, Pd / C 10% (55% wet) (1.2 g) was added and the whole mixture was stirred at 80 °C for 45 minutes, then cooled down to room temperature, filtered, washed with 40 mL of ethanol, and concentrated in vacuo. The resulting residue was diluted with DCM (70 mL) and with an aqueous saturated solution of NaHCCL (70 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 2.13 g (87% yield) of tert-butyl 4-(3-aminopyridazin-4-yl)piperidine-l -carboxylate as a grey solid which was engaged in the next step without further purification. LC / MS (m / z, M+H): calc. 279.2, found 279.1.

[0321] STEP 3: 4-(4-piperidyl)pyridazin-3-amine dihydrochloride

[0322] H ; 2HCI

[0323]

[0324] To a solution of tert-butyl 4-(3-aminopyridazin-4-yl)piperidine-l -carboxylate (2.12 g, 7.62 mmol) in MeOH (100 mL) was added a 4N solution of HC1 in 1,4-dioxane (20 mL, 80 mmol) and the resulting reaction mixture was stirred at room temperature for 4 hours. After 4 hours, the whole mixture was concentrated in vacuo and the resulting residue was triturated in i-PnO, filtered and dried under vacuum to give 1.73 g(90% yield) of 4-(4-piperidyl)pyridazin-3 -amine dihydrochloride as a pale brown solid. LC / MS (m / z, M+H -2HC1): calc. 179.1, found 179.0.

[0325] STEP 4: [4-(3-aminopyridazin-4-yl)-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0326]

[0327] To a solution of 4-(4-piperidyl)pyridazin-3-amine dihydrochloride (700 mg, 2.79 mmol) in DMF (12 mL) were successively added DiPEA (2 mL, 11.5 mmol), 4-(trifluoromethoxy)benzoic acid (640 mg, 3.1 mmol) and TBTU (985 mg, 3.07 mmol) and the resulting reaction mixture was stirred for 30 minutes at room temperature. After 30 minutes, the whole mixture was diluted with 100 mL of water and 100 mL of AcOEt. The aqueous layer was then extracted twice with 50 mL of AcOEt and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (SiO224 g) eluting with DCM / [DCM / MeOH 95 / 5] 100 / 0 to 0 / 100 to give 837 mg (82% yield) of [4-(3 -aminopyridazin-4-yl)-l -piperidyl] -[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 367.1, found 367.1.

[0328] STEP 5: (rac)-tert-butyl 2-[8-[l-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]imidazo[l,2-b]pyridazin-2-yl]morpholine-4-carboxylate

[0329]

[0330] In a 2-5 mL microwave vial, to a solution of [4-(3-aminopyridazin-4-yl)-l-piperidyl]-[4-(trifluoromethoxy)phenyl] methanone (400 mg, 1.09 mmol) in EtOH (3 mL) was added tert-butyl-2-(2-bromoacetyl)morpholine-4-carboxylate (400 mg, 1.3 mmol) (which was prepared following STEPS 1 & 2 of method A, using tert-butyl 2-2acetylmorpholine-4-carboxylate in STEP 1). The vial was sealed and irradiated for 1.5 hour at 100 °C. After 1.5 hour, the whole mixture was cooled down to room temperature, concentrated to dryness and the resulting residue was purified flash chromatography on silica gel (Si Ch 12 g) eluting with DCM / [DCM / MeOH 95 / 5] 100 / 0 to 0 / 100 to give 73 mg (12% yield) of (rac)-tert-butyl 2-[8-[l-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]imidazo[l,2-b]pyridazin-2-yl]morpholine-4-carboxylate as a yellow solid. LC / MS (m / z, M+H): calc. 576.2, found 576.2.

[0331] STEP 6 (example 16): (rac)-[4-(2-morpholin-2-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0332]

[0333] To a solution of (rac)-tert-butyl 2-[8-[l-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]imidazo[l,2-b]pyridazin-2-yl]morpholine-4-carboxylate (73 mg, 0.13 mmol) in MeOH (3 mL) was added a 4N HC1 solution in 1,4-dioxane (0.32 mL, 1.28 mmol) and the resulting mixture was stirred at room temperature for 6 hours. Then, the resulting reaction mixture was concentrated to dryness and the resulting residue was diluted with a minimum of MeOH, filtered through SCX cartridge, eluted with MeOH, followed by a 2N NH3 ammonium in MeOH. The resulting filtrate was concentrated in vacuo to give 49 mg (81% yield) of (rac)-[4-(2-morpholin-2-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4- (trifluoromethoxy)phenyl|methanone as an orange solid. LC / MS (m / z, M+H): calc. 476.2, found 476.3. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.76-1.93 (m, 2 H), 2.02 (br d, .7=13.0 Hz, 2 H), 2.73-2.87 (m, 3 H), 3.08-3.24 (m, 3 H), 3.45-3.58 (m, 1 H), 3.58-3.67 (m, 1 H), 3.84 (dt, .7=11.0, 2.5 Hz, 1 H), 4.01-4.29 (m, 2 H), 4.59 (dd, J=9.8, 2.6 Hz, 1 H), 7.02 (d, .7=4.8 Hz, 1 H), 7.38 br d, J=8.4 Hz, 2 H), 7.56 br (d, J=8.4 Hz, 2 H), 7.99 (s, 1 H), 8.33 (d, .7=4.8 Hz, 1 H) STEP 7: [4-[2-[(2R)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone and [4-[2-[(2S)-morpholin-2-yl]imidazo[l,2-b] pyridazin-8-yl] - 1 -piperidyl] - [4-(trifluoromethoxy)phenyl] methanone

[0334] FT 1

[0335]

[0336] Separation of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxy cyclobutyl) imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone (41 mg, 0.09 mmol) was performed using a Chiralpak IF column (5 pm, 250x4.6 mm), eluting with (Heptane 40 / EtOH 60)+0.1% TEA (flow rate 1 mL / min, UV detection at 265 nm) to give: 15 mg (36% yield) of 4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone isomer 1. LC / MS (m / z, M+H): calc. 476.2, found 476.1. 'H NMR (400 MHz, DMSO-Je, 100°C) 6 ppm 1.82-1.96 (m, 2 H), 2.00-2.10 (m, 2 H), 2.75-2.89 (m, 3 H), 3.11-3.23 (m, 3 H), 3.55 (tt, .7=11.7, 3.5 Hz, 1 H), 3.61-3.70 (m, 1 H), 3.84-3.90 (m, 1 H), 4.09-4.34 (m, 2 H), 4.61 (dd, 7=9.7, 2.4 Hz, 1 H), 7.05 (d, 7=4.8 Hz, 1 H), 7.41 (br d, 7=8.5 Hz, 2 H), 7.59 (br d, 7=8.5 Hz, 2 H), 8.01 (s, 1 H), 8.36 (d, 7=4.8 Hz, 1 H);

[0337] and 17 mg (41%yield) of4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone isomer 2. LC / MS (m / z, M+H): calc. 476.2, found 476.1. 'H NMR (400 MHz, DMSO-Ts, 100°C) 6 ppm 1.78-1.93 (m, 2 H), 1.96-2.07 (m, 2 H), 2.73-2.86 (m, 3 H), 3.08-3.21 (m, 3 H), 3.52 (tt, 7=11.8, 3.7 Hz, 1 H), 3.58-3.68 (m, 1 H), 3.84 (br dt, 7=11.1, 2.4 Hz, 1 H), 4.05-4.31 (m, 2 H), 4.59 (dd, 7=9.8, 2.5 Hz, 1 H), 7.02 (d, 7=4.8 Hz, 1 H), 7.38 (br d, 7=8.5 Hz, 2 H), 7.56 (br d, 7=8.5 Hz, 2 H), 7.99 (s, 1 H), 8.33 (d, 7=4.8 Hz, 1 H)

[0338] Examples 21, 8 & 9: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone , [2-amino-4- (trifluoromethoxy)phenyl]-[4-[2-[(2S)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl] methanone and [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(2R)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone

[0339]

[0340] STEP 1: (rac)-tert-butyl N-[2-[4-(3-aminopyridazin-4-yl)piperidine-l-carbonyl]-5- (trifluoromethoxy)phenyl]carbamate

[0341]

[0342] Step 1 of example 21, 8 & 9 was performed following the procedure described in step 4 of method C using 2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoic acid (1.07 g, 3.33 mmol) to give 1.25 g (86% yield) of (rac)-tert-butyl N-[2-[4-(3-aminopyridazin-4-yl)piperi dine- 1 -carbonyl] -5 -(trifluoromethoxy )phenyl] carbamate as a grey solid. LC / MS (m / z, M+H): calc. 482.2, found 482.2.

[0343] STEP 2: (rac)-tert-butyl 2-[8-[l-[2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy) benzoyl] -4-piperidyl]imidazo[l,2-b]pyridazin-2-yl]morpholine-4-carboxylate

[0344]

[0345] Step 2 of Examples 21, 8 and 9 was performed following the procedure described in step 5 of method C, under microwave irradiation at 120 °C, for 2 hours, using acetonitrile as solvent and 2.1 equivalents of NaHCCh, to give 135 mg (23% yield) of (rac)-tert-butyl 2-[8-[l-[2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoyl]-4-piperidyl]imidazo[l,2-b]pyridazin-2- yl]morpholine-4-carboxylate as an orange solid. LC / MS (m / z, M+H): calc. 691.3, found 691.3.

[0346] STEP 3 (example 21): (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone

[0347]

[0348] Step 3 of example 21, 8 & 9 was performed following the procedure described in step 6 of method C to give 127 mg (89% yield) of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone as an orange solid. LC / MS (m / z, M+H): calc. 491.2, found 491.2. 'H NMR (400 MHz, DMSO-rfe, 100°C) 6 ppm 1.78-1.93 (m, 2 H), 2.01 (br d, J=11.6 Hz, 2 H), 2.73-2.86 (m, 3 H), 3.05-3.19 (m, 3 H), 3.49 (tt, .7=11.9, 3.7 Hz, 1 H), 3.58-3.69 (m, 1 H), 3.84 (dt, J=ll.l, 2.5 Hz, 1 H), 4.16 (br d, J=13.5 Hz, 2 H), 4.59 (dd, J=9.6, 2.6 Hz, 1 H), 5.34 (br s, 2 H), 6.45-6.51 (m, 1 H), 6.65-6.71 (m, 1 H), 7.00 (d, .7=4,8 Hz, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 7.98 (s, 1 H), 8.33 (d, .7=4,8 Hz, 1 H) STEP 4 (example 8 & 9): [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[(2S)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone and [2-amino-4- (trifluoromethoxy)phenyl]-[4-[2-[(2R)-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl] methanone

[0349]

[0350] Step 4 of examples 8 & 9 was performed following the procedure described in step 7 of method C to give:

[0351] 30 mg (28% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone isomer 1. LC / MS (m / z, M+H): calc. 491.2, found 491.1. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.77-1.93 (m, 2 H), 1.96-2.08 (m, 2 H), 2.72-2.87 (m, 3 H), 3.06-3.20 (m, 3 H), 3.49 (tt, J=11.8, 3.7 Hz, 1 H), 3.58-3.69 (m, 1 H), 3.84 (dt, J=ll.l, 2.5 Hz, 1 H), 4.16 (br d, J=12.6 Hz, 2 H), 4.58 (dd, J=9.8, 2.7 Hz, 1 H), 5.34 (br s, 2 H), 6.43-6.52 (m, 1 H), 6.68 (br s, 1 H), 7.00 (d, .7=4,8 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 7.98 (s, 1 H), 8.33 (d, .7=4,8 Hz, 1 H);

[0352] and 32 mg (30% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-[-morpholin-2-yl]imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone isomer 2. LC / MS (m / z, M+H): calc.

[0353] 491.2, found 491.1. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.78-1.92 (m, 2 H), 1.95-2.05 (m, 2 H), 2.73-2.86 (m, 3 H), 3.06-3.17 (m, 3 H), 3.49 (tt, J=12.0, 4.0 Hz, 1 H), 3.58-3.69 (m, 1 H), 3.84 (dt, J=11.1, 2.4 Hz, 1 H), 4.11-4.21 (m, 2 H), 4.58 (dd, J=9.6, 2.6 Hz, 1 H), 5.34 (br s, 2 H), 6.44-6.51 (m, 1 H), 6.68 (br s, 1 H), 7.00 (d, .7=4,8 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 7.98 (s, 1 H), 8.33 (d, .7=4,8 Hz, 1 H)

[0354] Example 10: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxy-l -bicyclofl .1.1] pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone

[0355] 2

[0356]

[0357] Example 10 was prepared following method A using [2-nitro-4-(trifluoromethoxy)phenyl]-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-l-yl]methanone in step 4, to give in step 5, 182 mg (66% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxy-1 -bicyclofl .1. l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 502.2, found 502.1. 'H NMR (400 MHz, DMSO-rfe, 100°C) 6 ppm 1.77-1.93 (m, 2 H), 1.96-2.04 (m, 2 H), 2.18 (s, 6 H), 3.07-3.19 (m, 2 H), 3.27 (s, 3 H), 3.50 (tt, J=11.8, 3.7 Hz, 1 H), 4.15 (br d, J=13.3 Hz, 2 H), 5.34 (br s, 2 H), 6.45-6.52 (m, 1 H), 6.66-6.70 (m, 1 H), 6.99 (d, .7=4,8 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 7.95 (s, 1 H), 8.30 (d, .7=4,8 Hz. 1 H)

[0358] Example 11: [2-amino-3-fhioro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone 9

[0359]

[0360] Example 11 was prepared following method B using 2-amino-3-fluoro-4-(trifluoromethoxy)benzoic acid in step 5 to give 82 mg (58% yield) of [2-amino-3-fluoro-4-(trifluoromethoxy)phenyl] -[4-(2-tetrahy dropyran-4-ylimidazo[ 1 ,2-b]pyridazin-8-yl)- 1 -piperidyl] methanone as a white solid. LC / MS (m / z, M+H): calc. 508.2, found 508.1. 'HNMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.71-2.10 (m, 8 H), 2.99-3.09 (m partially hidden, 1 H), 3.17 (td, J=12.8, 2.4 Hz, 2 H), 3.47-3.60 (m, 3 H), 3.95 (dt, J=ll.l, 3.4 Hz, 2 H), 4.17 (br d, J=11.9 Hz, 2 H), 5.31 (br s, 2 H), 6.65 - 6.73 (m, 1 H), 6.99 (d, .7=4,8 Hz, 1 H), 7.03 (dd, J=8.6, 1.8 Hz, 1 H), 7.96 (s, 1 H), 8.32 (d, .7=4,8 Hz, 1 H)

[0361] Example 12: [4-[2-(l-hydroxy-l-methyl-ethyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0362]

[0363] Example 12 was prepared following method B using l-bromo-3-hydroxy-3-methyl-butan-2-one in step 1, to give in step 5, 101 mg (75% yield) of [4-[2-(l-hydroxy-l-methyl-ethyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 449.2, found 449.1. 'H NMR (400 MHz, DMSO- e, 30°C) 6 ppm 1.52 (s, 6 H), 1.75-2.17 (m, 4 H), 2.90-3.12 (m, 1 H), 3.22-3.45 (m, 1 H), 3.48-3.81 (m, 2 H), 4.54-4.82 (m, 1 H), 5.06 (s, 1 H), 7.07 (d, .7=4,8 Hz, 1 H), 7.46 (br d, J=8.8 Hz, 2 H), 7.60 (br d, J=8.8 Hz, 2 H), 8.00 (s, 1 H), 8.38 (d, .7=4,8 Hz, 1 H)

[0364] Example 13: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(l-hydroxy-l-methyl-ethy l)imidazo [ 1 ,2-b] pyridazin-8-yl] - 1 -piperidy l]methanone

[0365]

[0366] Example 13 was prepared following method B using l-bromo-3-hydroxy-3-methyl-butan-2-one in step 1 and 2-amino-4-(trifluoromethoxy)benzoic acid in step 5, to give 116 mg (83% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(l-hydroxy-l-methyl-ethyl)imidazo [l,2-b]pyridazin-8-yl]-l-piperidyl]methanone as a pale brown solid. LC / MS (m / z, M+H): calc.

[0367] 464.2, found 464.1. 'H NMR (400 MHz, DMSO- e, 30°C) 6 ppm 1.52 (s, 6 H), 1.74-1.91 (m, 2H), 1.99 (brd, J=11.9Hz, 2H), 2.99-3.23 (m, 2H), 3.51 (tt, J=11.9, 3.5 Hz, 1 H), 3.63-4.53 (m, 2 H), 5.05 (s, 1 H), 5.58 (s, 2 H), 6.46-6.52 (m, 1 H), 6.64-6.70 (m, 1 H,) 7.05 (d, .7=4,8 Hz, 1 H), 7.16 (d, .7=8.4 Hz, 1 H), 8.00 (s, 1 H), 8.38 (d, .7=4,8 Hz, 1 H)

[0368] Example 14: [4-(l,l,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)- 1 -piperidyl]methanone

[0369]

[0370] Example 14 was prepared following method B using 4-(l,l,2,2,2-pentafluoroethyl)benzoic acid in step 5, to give 66 mg (42% yield) of [4-(l, 1,2,2, 2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a white foam. LC / MS (m / z, M+H): calc. 509.2, found 509.0. 'H NMR (400 MHz, DMSO-rfc, 100°C) 6 ppm 1.67-2.11 (m, 8 H), 2.96-3.07 (m, 1 H), 3.16 (brt, J=12.4 Hz, 2 H), 3.42-3.59 (m, 3 H), 3.93 (dt, .7=10.9, 3.5 Hz, 2 H), 3.99-4.31 (m, 2H), 6.99 (d, .7=4.8 Hz, 1 H), 7.63-7.71 (m, 2H), 7.72-7.79 (m, 2 H), 7.94 (s, 1 H), 8.30 (d, .7=4,8 Hz, 1 H)

[0371] Example 15: [4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8 -y 1) - 1 -piperidyl] methanone

[0372]

[0373] Example 15 was prepared following method B using 4-cyclopropoxybenzoic acid in step 5, to give 81 mg (58% yield) of [4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 447.2, found 447.3. 'H NMR (400 MHz, DMSO-rfe, 100°C) 6 ppm 0.64-0.83 (m, 4 H), 1.69-2.09 (m, 8 H), 2.96-3.06 (m, 1 H), 3.11 (td, J=12.8, 2.5 Hz, 2 H), 3.43-3.56 (m, 3 H), 3.83-3.97 (m, 3 H), 4.22 (br d, J=13.0 Hz, 2 H), 6.98 (d, .7=4,8 Hz, 1 H), 7.08 (br d, J=8.6 Hz, 2 H), 7.38 (br d, .7=8.6 Hz, 2 H), 7.94 (s, 1 H), 8.29 (d, .7=4,8 Hz, 1 H)

[0374] Example 17: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)- 1 -piperidyl]methanone

[0375]

[0376] Example 17 was prepared following method C using 2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoic acid in step 4, and 2-bromo-l-(oxan-4-yl)ethan-l-one in step 5 , to give in step 6, 67 mg (73% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a yellow solid. LC / MS (m / z, M+H): calc. 490.2, found 493.3. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.68-2.09 (m, 8 H), 3.01 (tt, J=11.2, 4.0 Hz, 1 H), 3.12 (td, J=12.8, 2.5 Hz, 2 H), 3.49 (td, .7=11.4, 2.2 Hz, 3 H), 3.93 (dt, J=11.0, 3.4 Hz, 2 H), 4.16 (br d, J=13.1 Hz, 2 H), 5.34 (s, 2 H), 6.42-6.51 (m, 1 H), 6.64-6.70 (m, 1 H), 6.96 (d, .7=4,6 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 7.93 (s, 1 H), 8.29 (d, .7=4.6 Hz, 1 H)

[0377] Example 18: [2-fluoro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone

[0378]

[0379] Example 18 was prepared following method C using 2-fluoro-4-(trifluoromethoxy)benzoic acid in step 4, and 2-bromo-l-(oxan-4-yl)ethan-l-one in step 5 (no step 6), to give 43 mg (22% yield) of [2-fluoro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 493.2, found 493.3. *HNMR (400 MHz, DMSO-rfe, 100°C) 6 ppm 1.64-2.19 (m, 8 H), 2.96-3.83 (m, 6 H), 3.93 (br d, J=10.8 Hz, 2 H), 4.03-4.92 (m, 2 H), 6.96 (br d, .7=4,5 Hz, 1 H), 7.27 (br d, .7=8.0 Hz, 1 H), 7.35 (br d, J=9.5 Hz, 1 H), 7.52-7.62 (m, 1 H), 7.94 (s, 1 H), 8.29 (br d, .7=4,5 Hz, 1 H)

[0380] Example 19 : [4-(2-cy clopentylimidazo [ 1 ,2-b] pyridazin-8-yl)- 1 -piperidyl] - [4- (trifluoromethoxy)phenyl]methanone

[0381]

[0382] Example 19 was prepared following method A using commercially available 2-bromo-l-cyclopentylethanone in step 3, to give 127 mg (50% yield) of [4-(2-cyclopentylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 459.2, found 459.3. 'H NMR (400 MHz, DMSO-rfc, 100°C) 6 ppm 1.58-1.94 (m, 8 H), 1.96-2.10 (m, 4 H), 3.14 (br t, J=11.8 Hz, 2 H), 3.19-3.28 (m, 1 H), 3.51 (tt, J=11.8, 3.7 Hz, 1 H), 4.05-4.29 (m, 2 H), 6.96 (d, .7=4,8 Hz, 1 H), 7.34-7.41 (m, 2 H), 7.52-7.59 (m, 2 H), 7.90 (s, 1 H), 8.27 (d, .7=4,8 Hz, 1 H)

[0383] Example 20: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclopentylimidazo[l,2-b]pyridazin-8-yl)- 1 -piperidyl]methanone

[0384]

[0385] Example 20 was prepared following method A using commercially available 2-bromo-l-cyclopentylethanone in step 3 and [2-nitro-4-(trifluoromethoxy)phenyl]-[4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-l-yl]methanone (424 mg, 0.96 mmol, 1.2 eq.) in step 4, to give, in step 5, 125 mg (54% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclopentylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl] methanone as a white solid. LC / MS (m / z, M+H): calc. 474.2, found 474.2. 'HNMR (400 MHz, DMSO- / e. 100°C) 6 ppm 1.60-2.13 (m, 12 H), 3.08-3.19 (m, 2 H), 3.20-3.32 (m, 1 H), 3.44-3.59 (m, 1 H), 4.19 (br d, J=12.5 Hz, 2 H), 5.37 (br s, 2 H), 6.50 (br d, J=8.3 Hz, 1 H), 6.71 (br s, 1 H), 6.97 (d, .7=4,8 Hz, 1 H), 7.17 (d, J=8.3 Hz, 1 H), 7.93 (s, 1 H), 8.30 (d, .7=4,8 Hz, 1 H)

[0386] Example 22: (rac)-[4-(2-tetrahydrofuran-3-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4-(trifluoromethoxy )phenyl] methanone

[0387]

[0388] Example 22 was prepared following Method A using 2-bromo-l-tetrahydrofuran-3-yl-ethanone in step 3 to give in step 5, 50 mg (49% yield) of (rac)-[4-(2-tetrahydrofuran-3-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white foam. LC / MS (m / z, M+H): calc. 461.2, found 461.5. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.80-1.98 (m, 2 H), 2.05 (br d, J=12.3 Hz, 2 H), 2.13-2.26 (m, 1 H), 2.27-2.39 (m, 1 H), 3.17 (br t, J=12.1 Hz, 2 H), 3.48-3.69 (m, 2 H), 3.79-3.98 (m, 3 H), 4.09 (t, J=1.8 Hz, 1 H), 4.12-4.32 (m, 2 H), 7.03 (d, .7=4,8 Hz, 1 H), 7.41 (br d, J=8.5 Hz, 2 H), 7.59 (d, J=8.5 Hz, 2 H), 8.03 (s, 1 H), 8.34 (d, .7=4,8 Hz, 1 H) Example 23: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-ylimidazo [ 1 ,2-b] py ridazin-8-y 1)- 1 -piperidyl] methanone

[0389]

[0390] Example 23 was prepared following method A using 2-bromo-l-tetrahydrofuran-3-yl-ethanone in step 3 and [2-nitro-4-(trifluoromethoxy)phenyl]-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-l-yl]methanone in step 4, to give in step 5, 179 mg (78% yield) of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 476.2, found 476.1. *HNMR (400 MHz, DMSO-rfe, 100°C) 6 ppm 1.78-1.93 (m, 2 H), 1.97-2.05 (m, 2 H), 2.09-2.22 (m, 1 H), 2.24-2.35 (m, 1 H), 3.12 (td, J=12.8, 2.6 Hz, 2 H), 3.49 (tt, J=11.8, 3.7 Hz, 1 H), 3.59 (quin, J=1 A Hz, 1 H), 3.76-3.96 (m, 3 H), 4.06 (t, J=1.8 Hz, 1 H), 4.16 (br d, J=13.1 Hz, 2 H), 5.34 (br s, 2 H), 6.44-6.51 (m, 1 H), 6.66-6.70 (m, 1 H), 6.98 (d, .7=4,8 Hz, 1 H), 7.14 (d, .7=8,4 Hz, 1 H), 8.00 (s, 1 H), 8.30 (d, .7=4,8 Hz, 1 H)

[0391] Example 24: [4-(pentafluoro-X6-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone

[0392]

[0393] Example 24 was prepared following method B using 2-bromo-l-tetrahydropyran-4-yl-ethanone in step 1 and 4-(pentafluoro-Z6-sulfany I (benzoic acid in step 5 to give 90 mg (70% yield) of [4-(pentafluoro-X6-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 517.2, found 517.1. 'H NMR (400 MHz, DMSO- e, 100°C) 6 ppm 1.68-2.09 (m, 8 H), 3.01 (tt, J=11.1, 4.0 Hz, 1 H), 3.16 (br t, J=12.3 Hz, 2 H), 3.44-3.58 (m, 3 H), 3.87-3.97 (m, 2 H), 3.98-4.39 (m, 2 H), 6.98 (d, .7=4,8 Hz, 1 H), 7.65 (br d, J=8.6 Hz, 2 H), 7.90-7.98 (m, 3 H), 8.30 (d, .7=4.8 Hz, 1 H)

[0394] Example 25: |2-amino-4-(pentafluoro-Z6-sulfanyl)phenyl|-|4-(2-tetrahydropyran-4-y limidazo [ 1 ,2-b] py ridazin-8-y 1)- 1 -piperidyl] methanone

[0395]

[0396] Example 25 was prepared following method B using 2-bromo-l-tetrahydropyran-4-yl-ethanone in step 1 and 2-amino-4-(pentafluoro-Z6-sulfanyl)benzoic acid;hydrochloride in step 5 to give 115 mg (70% yield) of [2-amino-4-(pentafluoro-Xs-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): calc. 532.2, found 532.1. 'H NMR (400 MHz, DMSO-de, 100°C) 6 ppm 1.69-2.09 (m, 8 H), 3.01 (tt, J=11.2, 4.0 Hz, 1 H), 3.13 (td, J=12.8, 2.4 Hz, 2 H), 3.44-3.54 (m, 3 H), 3.93 (dt, J=ll.l, 3.4 Hz, 2 H), 4.07-4.22 (m, 2 H), 5.45 (br s, 2 H), 6.97 (d, .7=4,8 Hz, 1 H), 6.99 (dd, .7=8.4, 2.3 Hz, 1 H), 7.23 (br d, J=8.4 Hz, 1 H), 7.27 (d, .7=2.3 Hz, 1 H), 7.94 (s, 1 H), 8.30 (d, .7=4.8 Hz, 1 H)

[0397] ERK5 inhibitory activity of compounds

[0398] Two assays were performed to assess the ERK5 inhibitory activity of compounds of the Examples, a cell-based assay and a cell-free biochemical assay. Results of the assays are shown below in Table 2. Where repeat measurements were taken, the value reported is a mean average.

[0399] Inhibition of cellular ERK5 activity

[0400] The renal cancer cell line SN12C was transduced by a lentivirus pGreenFirel MEF2 EFl Neo (ref TR030VA-N) from SBI using standard infection protocol. pGreenFirel MEF2 EFl Neo allows the expression of luciferase gene under the control of minimal promoter with MEF2 transcriptional response elements. Cells harboring the reporter construct were selected by geneticin treatment. The selected cells were then transposed by a piggyback based plasmid pCM4007 allowing the expression of constitutively activated MEK5DD under control of TREG3 promoter, a doxycycline regulated promoter. Transposed cells were selected by puromycin treatment. Upon doxycycline treatment (Ipg / ml) MEK5DD was expressed.

[0401] MEK5DD activates ERK5 that phosphorylates MEF2C protein. Activated MEF2C protein can bind to its transcriptional response elements. Then the luciferase is expressed. In a 96-well plate (96F nuncleon refl37101 thermofisher), 50,000 cells were inoculated in 142.5pl of RPMI medium containing 10% fetal calf serum, 1% glutamine, and Ipg / ml doxycycline. After 24 hours, compounds were added in 7.5 pl culture medium (with 2% DMSO to give a final concentration of 0.1%) in order to obtain the desired concentration (0.3-10000nM). The luciferase activity was measured using the Kit Bright Gio Luminescent Cell Assay Cat E2610 (Promega) according to the manufacturer’s protocol. Luminescence was determined using 0.2 second reading / well using a Tecan SPARK. ICso values were calculated using XLFIT5 for Microsoft Excel using method 205. The ICso values represent the concentration of compound which inhibits the measurable luminescence signal by 50% as compared to DMSO-treated control cells.

[0402] Cell-free assay of ERK5 inhibition

[0403] An assay was performed to measure the capacity of each compound to inhibit ERK5 enzymatic activity. Compound potency was evaluated by Time-Resolved Forster Resonance Energy Transfer (FRET system). The activated catalytic domain of protein ERK5 (CamaBiosciences #04-146) was mixed at 4 nM with varying concentrations of compound and incubated for 30 minutes at room temperature. A mixture of ImM ATP and I M biotinylated synthetic peptide was added (Biosyntan GmbH). This synthetic peptide represents amino acids 30-52 of Eukaryotic translation initiation factor 4E-binding protein 1 (see, e.g., the sequence under accession No. NP_004086.1) biotinylated at the N-terminus. After 30 minutes at 37°C, the peptide phosphorylation by ERK5 was measured by addition of FRET reagents consisting of 12.5 pg / ml Streptavidin-XL665, 1 nM Anti-P-4EBP1 antibody and 300ng / ml Anti-rabbit-K antibody. Following 90 minutes at room temperature fluorescent signals were read on the Pherastar FSX multimod detector from BMG Labtech (Exc° 340 nm, Eml 620 nm, Em2665 nm). The ICso values represent the concentration of compound which inhibits the measurable fluorescence signal by 50% as compared to the DMSO only control. Table 2: Results of cell-based and cell-free assays

[0404] Compound Cell-free assay Cell-based assay (Example No.) (IC50 in nM) (IC50 in nM)

[0405] 1 4471 548

[0406] 2 2061 206

[0407] 3 4176 533

[0408] 4 5434 553

[0409] 5 15094 1073

[0410] 6 8247 1359

[0411] 7 2849 648

[0412] 8 1405 656

[0413] 9 497 341

[0414] 10 1167 226

[0415] 11 1423 259

[0416] 12 11126 1962

[0417] 13 2228 586

[0418] 14 6410 1096

[0419] 15 2140 1022

[0420] 16 2052 134

[0421] 17 308 113

[0422] 18 508 695

[0423] 19 2498 761

[0424] 20 676 506

[0425] 21 538 580

[0426] 22 1489 883

[0427] 23 439 318

[0428] 24 1637 583

[0429]

[0430] 25 613 289

[0431] The data in Table 2 indicate that the compounds synthesised are active in the micromolar or nanomolar concentration range in cell-based and / or cell-free systems. All of the compounds synthesised have an ICso value below 2 pM in at least one of the cell-based and cell-free assays.

Claims

CLAIMS1. A compound of Formula (I):(I)wherein:R1 represents a hydrogen atom, a fluorine atom or a -NH2 group;R2 represents a hydrogen atom or a fluorine atom;R3 is selected from the groups -OCF3, -CF2CF3, -O-cycloalkyl and -SFs; and R4 represents a (Cl-C4)alkyl group or a (C4-C6)cycloalkyl group, optionally substituted by a hydroxy or methoxy group, or R4 represents a 5 or 6-membered heterocycloalkyl group,or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (I) according to claim 1, wherein R1 represents a hydrogen atom or a -NH2 group,or a pharmaceutically acceptable salt thereof.

3. A compound of Formula (I) according to claim 1 or claim 2, wherein R2 represents a hydrogen atom,or a pharmaceutically acceptable salt thereof.

4. A compound of Formula (I) according to any of claims 1 to 3, wherein R3 represents a group -OCF3,or a pharmaceutically acceptable salt thereof.

5. A compound of Formula (I) according to any of claims 1 to 4, wherein R4 is selected from: . an isopropyl, cyclobutyl, cyclopentyl or bicyclo[l.l.l]pentanyl, said groups being optionally substituted by a hydroxy or methoxy group; and. a tetrahydrofuranyl, tetrahydropyranyl or morpholinyl group,or a pharmaceutically acceptable salt thereof.

6. A compound of Formula (I) according to any of claims 1 to 5, which is selected from the group consisting of:[4-[2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)imidazo[l,2-b]pyridazin-8-yl]-l- piperidyl] - [4-(trifluoromethoxy)phenyl] methanone(trans)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3- methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]methanone(cis)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(3-methoxycyclobutyl)imidazo[l,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone(trans)-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone(cis)-[4-[2-(3-methoxycyclobutyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone[4- [2-[(2R)-morpholin-2-yl] imidazo [ 1 ,2-b] pyridazin-8-yl] - 1 -piperidyl] - [4- (trifluoromethoxy)phenyl]methanone[4- [2-[(2S)-morpholin-2-yl] imidazo [ 1 ,2-b] py ridazin-8-yl] - 1 -piperidyl] - [4- (trifluoromethoxy)phenyl]methanone[2-amino-4-(trifluoromethoxy)pheny 1] - [4- [2- [(2S)-morpholin-2-yl] imidazo [1,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone[2-amino-4-(trifluoromethoxy)pheny 1] - [4- [2- [(2R)-morpholin-2-yl] imidazo [1,2- b] pyridazin-8-yl] - 1 -piperidyl] methanone[2-amino-4-(trifluoromethoxy)phenyl]- [4- [2-(3 -methoxy- 1- bicy clo[ 1.1.1 ]pentanyl)imidazo[ 1 ,2-b]pyridazin-8-yl]- 1 -piperidyl] methanone[2-amino-3-fluoro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4- ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]methanone[4-[2-(l-hydroxy-l-methyl-ethyl)imidazo[l,2-b]pyridazin-8-yl]-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone[2-amino-4-(trifluoromethoxy)phenyl]-[4-[2-(l-hydroxy-l-methyl-ethyl)imidazo[l,2-b] pyridazin-8-yl] - 1 -piperidyl] methanone[4-(l,l,2,2,2-pentafluoroethyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone[4-(cyclopropoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2-b]pyridazin-8-yl)-l- piperidyl]methanone(rac)-[4-(2-morpholin-2-ylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone[2-fluoro-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone[4-(2-cyclopentylimidazo[l,2-b]pyridazin-8-yl)-l-piperidyl]-[4- (trifluoromethoxy)phenyl]methanone[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-cyclopentylimidazo[l,2-b]pyridazin-8- yl)- 1 -piperidyl] methanone(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-morpholin-2-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone(rac)-[4-(2-tetrahydrofuran-3-ylimidazo[l,2-b]pyridazin-8-yl)-l -piperidyl] -[4- (trifluoromethoxy)phenyl]methanone(rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(2-tetrahydrofuran-3-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone[4-(pentafluoro-Xs-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone[2-amino-4-(pentafluoro-X6-sulfanyl)phenyl]-[4-(2-tetrahydropyran-4-ylimidazo[l,2- b]pyridazin-8-yl)-l-piperidyl]methanone,and the pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

8. A compound according to any of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for use in therapy.

9. A compound according to any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for use in the treatment or prevention of cancer.

10. The compound or pharmaceutical composition for use according to claim 9, wherein the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

11. The compound or pharmaceutical composition for use according to claim 9 or claim 10, wherein the cancer is selected from leukaemia, breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

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