EP4642773A1 - Nouveaux dérivés de benzimidazole - Google Patents

Nouveaux dérivés de benzimidazole

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Publication number
EP4642773A1
EP4642773A1 EP23840681.3A EP23840681A EP4642773A1 EP 4642773 A1 EP4642773 A1 EP 4642773A1 EP 23840681 A EP23840681 A EP 23840681A EP 4642773 A1 EP4642773 A1 EP 4642773A1
Authority
EP
European Patent Office
Prior art keywords
methyl
difluoromethyl
benzimidazol
pyridyl
methylpyridazin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23840681.3A
Other languages
German (de)
English (en)
Inventor
Mahendra AWALE
Stefan Berchtold
Julie CHARPENTIER
Héloïse Marie Albine COLOMBANO
Guillaume Stéphane DÉCORET
Katrin Groebke Zbinden
Nicole Denise GROSSMANN
Wolfgang Juergen HAAP
Philip Anthony Harris
Jérôme HERT
Jonah Milton KALLENBACH
Christian Kramer
Lukas Matthias KREIS
Danny KRUMM
Xavier LUCAS CABRÉ
Nenad MANEVSKI
Philippe Pflieger
Amir Mohsen POURMOUSA ABKENAR
Etienne RAUBER
Dazhi TAN
Jean-Yves WACH
Roger WERMUTH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP4642773A1 publication Critical patent/EP4642773A1/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that modulate SIK activity.
  • the invention relates in particular to a compound of formula (I) wherein
  • R 1 is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl or heterocycloalkyl, wherein heterocycloalkyl carbonyl, heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 2 is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy or alkylheteroarylamino;
  • R 3 is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkylcarbonyl, heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 ; or R 2 and R 3 together with the carbon atoms to which they are attached to form a 4 to 6 membered heterocycloalkyl optionally substituted with alkylheteroaryl; each instance of R 4 is individually selected from alkyl, amino, alkyl sulfonyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy and haloalkyl; each instance of R 5 is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(al
  • a 1 is -N- or -CH-
  • L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof.
  • Salt-inducible kinases belong to a subfamily of AMP-activated protein kinases (AMPK) called AMPK-related kinases. There are three members, named SIK1, SIK2 and SIK3, that are broadly expressed. Their major biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two key classes of transcriptional regulatory factors: CRTCs (c AMP -regulated transcriptional coactivators) and class Ila HDACs (Histone deacetylases). Indeed, in basal state, both CRTCs and HDACs are phosphorylated by SIK kinases, and sequestered in the cytoplasm through interactions with their cytoplasmic chaperones 14-3-3.
  • CRTCs c AMP -regulated transcriptional coactivators
  • HDACs Histone deacetylases
  • the SIK kinases In response to extracellular cues that usually increase intracellular levels of cAMP, the SIK kinases’ activity is inhibited, CRTCs and HDACs are no longer phosphorylated and are hence released from 14-3-3. They can therefore translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).
  • SIK kinases In macrophages, the inhibition of SIK kinases leads to 1) CRTC3 shuttling to the nucleus and increasing the transcription of IL-10,; and 2) translocation of HDAC4/5 to the nucleus and subsequent deacetylation of NF-KB resulting in decreased transcription of pro-inflammatory cytokines (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986-91.).
  • Macrophages are critical to maintaining tissue homeostasis, mediating inflammation, and promoting the resolution of inflammation. To achieve this diversity of function, macrophages have the ability to “polarize” differently in response to environment cues.
  • the two extreme phenotypes along their activation state continuum are the “Ml” or “pro-inflammatory macrophages” and the “M2” or “pro-resolution macrophages”.
  • SIKs have since been shown to be important players in the functions of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-
  • SIK1 is poorly expressed in macrophages and one embodiment of the invention are SIK2/3 inhibitors sparing SIK1, thus limiting potential SIKl-related toxicities.
  • SIK inhibitors have a high therapeutic potential in diseases that are 1) characterized by pro-inflammatory macrophage influx in the tissues and impaired tissue homeostasis and healing, or 2) where anti-TNF therapies are beneficial (partially or fully) or with insufficient levels of the IL10.
  • Diseases with an inflammatory macrophage signature are e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel diseases (“IBD”), atherosclerosis, type 2 diabetes and glomerulonephritis.
  • IBD Intracellular IL- 10 and TNF-a.
  • Genetic alterations that reduce the function of IL- 10 such as SNPs in IL- 10 or its receptor) are associated with an increased risk for IBD in humans.
  • anti-TNF therapies are successful but only a subset of IBD patients are responsive and much of this limited responsiveness is lost over time.
  • the described dual effect of SIK inhibitors (increased IL- 10 and decreased TNF-a) make them particularly pertinent for the treatment of IBD.
  • SIK kinase isoforms are expressed broadly in human tissues with the highest expression observed in skin and adipose tissues for SIK1, adipose tissue for SIK2 and testis and brain for SIK3. Similarly to their role in macrophages, SIKs in these cells phosphorylate CRTCs and class II HDACs in response to extracellular signals, which subsequently change the expression of several cellular factors.
  • SIK2 has been described as a risk locus for primary sclerosing cholangitis, a fibrotic disease regularly associated with IBD.
  • SIK2 and SIK3 expression is higher in ovarian and prostate cancers and correlated with poor survival (Miranda et al., Cancer Cell. 2016 Aug 8;30(2):273-289; Bon et al., Mol Cancer Res. 2015 Apr;13(4):620-635).
  • the present invention relates to a novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases.
  • SIK inhibitors can thus also be of potential relevance in cancer, metabolic diseases, bone density dysregulation diseases, pigmentation-related diseases or cosmetology, fibrotic diseases and depressive disorders.
  • alkyl signifies a straightchain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms.
  • Examples of straight-chain and branched- chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl.
  • Particular examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
  • Methyl, ethyl, propyl and butyl, like isobutyl are further particular examples of “alkyl” in the compound of formula (I).
  • heterocycloalkyl denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 12 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common.
  • “Hetercycloylkyl” may comprise a carbonyl group, wherein the carbon is part of the ring system. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heterocycloalkyl).
  • heterocycloalkyl examples include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-3-yl, piperidyl, 1 -piperidyl, 3 -piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-1- yl, [3-oxo-piperazin-l-yl], (l,l-dioxo-l,2-thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3- c]pyridin-l-yl), (3-oxo-l,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS
  • heterocycloalkyl are diazaspiroheptanyl, tetrahydrofuranyl, piperidinyl and oxetanyl, more particularly 2,6-diazaspiro[3.3]heptanyl, 6-tetrahydrofuran-3-yl, 4-piperidyl and oxetan-3-yl.
  • heterocycloalkyl is “N-heterocycloalkyl”.
  • heteroaryl signifies a fully aromatic or partially aromatic mono- or bicyclic ring system with 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, the remaining ring atoms being carbon.
  • the ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heteroaryl).
  • heteroaryl examples include, but are not limited to, pyrazolyl, pyrazol-l-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol- 3-yl, isoxazol-4-yl, pyrimidinyl, pyrimidin-5-yl, benzotri azolyl, lH-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-lH-pyridazin-5-yl], triazolyl, triazol-l-yl, triazol-2-yl, 2-oxo-4- pyr
  • pyrimidin-2-yl pyrimidin-5-yl, (l,3,4-oxadiazol-2-yl), (l,3,4-thiadiazol-2-yl), (1,2,4- triazin-3-yl), 2-oxo-pyrimidin-4-yl, (l-methyl-2-oxo-3-pyridyl), (2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl), 1 -methyl -6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][l,4]oxazin-8- yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6-dihydropyrrolo[2,3-c]
  • heteroaryl are pyrazolyl and pyridazinyl, more particularly pyrazol-l-yl, pyrazol-4-yl and pyridazin-3-yl.
  • heteroaryl is “N-heteroaryl”.
  • cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • Bicyclic means consisting of two saturated carbocycles having two carbon atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two carbon atoms.
  • Particular cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl or adamantanyl.
  • aryl denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms.
  • aryl moi eties include phenyl and naphthyl.
  • a particular example of “aryl” is phenyl.
  • alkoxy or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
  • alkoxy are methoxy and ethoxy.
  • cyano alone or in combination, signifies carbon atom linked to a nitrogen atom via a triple bond; this group is also referred to as carbonitrile group.
  • alkylsulfonyl alone or in combination, signifies a group of the formula alkyl-sulfonyl- in which the term “alkyl” has the previously given significae.
  • halogen or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine.
  • halo in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens.
  • haloalkyl denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens, more particularly two to three halogens.
  • Particular “haloalkyl” are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl. More particular “haloalkyl” are difluoromethyl and trifluoroethyl.
  • haloalkoxy denotes an alkoxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens.
  • a particular “haloalkoxy” is difluoromethoxy.
  • hydroxyl and “hydroxy”, alone or in combination, signify the -OH group.
  • carbonyl alone or in combination, signifies the -C(O)- group.
  • heterocycloalkylcarbonyl alone or in combination, signifies a” heterocycloalkyl” linked to a “carbonyl” group.
  • heterocycloalkyloxy alone or in combination, signifies a “heterocycloalkyl” group linked to an “oxy” group.
  • heterocycloalkylalkoxy alone or in combination, signifies a “heterocycloalkyl” group linked to an “alkoxy” group.
  • heterocycloalkyalkoxy alone or in combination, signifies a “heterocycloalkyl” group linked to an “alkoxy” group.
  • amino alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).
  • alkylamino alone or in combination, is an alkyl group linked to a -NH- group.
  • dialkylamino denotes two alkyl groups linked to a -N- atom.
  • An example of a” dialkylamino” group is for instance dimethylamino.
  • dialkylaminocarbonylalkoxy refers to a “dialkylamino” group linked to a “carbonyl” group, wherein the carbonyl group is further linked to an “alkoxy” group.
  • alkylheteroarylamino refers to an “alkyl” group linked to a “heteroaryl” group, wherein the heteroaryl is further linked to a “amino” group.
  • cycloalkylcarbonyl signifies a “cycloalkyl” group linked to a “carbonyl” group.
  • cycloalkylcarbonyl include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexyl carbonyl.
  • the terhm “cycloalkylalkyl”, alone or in combination, denotes an “alkyl” group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a “cycloalkyl” group.
  • cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl.
  • alkylcarbonyl alone or in combination, signifies an “alkyl” group linked to a “carbonyl” group.
  • alkylcarbonyl are for instance methylcarbonyl, ethylcarbonyl and propylcarbonyl.
  • alkylheteroaryl denotes a “heteroaryl” wherein at least one of the hydrogen atoms of the heteroaryl group has been replaced by an alkyl group.
  • alkylheteroaryl are for instance methylheteroaryl, ethylheteroaryl and propylheteroaryl.
  • alkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group.
  • alkoxyalkyl groups include 2-methoxy ethyl, 3 -methoxypropyl, l-methyl-2-methoxy ethyl, l-(2- methoxyethyl)-3 -methoxypropyl, and 1 -(2-methoxyethyl)-3 -methoxypropyl .
  • dialkylaminocarbonyl alone or in combination, denotes a “carbonyl” group linked to an “dialkylamino” group.
  • alkoxycarbonyl alone or in combination, signifies an “alkoxy” group linked to a “carbonyl” group.
  • alkylheterocycloalkyl denotes a heterocycloalkyl group wherein one of the hydrogen atoms is replaced by an “alkyl” group.
  • alkylheterocycloalkyl are for instance methylheterocycloalkyl, ethylheterocycloalkyl and propylheterocycloalkyl.
  • alkylheterocycloalkyloxy denotes an “oxy” group linked to a “heterocycloalkyl” group, wherein one of the hydrogen atoms of heterocycloalkyl has been replaced by an “alkyl” group.
  • heterocycloalkylheterocycloalkyloxy denotes an “oxy” group linked to a “heterocycloalkyl” group, wherein one of the hydrogen atoms of “heterocycloalkyl” has been replaced by a further “heterocycloalkyl” group.
  • aminocarbonyl alone or in combination, signifies an “amino” group linked to a “carbonyl” group.
  • dialkylaminocarbonylalkyl denotes an “alkyl” group, wherein one of the hydrogen atoms of alkyl has been replaced by a dialkylamino group.
  • hydroxyalkyl denotes an “alkyl” group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a “hydroxy” group.
  • hydroxyalkyl examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,
  • arylalkoxycarbonylaminoheterocycloalkyl denotes a “heterocycloalkyl” group wherein a hydrogen atom of heterocycloalkyl has been replaced by a cabonylamino group linked to an “alkoxy” group, and wherein one of the hydrogen of alkoxy has been replaed by an “aryl” group.
  • pharmaceutically acceptable salts denotes salts which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include both acid and base addition salts.
  • pharmaceutically acceptable acid addition salt denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid
  • pharmaceutically acceptable base addition salt denotes those pharmaceutically acceptable salts formed with an organic or inorganic base.
  • acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.
  • substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, trieth
  • compound(s) of this invention and “compound(s) of the present invention” refers to compounds of formula (I) and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.
  • Tautomeric forms i.e. structural isomers which interconvert with the compound of formula (I), in particular in solution, may in some instances exist and are to be understood as being included in the invention.
  • one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps
  • appropriate protecting groups as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3 rd Ed., 1999, Wiley, New York
  • Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.
  • protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p- methoxybenzyloxycarbonyl (Moz).
  • the compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • asymmetric carbon atom means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration.
  • the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers as well as their solvates, wherever applicable, of the compound of formula (I).
  • racemic mixtures of the compound of the invention may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer of the compound.
  • a chirally pure or chirally enriched compound may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Particular examples of radioisotopes are 2 H, 3 H, 13 C, 14 C and 18 F.
  • the structures wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a 13 C- or 14 C- enriched carbon are within the scope of this invention.
  • the invention thus relates to:
  • R 1 is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl or heterocycloalkyl, wherein heterocycloalkyl carbonyl, heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 2 is hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyl oxy, heterocycloalkyl alkoxy or alkylheteroarylamino;
  • R 3 is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkylcarbonyl, heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 ; or R 2 and R 3 together with the carbon atoms to which they are attached to form a 4 to 6 membered heterocycloalkyl optionally substituted with alkylheteroaryl; each instance of R 4 is individually selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy and haloalkyl; each instance of R 5 is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dial
  • a 1 is -N- or -CH-
  • L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof;
  • R 1 is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 1 is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with 1 or 2 substituents individually selected from R 4 ;
  • R 1 is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with a substituent selected from R 4 ;
  • R 1 is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 1 is pyrazolyl optionally substituted with a substituent selected from R 4 ;
  • R 2 is hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R 2 and R 3 , together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;
  • R 2 is hydrogen, methoxy, methyl, fluoro, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R 2 and R 3 , together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;
  • R 2 is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R 2 and R 3 , together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;
  • R 2 is hydrogen, methoxy, methyl, fluoro, difluoromethoxy, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R 2 and R 3 , together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;
  • R 3 is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3-c]pyridazinyl, 1- methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][l,4]oxazinyl, 6-oxo-pyrrolo[2,3- c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl or 5,6-dihydropyrrolo[2,3- c]pyridazinyl; wherein piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H- pyrano[4,3-c]pyridazinyl, l-methyl-6-oxo-
  • R 3 is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yl, 1 -methyl -6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl or 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl; wherein piperidinylcarbonyl, 2,6- diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-d
  • R 4 is at each instance independently selected from cyano, methyl, amino, methylsulfonyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (lR)-2,2-difluoro-l-methyl-ethoxy, difluoromethyl, trifluoromethyl and trifluoroethyl;
  • R 4 is at each instance independently selected from cyano, methyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (lR)-2,2-difluoro-l-methyl-ethoxy, difluoromethyl, trifluoromethyl and tri fluoroethyl;
  • R 4 is amino or methyl sulfonyl
  • R 5 is at each instance independently selected from tert-butyl oxy carbonyl, methyl, ethyl, tetrahydrofuranyl, oxetanyl, 4-hydroxy-3 -methyl - tetrahydrofuranyl, dimethylaminocarbonyl, 5-[rac-(lS,5R)-3-oxa-6-azabicyclo[3.1.1]heptanyl, l-methyl-5-oxo-pyrrolidinyl, 2-morpholinoethoxy, (l-methyl-4-piperidyl)oxy, (3R)-l-methyl-2- oxo-pyrrolidinyl, (3 S)- 1 -methyl-2-oxo-pyrrolidinyl, 1 -(ox etan-3 -yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-l,3-dioxan-2-
  • R 5 is at each instance independently selected from tert-butyl oxy carbonyl, methyl, ethyl, 6-tetrahydrofuran-3-yl, oxetan-3-yl, 4-hydroxy-3- m ethyl -tetrahydrofuran-3-yl, dimethylaminocarbonyl, 5-[rac-(l S,5R)-3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, l-methyl-5-oxo-pyrrolidin-2-yl, 2-morpholinoethoxy, (1 -methyl - 4-piperidyl)oxy, (3R)-l-methyl-2-oxo-pyrrolidin-3-yl, (3 S)-l -methyl -2-oxo-pyrrolidin-3-yl, 1- (oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyl
  • R 5 is alkyl, in particular methyl
  • a compound according to the invention wherein A 1 is -CH-;
  • a compound according to the invention wherein A 1 is -N-;
  • the invention further relates to a compound of formula (I) selected from l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-(di
  • the invention further relates to a compound of formula (I) selected from l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-(di
  • the invention further relates in particular to a compound of formula (I) selected from l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3
  • the invention further relates in particular to a compound of formula (I) selected from
  • One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (Ila) wherein A 1 , L, R 2 and R 3 are as described herein; and R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular cyano and difluoromethyl.
  • the compound is a compound of formula (Ila) wherein A 1 , L, R 2 and R 3 are as described herein; and R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular cyano and difluoromethyl.
  • One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (lib) wherein L, R 2 and R 3 are as described herein; and R 4 is selected from cycloalkylalkyl and haloalkyl, in particular cyclopropylmethyl and trifluoroethyl.
  • One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (III) wherein A 1 , L, R 1 , R 2 , R 4 and R 5 are as described herein; and R 6 is at each instance individually selected from alkyl and alkylazetidinyl, in particular methyl and l-methylazetidin-3-yl; or two R 6 groups together with the carbon they are attached to form a 5 to 7 membered heterocyl cloalkyl.
  • the compound is a compound of formula (III) wherein A 1 , L, R 1 , R 2 , R 4 and R 5 are as described herein; and R 6 is at each instance individually selected from alkyl and alkylazetidinyl, in particular methyl and l-methylazetidin-3-yl; or two R 6 groups together with the carbon they are attached to form a 5 to 7 membered heterocyl cloalkyl.
  • the synthesis of the compound of formula (I) can, for example, be accomplished according to the non-exhaustive procedures described below in general schemes 1-4. In some instances, the sequence of the reaction steps can be altered and the individual steps of the different schemes can be combined in different ways as disclosed herein and according to common general knowledge. In general, the reaction conditions provided below and the reaction conditions can in some instances be further modified according to the procedures described herein and according to common general knowledge.
  • the compound of formula (I-a) is a compound of formula (I), wherein A 1 is C; R 1 is pyrazol optionally substituted with R 4 , R 4 ’ and R 4 ”; R 2 is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroaryl amino; R 3 is methylpyridazinyl; L is -NH-; R 4 and R 4 ” are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy and haloalkyl; R4’ is hydrogen or dialkylaminocarbonyl.
  • the compound of formula (I-a’) is a compound of formula (I), wherein A 1 is C; R 1 is pyrazol optionally substituted with R 4 , R 4 ’ and R 4 ”; R 2 is methylpyridazinylamino; L is absent; R 3 is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroaryl amino; R 4 and R 4 ” are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy and haloalkyl; R 4 ’ is hydrogen or dialkylaminocarbonyl.
  • R2/R3 means that the group is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroarylamino.
  • Step A 2-chloro-6-fluoro-pyridine 1 can be reacted in the presence of a suitable base (such as for instance LDA) in the presence of a suitable solvent (such as for instance THF, MeTHF or dioxane) at temperatures from about -78 °C to about 25 °C and the deprotonated intermediate can be reacted with DMF at temperatures from about -78 °C to about 25°C to yield intermediate 2.
  • a suitable base such as for instance LDA
  • a suitable solvent such as for instance THF, MeTHF or dioxane
  • Step B 6-chloro-2-fluoro-pyridine-3-carbaldehyde 2 can be reacted with a substituted pyrazole 3 in the presence of a suitable organic or mineral base (such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH), in a suitable polar solvent (such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF) at temperatures ranging from about -10 °C and about 120 °C to yield intermediate 4.
  • a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH
  • a suitable polar solvent such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF
  • Step C Intermediate 4 can be reacted with a fluorinated reagent, such as for instance DAST, in a suitable solvent, such as for instance DCM or ACN at temperatures ranging from about -30 °C and about 30 °C to yield intermediate 5.
  • a fluorinated reagent such as for instance DAST
  • a suitable solvent such as for instance DCM or ACN
  • Step D Intermediates 5 and 6 can be reacted in the presence of a suitable organic or mineral base (such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH), in a suitable polar solvent (such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF), at a temperature ranging from about 80 °C to about 110 °C to yield the regioisomeric compounds 7 and 7’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.
  • a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH
  • a suitable polar solvent such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF
  • Step E Introduction of the aminopyridazine can be performed via a Buchwald- Hartwig coupling using a suitable base, such as for instance CS2CO3, K2CO3 or K3PO4, and as suitable palladium catalyst, such as for instance tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf, in a suitable solvent (such as for instance 1,4-di oxane), at a temperature ranging from around 80 °C to around 100 °C to yield compounds I-a and I-a’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC.
  • a suitable base such as for instance CS2CO3, K2CO3 or K3PO4
  • suitable palladium catalyst such as for instance tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf
  • a suitable solvent such as for instance 1,4-di oxane
  • Step A (4-bromo-5-fluoro-2-nitro-phenyl)amine 8 and alcohol 9 can be reacted in the presence of a suitable organic or mineral base (such as for instance NaH, CS2CO3 or DBU), in a suitable solvent (such as THF, MeTHF or dioxane), at temperatures ranging from about -10 °C to about 120 °C to yield the intermediate 10.
  • a suitable organic or mineral base such as for instance NaH, CS2CO3 or DBU
  • a suitable solvent such as THF, MeTHF or dioxane
  • Step B The nitro group of intermediate 10 can be reduced in the presence of a metallic reducing agent (such as for instance Zn or Fe), an acid (such as for instance AcOH or HC1) in a suitable polar protic solvent (such as for instance MeOH or EtOH) at temperatures ranging from about -10 °C and about 120 °C to yield the diamino intermediate 11.
  • a metallic reducing agent such as for instance Zn or Fe
  • an acid such as for instance AcOH or HC1
  • a suitable polar protic solvent such as for instance MeOH or EtOH
  • the nitro group of intermediate 10 can be reduced in the presence of hydrogen gas, in the presence of a catalyst (such as for instance Pd on charcoal), in a suitable polar protic solvent (such as for instance MeOH or EtOH), at a temperature ranging from about -10 °C to about 65 °C to yield the diamino intermediate 11.
  • Step C The diamino intermediate 11 can be cyclized in the presence of orthoformate (such as for instance trimethylorthoformate of triethylorthoformate) which can be used as the reaction solvent at temperatures between about 50 °C and about 100 °C to yield the benzimidazol intermediate 6.
  • orthoformate such as for instance trimethylorthoformate of triethylorthoformate
  • the compound of formula (I-b) is a compound of formula (I), wherein A 1 is C; R 1 is pyrazol substituted with methyl and R 4 ’; R 2 is selected from hydrogen, alkoxy and halogen; R 3 is methylpyridazinyl; L is -NH-; R 4 ’ is 1,1,1 -trifluoroethyl, methoxyethyl or cyclopropylmethyl.
  • the compound of formula (I-b’) is a compound of formula (I), wherein A 1 is C; R 1 is pyrazol substituted with methyl and R 4 ’; R 2 is methylpyridazinylamino, R 3 is selected from hydrogen, alkoxy and halogen; L is absent; R 4 ’ is 1,1,1 -trifluoroethyl, methoxyethyl or cyclopropylmethyl.
  • R2/R3 means that the group is selected from hydrogen, alkoxy and halogen.
  • Step A 2,6-dichloronicotinaldehyde 12 and ethane- 1,2-diol can be reacted in the presence of a suitable organic or mineral acid (such as for instance pTSOH), in a suitable solvent (such as toluene), at temperatures between about 80 °C and about 110 °C (reflux) with continuous water removal using a Dean-Stark apparatus to yield the intermediate 13.
  • a suitable organic or mineral acid such as for instance pTSOH
  • a suitable solvent such as toluene
  • Step B Intermediates 13 and 14 can be reacted in the presence of a suitable organic or mineral base (such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH), in a suitable polar solvent (such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF), at a temperature ranging from about -10 0 to about 120 °C to yield the regioisomeric compounds 15 and 15’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.
  • a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH
  • a suitable polar solvent such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF
  • Step C A Palladium-catalyzed cross-coupling reaction ( Suzuki -Miy aura) between intermediate 15 and the corresponding heteroaryl pinacol borane 16, a Pd catalyst (such as for instance P(Ph3)4 or Pd(dppf)C12 CH2C12 or other suitable Pd catalysts) and a suitable base such as for instance K3PO4, CS2CO3, K2CO3, ISfeCCh) in a suitable solvent (such as for instance 1,4- dioxane or a mixture of 1,4-dioxane and water) while heating (e.g.
  • a Pd catalyst such as for instance P(Ph3)4 or Pd(dppf)C12 CH2C12 or other suitable Pd catalysts
  • a suitable base such as for instance K3PO4, CS2CO3, K2CO3, ISfeCCh
  • a suitable solvent such as for instance 1,4- dioxane or a mixture of 1,4-dioxane and water
  • regioisomeric compounds 17 and 17’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.
  • Step D Intermediates 17 can be deprotected using an acid (such as for instance HC1) in a suitable solvent (such as for instance dioxane, THF, MeTHF), at a temperature between about 0 °C to about 50 °C to yield the regioisomeric compounds 18 and 18’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.
  • an acid such as for instance HC1
  • a suitable solvent such as for instance dioxane, THF, MeTHF
  • Step E Intermediate 18 can be reacted with a fluorinating reagent (such as for instance DAST), in a suitable solvent (such as for instance DCM) at temperatures ranging from about -30 °C to about 30 °C to yield the compound of formula I-b or I-b’ which can be purified by flash column chromatography or preparative HPLC or preparative TLC.
  • a fluorinating reagent such as for instance DAST
  • a suitable solvent such as for instance DCM
  • the compound of formula (I-c) is a compound of formula (I), wherein A 1 is NH; L is -NH-; R 1 is pyrazol substituted with cyano and methyl; R 2 is alkoxy; R 3 is methylpyridazinyl.
  • Step A 3,5-dichloropyrazine-2-carbaldehyde 18 can be reacted with a fluorinating reagent (such as for instance DAST), in a suitable solvent (such as for instance DCM) at temperatures ranging from about -30 °C to about 30 °C to yield the compound of formula 20.
  • a fluorinating reagent such as for instance DAST
  • a suitable solvent such as for instance DCM
  • Step B Intermediates 20 and 14 can be reacted in the presence of a suitable organic or mineral base (such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH), in a suitable polar solvent (such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF), at a temperature ranging from about -10 °C to about 120 °C to yield the compound 21 which can be purified by flash column chromatography or preparative HPLC or preparative TLC.
  • a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH
  • a suitable polar solvent such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF
  • Step C Intermediates 21 and 22 can be reacted in the presence of a suitable organic or mineral base (such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH), in a suitable polar solvent (such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF), at a temperature ranging from about -10 0 to about 120 °C to yield the compound of formula (I-c) which can be purified by flash column chromatography or preparative HPLC or preparative TLC.
  • a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH
  • a suitable polar solvent such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF
  • the solvent can be for example toluene, xylene, 1,4-di oxane or a mixture thereof, in particular 1,4-di oxane;
  • the base can be for example CS2CO3, K2CO3 or K3PO4, in particular K3PO4;
  • the catalyst can be a Pd catalyst, such as for instance tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf;
  • step (a) is performed at a temperature from about 50 °C to about 120 °C, in particular from about 70 °C to about 110 °C, more particular from about 80 °C to about 100 °C;
  • reaction of step (a) is performed during about 1 hour to about 48 hours, in particular from about 2 hours to about 24 hours, more particular from about 4 hours to about 18 hours or from about 4 to about 16 hours;
  • step (a) is performed in presence of 1,4-di oxane, K3PO4 and tBuXPhos Pd G3, at a temperature from about 70 °C to about 110 °C;
  • step (a) is performed in presence of 1,4-di oxane, CS2CO3 and [tBuBrettPhos Pd(allyl)]OTf, at a temperature from about 70 °C to about 110 °C;
  • the solvent can be for example dichloromethane or diethyl ether, in particular di chloromethane;
  • the deoxofluorination agent can be for example DAST, cesium fluoride, Deoxo-Fluor, or MOST, in particular DAST;
  • the reaction of step (b) is performed at a temperature from about -30 °C to about 30 °C, in particular from about 0 °C to about 30 °C, more particular from about 0 °C to room temperature;
  • reaction of step (b) is performed during about 30 minutes to about 48 hours, in particular from about 1 hour to about 24 hours, more particular from about 2 hours to 12 hours;
  • step (b) is performed in presence of dichloromethane, in presence of D AST, at a temperature from about -30 °C to about 30 °C;
  • the solvent can be a polar solvent such as for instance DMF, DMA, NMP, DMSO, THF or 2-MeTHF, in particular DMSO;
  • the base can be an organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH, in particular DIPEA;
  • step (b) is performed at a temperature from about 60 °C to about 140 °C, in particular from about 70 °C to about 130 °C, more particular from about 80 °C to about 120 °C;
  • reaction of step (c) is performed during about 1 hour to about 48 hours, in particular from about 3 hour to about 30 hours, more particular from about 3 hours to 18 hours;
  • step (c) is performed in presence of DMSO, in presence of DIPEA, at a temperature from about 80 °C to about 120 °C.
  • the invention also relates in particular to:
  • a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier;
  • a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);
  • a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);
  • a method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis which method comprises administering an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula (I) is formulated in an acetate buffer, at pH 5.
  • the compound of formula (I) is sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • RuPhos Pd G4 methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1,1'- biphenyl)(2'-m ethylamino- l,l'-biphenyl-2-yl)palladium(II) (CAS# 1599466-85-9) sat. saturated
  • XantPhos Pd G4 (6-diphenylphosphanyl- 10H-phenoxazin-4-yl)- diphenylphosphane;methanesulfonic acid;N-methyl-2- phenylaniline;palladium (CAS# 1621274-19-8)
  • Step 2 l-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile
  • 6-chloro-2-fluoro-nicotinaldehyde 1.0 g, 6.27 mmol, 1.0 eq.
  • DMF 10 mL
  • 5-methyl-lH-pyrazole-3-carbonitrile 738.5 mg, 6.9 mmol, 1.1 eq.
  • K2CO3 1.0 g, 7.5 mmol, 1.2 eq.
  • the reaction mixture was stirred at RT over 1 hour.
  • the reaction mixture was partitionned between sat. aq. NH4CI solution and EtOAc; the product was extracted and the organic layer was dried over Na2SO4 and the volatiles removed in vacuo.
  • Step 3 l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • Step 4 l-[ 6-(5-bromobenzimidazol-l-yl)-3-(dijluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile
  • Step 5 l-[3-(dijluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile; formic acid
  • Example 2 l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile; formic acid (15 mg, 12.8%) was obtained in Example 1, step 5 as an off-white lyophilized powder.
  • Step 4 l-[ 6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile
  • Step 2 6-chloro-3-(difluoromethyl)-2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl] pyridine
  • Step 3 4-[2-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2- pyridyl]benzimidazol-5-yl oxyethyl morpholine
  • Step 4 l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine
  • Step 4 l-[ 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile
  • Step 2 l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine
  • Step 4 l-[6-chloro-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine
  • Step 6 3-methyl-4-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-l-(2, 2, 2- trijluoroethyl)pyrazole
  • Step 7 l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine and l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2,2- trifluoroethyl)pyrazole (45.0 mg, 0.16 mmol, 1.5 eq.) and l-[6-chloro-5-(difluoromethyl)-2- pyrid
  • Step 1 l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethyl)-N,N,5-trimethyl-pyrazole- 4-carboxamide
  • Step 2 3-(difluoromethyl)-l-[3-(difluoromethyl)-6-[ 6-methoxy-5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl -N,N, 5-trimethyl-pyrazole-4-carboxamide
  • TluXPhos Pd G3 14.09 mg, 0.018 mmol, 0.100 eq. was added, the vial was locked and the mixture heated to 80 °C for 16 hours. The reaction was cooled to 23 °C and extracted with DCM and H2O. The organic layer was washed with brine, dried over MgSCE; filtered and concentrated in vacuo.
  • Step 3 2-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-(difluoromethoxy)pyrazole-3-carbonitrile
  • 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine 101.7 mg, 0.56 mmol, 1.0 eq.
  • DMF 0.56 mmol, 1.0 eq.
  • 3 -(difluoromethoxy)- lH-pyrazole-5-carbonitrile 98.0 mg, 0.62 mmol, 1.1 eq.
  • K2CO3 77.4 mg, 0.56 mmol, 1.000 eq.
  • the reaction mixture was heated to 50 °C and stirred for 4 hours.
  • the mixture was cooled to 20 °C, diluted with H2O and extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous MgSCE, filtered and concentrated under reduced pressure.
  • Step 4 5-(difluoromethoxy)-2-[ 3-(difluoromethyl)-6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]pyrazole-3-carbonitrile
  • Step 1 3-[[ l-[ 6-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl amino ]-N,N, 6-trimethyl-pyridazine-4-carboxamide
  • Example 12 l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2- pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (3.5 mg, 17.5% yield) was obtained as a white solid after separation by SFC from its isomer as described in Example 6, step 7.
  • Step 1 5-bromo-l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]- 6-(oxetan-3 -yloxy) benzimidazole
  • Step 2 l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine
  • step 4 to give l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5- amine (106.7 mg, 0.19 mmol, 32.07% yield) as yellow solid after purification by preparative HPLC (Phenomenex Synergi Max-RP (250 x 50 mm, 10 pm), 15 - 45% CH3CN in H2O (with HCOOH) over 21 minutes, flow rate: 100 mL/min).
  • Step 1 l-(6-chloro-3-formyl-2-pyridyl)-5-fluoro-pyrazole-3-carboxylic acid ethyl ester
  • Step 2 l-(6-chloro-3-formyl-2-pyridyl)-5-fluoro- pyrazole-3 -carboxylic acid ethyl ester (231 mg, 61.9%) as an off-white solid.
  • LC-MS: m/z 298.1 [M+H] + , ESI pos.
  • Step 2 l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester
  • Step 3 l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid Under argon, l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester (280 mg, 0.88 mmol, 1.0 eq.) was dissolved in THF (14.5 mL). At RT, IM LiOH in H2O (1.31 mL, 1.31 mmol, 1.5 eq.) was added and the reaction mixture was stirred at RT over 1.5 hours. Sat. aq.
  • Step 4 l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxamide Under argon, l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid (255 mg, 0.88 mmol, 1.0 eq.) was dissolved in DMF (4.13 mL). 25% NH4OH aq. sol.
  • Step 5 l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile
  • Step 6 l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-fluoro-pyrazole-3-carbonitrile
  • Step 1 3-(benzhydrylideneamino)-5,5, 7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one
  • Step 2 3-amino-5,5, 7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one; hydrogen chloride
  • Step 3 l-[3-(difluoromethyl)-6-[5-[(6-keto-5,5, 7-trimethyl-pyrrolo[2,3-c]pyridazin-3- yl)amino ] -6-methoxy-benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile
  • Step 2 4- [2-(6-chloropyridazin-3-yl)oxyethyl] morpholine
  • 2-morpholinoethanol (1 g, 933 pL, 7.62 mmol, 1.0 eq.) was dissolved in THF (30 mL), cooled to 0 °C, NaH 60% in mineral oil (320.2 mg, 8.0 mmol, 1.05 eq.) was added and stirred for 1 hour.
  • Step 3 N-[6-(2-morpholinoethoxy)pyridazin-3-yl] carbamic acid tert-butyl ester
  • Step 4 [6-(2-morpholinoethoxy)pyridazin-3-yl] amine; 2 2,2,2-trifluoroacetic acid N-[6-(2-morpholinoethoxy) pyridazin-3-yl]carbamic acid tert-butyl ester (500 mg, 1.54 mmol, 1.0 eq.) was dissolved in DCM (10 mL), TFA (1.76 g, 1.2 mL, 15.4 mmol, 10.0 eq.) was added and stirred for 2 hours. The volatiles were removed under vacuum to yield an orange oil. 10 mL of Et2O was added, and the suspension ultrasonicated for 10 minutes.
  • Step 5 l-[3-(difluoromethyl)-6-[5-[[ 6-(2-morpholinoethoxy)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • step 4 to yield l-[3-(difluoromethyl)-6-[5-[[6-(2- morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (47 mg, 74.%) as a white solid.
  • Step 1 benzhydrylidene ( 7, 8-dihydro-5H-pyrano[ 4, 3-c ]pyridazin-3-yl)amine
  • Step 3 l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • Step 2 4-bromo-5-tetrahydropyran-4-yloxy-benzene-l, 2 -diamine
  • Step 4 l-[ 6-(5-bromo-6-tetrahydropyran-4-yloxy-benzimidazol-l-yl)-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • Step 5 l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy- benzimidazol-l-yl] -2-pyridyl] -5-methyl-pyrazole-3-carbonitrile
  • Step 1 5-bromo-l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl]-6-(oxetan-3-yloxy)benzimidazole
  • Step 2 l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine
  • Step 1 2-[ 3, 5-bis(difluoromethyl)pyrazol-l-yl ]-6-chloro-3-(difluoromethyl )pyridine Prepared according to Example 4, step 1 using 3, 5-bis-(difluoromethyl)-lH-pyrazole (78.7 mg, 0.47 mmol, 1.0 eq.) at 50 °C to afford 2-[3, 5-bis(difluoromethyl)pyrazol-l-yl]-6-chloro-3- (difluoromethyl)pyridine (100.0 mg, 64.8%) as an off-white liquid.
  • LC-MS: m/z 329.8 [M+H] + , ESI pos.
  • Step 2 l-[ 6-[ 3, 5-bis(difluoromethyl)pyrazol-l-yl / -5-(difluoromethyl)-2-pyridyl / -5-bromo-6- (oxetan-3-yloxy)benzimidazole
  • Step 3 l-[ 6-[ 3, 5-bis(difluoromethyl)pyrazol-l-yl / -5-(difluoromethyl)-2-pyridyl ]-N-( 6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine
  • Step 1 tert-butyl (2S,4S)-2-methyl-4-methylspLfonyloxy-pyrrolidine-l -carboxylate
  • Step 3 (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2, 2, 2 -trifluoroacetic acid
  • Step 4 (3R, 5S)-l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile
  • 2,2,2-trifluoroacetic acid 850.0 mg, 3.79 mmol, 1.0 eq.
  • DMSO 20 mL
  • 6-chloro-3-(difluoromethyl)-2-fluoro- pyridine 689.0 mg, 3.8 mmol, 1.0 eq.
  • K2CO3 (2620.1 mg, 18.96 mmol, 5.0 eq.
  • the reaction mixture was heated to 100 °C and stirred for 16 hours under a N2 atmosphere.
  • the brown suspension was cooled to 20 °C and quenched by the addition of sat. aq. NH4CI sol. (100 mL).
  • the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 5, 8-dichloro-l -cyclopropyl- 7-isobutyryl-3, 3-dimethyl-l, 6, 7-triazaspiro[ 3.5 ]nona-5, 8- dien-2-one
  • Step 3 3-chloro-7-cyclopropyl-5,5-dimethyl-5H-pyrrolo[2,3-c]pyridazin-6(7H)-one
  • 5,8-dichloro-l-cyclopropyl-7-isobutyryl-3,3-dimethyl-l,6,7- triazaspiro[3.5]nona-5,8-dien-2-one (98 mg, 285 pmol, Eq: 1.00) was dissolved in DMF (2.5 ml).
  • CS2CO3 186 mg, 569 pmol, Eq: 2
  • Step 4 3-(benzhydrylideneamino)-7-cyclopropyl-5, 5-dimethyl-pyrrolo[2, 3-c]pyridazin-6-one
  • 3-chloro-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one 786 mg, 3.31 mmol, 1.0 eq.
  • benzophenone imine 946.26 mg, 876.16 pL, 4.96 mmol, 1.5 eq.
  • CS2CO3 (2.15 g, 6.61 mmol, 2.0 eq.
  • BINAP 205.91 mg, 0.331 mmol, 0.1 eq.
  • tris(dibenzylideneacetone)dipalladium (0) chloroform adduct 171.14 mg, 0.165 mmol, 0.050 eq.
  • the vial was sealed, the mixture was heated to 100 °C and stirred for 16 hours.
  • the reaction mixture was cooled to 23 °C, added to 10 g SiCh and concentrated in vacuo.
  • Step 5 3-amino-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one; 1 : 1 hydrogen chloride
  • Step 6 l-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6- methoxy-benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • step 4 Step 4 to yield l-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl- pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-l-yl]-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (46 mg, 78.7%) as an off-white solid.
  • LC-MS: m/z 641.4 [M+HCOO]', ESI neg
  • Step 1 l-[3-(difluoromethyl)-6-[5-[(6-keto-l-methyl-pyridazin-3-yl)amino]-6-methoxy- benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile
  • Step 2 N-[ 6-[(l-methyl-4-piperidyl)oxy]pyridazin-3-yl]-l, 1-diphenyl-methanimine
  • Step 4 l-[ 3-(difluoromethyl)-6-[ 6-methoxy-5-[[ 6-[ ( 1 -methyl-4-piperidyl)oxy]pyridazin-3- yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • Step 1 l-(2-methoxyethyl)-3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole
  • 2-bromoethyl methyl ether 5.85 mL, 62.29 mmol, 4.32 eq.
  • potassium carbonate 4.42 g, 32.01 mmol, 2.22 eq.
  • Step 2 l-[5-(l, 3-dioxolan-2-yl)-6-[ l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl] -2-pyridyl] -N-(6- methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 3 2-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde
  • Step 4 l-[5-(difluoromethyl)-6-[ l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl] -2-pyridyl] -N-(6- methylpyridazin-3-yl)benzimidazol-5-amine
  • aqueous mixture was directly purified by reverse-phase HPLC (60% CH3CN in H2O (with 1% FA)) to yield l-[5- (difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (20.0 mg, 31.8%) as a yellow solid (mixture of regioisomers).
  • LC-MS: m/z 491.3 [M+H] + , ESI pos.
  • Example 26 l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (8.1 mg, 0.02 mmol, 40.5% yield) was isolated in Example 25, step 4 as the second regioisomer and was obtained as a white solid.
  • Step 1 tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l -carboxylate
  • Step 3 3-chloro-6-[[ l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine
  • Step 4 N-[ 6-[[l -(oxetan-3-yl)-4-piperidyl] oxy]pyridazin-3-yl] -1 , 1-diphenyl-methanimine
  • benzophenone imine (0.75 mL, 4.45 mmol, 1.5 eq.
  • 3-chloro-6-[[l-(oxetan- 3-yl)-4-piperidyl]oxy]pyridazine 800.0 mg, 2.97 mmol, 1.0 eq.
  • 1,4-dioxane (10 mL) were added CS2CO3 (1932.72 mg, 5.93 mmol, 2.0 eq.) and Xantphos Pd G4 (142.72 mg, 0.15 mmol, 0.05 eq.) at 20 °C under N2 atmosphere.
  • Step 5 6-[[ l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine
  • Step 6 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin- 3-yl amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile
  • Step 1 2-[ (5, 6-dichloropyridazin-4-yl)-methyl-amino] ethanol
  • Step 2 8-chloro-4-methyl-2, 3-dihydropyridazino[ 4, 5-b ][ 1, 4 ] oxazine
  • Step 3 benzhydrylidene-(4-methyl-2, 3-dihydropyridazino[ 4, 5-b ] [ 1, 4 ]oxazin-8-yl)amine
  • 8-chloro-4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazine 250 mg, 1.35 mmol, 1.0 eq.
  • benzophenone imine 385.42 mg, 356.87 pL, 2.02 mmol, 1.5 eq.
  • CS2CO3 877.7 mg, 2.69 mmol, 2.0 eq.
  • BINAP 83.87 mg, 0.135 mmol, 0.1 eq.
  • tris(dibenzylideneacetone)dipalladium (0) chloroform adduct 69.71 mg, 0.067 mmol, 0.05 eq.
  • More benzophenone imine (385.42 mg, 356.87 pL, 2.02 mmol, 1.5 eq.), CS2CO3 (877.7 mg, 2.69 mmol, 2.0 eq.), BINAP (83.87 mg, 0.135 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (69.71 mg, 0.067 mmol, 0.05 eq.) were added. The mixture was stirred at 100 °C for 2 days. The reaction was cooled to 23 °C, added to 10 g SiCh an d concentrated in vacuo.
  • Step 4 (4-methyl-2,3-dihydropyridazino[4,5-b] [l,4]oxazin-8-yl)amine dihydrochloride
  • benzhydrylidene-(4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8- yl)amine (188 mg, 0.535 mmol, 1.0 eq.) in THF (10 mL) were added HC1 2 M in Et2O (2.67 mL, 5.35 mmol, 10.0 eq.) and H2O (9.64 mg, 9.64 pL, 0.535 mmol, 1.0 eq.).
  • Step 5 l-[ 3-(difluoromethyl)-6-[ 6-methoxy-5-[ ( 4-methyl-2, 3-dihydropyridazino[ 4, 5- b] [1,4 oxazin-8-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile
  • step 4 using l-[6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3- (difluoromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (50 mg, 0.098 mmol, 1.0 eq, prepared in Example 3, step 4), (4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8- yl)amine;dihydrochloride (46.9 mg, 0.196 mmol, 2.0 eq
  • Step 1 l-(cyclopropylmethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole and l-(cyclopropylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole
  • Step 2 l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl ]-5-( 1, 3-dioxolan-2-yl)-2 -pyridyl ]-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 3 2-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde
  • Step 4 l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine;formic acid
  • Step 1 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester
  • 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester 300 mg, 1.79 mmol, 1.0 eq.
  • THF 15 mL
  • LiOH 1 M in H2O 2.69 mL, 2.69 mmol, 1.5 eq.
  • the reaction mixture was partitioned between H2O and DCM.
  • 6-amino-4-methyl-pyridazine-3-carboxylic acid (457 mg) was obtained as a solid and used without further purification.
  • LC-MS: m/z 154.0 [M+H] + , ESI pos.
  • 6-amino-4-methyl-pyridazine-3-carboxylic acid 167 mg, 0.654 mmol, 1.0 eq.
  • DMF dimethylamine 2M in THF (436.75 mg, 490.73 pL, 0.981 mmol, 1.5 eq.) was added, the reaction mixture turning to a solution.
  • DIPEA 169.14 mg, 216.84 pL, 1.31 mmol, 2.0 eq.
  • TBTU 252.1 mg, 0.785 mmol, 1.2 eq.
  • Step 1 trimethyl- [2- [ (5-nitrobenzimidazol-l-yl)methoxy] ethyl] silane
  • Step 3 N-[ l-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] cyclopropanecarboxamide
  • cyclopropanecarboxylic acid (196.1 mg, 2.28 mmol, 1.2 eq.) and l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine (500 mg, 1.9 mmol, 1.0 eq.) (mixture of regioisomers) in DMF (5 mL) was added HATU (669.87 mg, 2.85 mmol, 1.5 eq.) and stirring was contiued for 0.5 hour at 25 °C.
  • Step 4 N-(lH-benzimidazol-5-yl)cyclopropanecarboxamide ; 2, 2, 2 -trifluoroacetic acid
  • a solution of N-[l -(2 -trimethylsilyl ethoxymethyl)benzimidazol-5-yl] in TFA (1 mL) was stirred at 25 °C for 1 hours.
  • the reaction mixture was concentrated to dryess to yield N-(1H- benzimidazol-5-yl)cyclopropanecarboxamide; 2,2,2-trifluoroacetic acid (500.0 mg, 94.6%) as an orange oil.
  • LC-MS: m/z 202.1 [M+H] + , ESI pos.
  • Step 5 N-[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl cyclopropanecarboxamide
  • reaction mixture was heated to 100 °C and stirring under N2 atmosphere was continued for 3 hours.
  • the mixture was cooled to 25 °C, quenched with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered and concentrated under reduced pressure.
  • Step 1 l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3- yl) benzimidazol-5-amine
  • Step 2 l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl -5-( 1, 3-dioxolan-2-yl)-2 -pyridyl -6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 3 2-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3- yl)amino]benzimidazol-l-yl ]pyridine-3-carbaldehyde
  • Step 4 l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 2 3-hydroxy-4-keto-5-methyl-6, 7-dihydropyrazolo[4,3-c]pyridine-l-carboxylic acid tertbutyl ester
  • Step 4 3-(difluoromethoxy)-5-methyl-6, 7-dihydro-lH-pyrazolo[4,3-c]pyridin-4-one; 1:1 hydrogen chloride
  • Step 5 6-chloro-2-[3-(difluoromethoxy)-4-keto-5-methyl-6, 7-dihydropyrazolo [4, 3-c]pyridin-l- yl nicotinaldehyde
  • Step 6 l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethoxy)-5-methyl-6, 7- dihydropyrazolo[ 4, 3-c ]pyridin-4-one
  • Step 7 3-(difluoromethoxy)-l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-6, 7-dihydropyrazolo[ 4, 3-c ]pyridin-4-one
  • step 2 3-(difluoromethoxy)-l-[3-(difluoromethyl)-6-[6- methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-6,7- dihydropyrazolo[4,3-c]pyridin-4-one (19.8 mg, 20.5%) as a yellow solid.
  • LC-MS: m/z 598.2 [M+H] + ,
  • Step 4 2-[ 6-bromo-3-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide
  • Step 5 2-[ 3-[6-( 3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl -6-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide
  • Step 4 2-[(5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane and 2- [(6- bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane
  • Step 5 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2-trimethylsilylethoxymethyl)benzimidazol-5- amine and 6-methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol- 5-amine
  • Step 6 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine
  • 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6-methylpyridazin-3-yl)- 3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.39 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 130 mmol, 18 eq.) at RT was stirred at RT for 3 hours.
  • Step 7 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine
  • a solution of 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine (10.6 g, 27.49 mmol, 1.0 eq.) in TFA (20.0 mL, 259.6 mmol, 9.44 eq.) was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure.
  • Step 8 l-[5-(l, 3-dioxolan-2-yl)-6-[ l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl] -2-pyridyl] -6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 8 2-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde
  • Step 10 l-[5-(difluoromethyl)-6-[ 1 ⁇ (2-methoxyethyl)-3-methyl-pyrazol-4-yl] -2-pyridyl] -6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • This regioisomeric mixture was purified by SFC (Daicel Chiralpak AS (250 mm x 30 mm, 10 pm) with EtOH (0.1% NH4OH) in CO2) to yield l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (17.1 mg, 28.5%) as a yellow solid.
  • LC-MS: m/z 521.3 [M+H] + , ESI pos.
  • Example 36 l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]- 6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine (14.2 mg, 23.4%) was obtained in Example 35, step 4 as a yellow solid.
  • Example 37 l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2- pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 1 l-[5-(l,3-dioxolan-2-yl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine and l-[5-(l, 3-dioxolan-2-yl)-6-[5- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyri
  • Step 2 6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3-yl )amino]benzimidazol-l-yl -2-[ 3-methyl-l- (2,2, 2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbaldehyde and 6-[ 6-methoxy-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4- yl pyridine-3-carbaldehyde
  • Step 3 l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 2 6-fluoro-N-( 6-methylpyridazin-3-yl)-l-(2-trimethylsilylethoxymethyl)benzimidazol-5- amine
  • Step 4 l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3- yl) benzimidazol-5-amine
  • Step 5 l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl -5-( 1, 3-dioxolan-2-yl)-2 -pyridyl -6- fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 6 2-[ I -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl -6-[ 6-fluoro-5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde
  • Step 7 l-[ 6-[ I -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine
  • Step 1 l-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-
  • Step 1 6-( 6-chloropyridazin-4-yl)-3-oxa-6-azabicyclo[ 3.1.1 ] heptane
  • Step 2 N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester
  • Step 3 [5-[ 3-oxa-6-azabicyclo[ 3.1.1 ]heptan-6-yl]pyridazin-3-yl] amine ; 2, 2, 2-trifluoroacetic acid
  • N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester (64.1 mg, 0.219 mmol, 1.0 eq.) was dissolved in DCM (1.42 mL), TFA (250.01 mg, 168.93 pL, 2.19 mmol, 10.0 eq.) was added and stirring was continued for 18 hours at 23 °C. The solution was evaporated to dryness. The residue was triturated in 3 ml of Et2O and the resulting suspension was stirred for 30 minutes.
  • Step 4 l-[ 3-(difluoromethyl)-6-[ 6-methoxy-5-[[5-[ 3-oxa-6-azabicyclo[ 3.1.1 ]heptan-6- yl ]pyridazin-3-yl amino] benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile
  • step 4 to yield l-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[3- oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile as a yellow solid (35.6 mg, 50.9%).
  • LC-MS: m/z 571.2 [M+H] + , ESI pos.
  • Step 2 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate; lithium salt
  • a mixture of ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (1200.0 mg, 3.47 mmol, 1.0 eq.) in THF (6 mL), MeOH (6 mL) and H2O (6 mL) was added LiOH (249.11 mg, 10.42 mmol, 3.0 eq.), and the reaction mixture was stirred at 30 °C for 12 hours, turning to a clear solution.
  • Step 5 5-bromo-l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl] -6-methyl-benzimidazole
  • Step 6 3-[[ l-[ 6-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methyl-benzimidazol-5-yl] amino] -N,N,6-trimethyl-pyridazine-4-carboxamide
  • Step 2 6-chloro-3-(difluoromethyl)-2-(2, 2-difluoro-l-methyl-ethoxy)pyridine
  • Step 6 5-bromo-l-[5-(difluoromethyl)-6-(2, 2-difluoro-l-methyl-ethoxy)-2-pyridyl]-6-(oxetan-3- yloxy) benzimidazole
  • Step 7 l-[5-(difluoromethyl)-6-(2,2-difluoro-l-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin- 3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine
  • Step 8 l-[5-(difluoromethyl)-6-[(lR)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine l-[5-(difluoromethyl)-6-(2,2-difluoro-l-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin-3-yl)- 6-(oxetan-3-yloxy)benzimidazol-5-amine (85.0 mg, 0.16 mmol, 1.0 eq.) was purified by chiral SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 pm) with EtOH (0.1% NH4OH) in CO2 over 6.5 min, flow rate 70 mL / min) to yield l-[5-(
  • Step 1 methyl l-(oxetan-3-yl)piperidine-4-carboxylate
  • Step 3 l-[ 6-(5-amino-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile
  • Step 4 N-[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-l-(oxetan-3-yl)piperidine-4-carboxamide
  • HATU (12.45 mg, 0.050 mmol, 1.5 eq.) was then added portionwise to give a brown solution. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by the addition of NH4CI (10 ml) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 3 -(trifluoromethyl) -1,4, 5, 7-tetrahydropyrano[3,4-c]pyrazole
  • Step 3 l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5, 7-dihydro-4H- pyrano[ 3, 4-c pyrazole
  • reaction mixture was purified by reverse phase HPLC (CH3CN in H2O (with 0.1% FA)) to yield l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7- dihydro-4H-pyrano[3,4-c]pyrazole (180.0 mg, 0.51 mmol, 39.11% yield) as a white solid.
  • LC- MS: m/z 354.1 [M+H] + , ESI pos.
  • Step 4 l-[ 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-3- (trifluoromethyl)-5, 7-dihydro-4H-pyrano[ 3, 4-c]pyrazole
  • Step 5 l-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5, 7-dihydro-4H-pyrano[3,4-c]pyrazol-l- yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine
  • Step 1 methyl 5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate
  • Step 2 methyl 4-bromo-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate
  • CH CN methyl 5-methyl-l -(2 -trimethyl silyl ethoxymethyl)pyrazole-3-carboxylate
  • NBS 3949.7 mg, 22.19 mmol, 1.5 eq.
  • SiCh 6 g was added to the orange solution.
  • Step 3 methyl 4-[(tert-butoxycarbonylamino)methyl]-5-methyl-l-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate
  • Step 4 methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate
  • Step 5 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid
  • a solution of methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (1.2 g, 4.01 mmol, 1.0 eq.) in a mixture THF (10 mL), MeOH (10 mL) and H2O (1 mL) was added LiOH hydrate (420.79 mg, 10.02 mmol, 2.5 eq.). The mixture was stirred at 25 °C for 1 hour.
  • Step 6 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one
  • DMF 50 mL
  • DIPEA 0.52 mL, 10.51 mmol, 3.0 eq.
  • HATU 89.17 mg, 4.2 mmol, 1.2 eq.
  • Step 9 2-[ 6-chloro- 3 -(difluoromethyl) -2 -pyridyl J -3, 5-dimethyl-4H -pyrrolo[ 3, 4-c ]pyrazol-6-one To a solution of 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine (20.0 mg, 0.110 mmol, 1 eq.) and
  • Step 10 2-[ 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-3, 5- dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one
  • Step 11 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl] -2-pyridyl] -3, 5-dimethyl-4H-pyrrolo[ 3, 4-c]pyrazol-6-one
  • step 4 to yield 2-[3-(difluoromethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-pyridyl]-3,5-dimethyl- 4H-pyrrolo[3,4-c]pyrazol-6-one (2.65 mg, 15.1% yield) as a white solid after purification by preparative HPLC (Phenomenex Cl 8 (75 mm x 30 mm, 3 pm), 8 - 38% CH3CN
  • Step 1 tert-butyl N-(6-formyllpyridazin-3-yl)carbamate
  • Step 3 tert-butyl N-[6-(l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl] carbamate
  • MeOH MeOH
  • HO Ac 7.77 mg, 0.13 mmol, 0.1 eq.
  • methylamine 2 M sol. in THF 3.23 mL, 6.47 mmol, 5.0 eq.
  • Step 5 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile
  • Step 4 3-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl amino J-N,N, 5-trimethyl-pyridazine-4-carboxamide
  • Step 1 3-chlor o-5, 6-dimethyl-pyridazine-4-carboxylic acid
  • Step 5 3-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl amino J-N,N, 5, 6-tetramethyl-pyridazine-4-carboxamide
  • Step 2 3-[[ 6-methoxy-l -(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] amino] -6-methyl- pyridazine-4-carboxylic acid
  • Step 3 3-[[ 6-methoxy-l -(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] amino] -N, 6-dimethyl- N-(2, 2, 2-trifluoroethyl)pyridazine-4-carboxamide
  • the mixture was stirred at 30 °C for 2 hours.
  • the reaction mixture was diluted with H2O (50 mL), and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (60 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum.
  • Step 4 3-[(6-methoxy-lH-benzimidazol-5-yl)amino]-N,6-dimethyl-N-(2,2,2- trifluoroethyl)pyridazine-4-carboxamide; 2, 2, 2-trifluoroacetic acid 3-[[6-methoxy- 1 -(2 -trimethyl silyl ethoxym ethyl)benzimidazol-5-yl]amino]-N, 6-dimethyl-N- (2,2,2-trifluoroethyl)pyridazine-4-carboxamide (100.0 mg, 0.19 mmol, 1.0 eq.)was dissolved in TFA (1.0 mL).
  • Step 5 3-[[ l-[ 6-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4- carboxamide
  • Step 1 diethyl 2-(6-chloropyridazin-3-yl)propanedioate
  • Step 2 diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate
  • the isolqted material was purified by preparative HPLC (ACS-WH-GX-S, 35% - 65% CH3CN in H2O (with NH4CO3) over 10 minutes, flow rate: 60 mL/min) to yield diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate (200.0 mg, 5.7%) as a white solid.
  • LC-MS: m/z 354.0 [M+H] + , ESI pos.
  • Step 3 2- [6-(tert-butoxycarbonylamino)pyridazin-3-yl] acetic acid
  • diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate (160.0 mg, 0.45 mmol, 1.0 eq.) in a mixture of MeOH (2 mL) and H2O (1 mL)
  • Li OH monohydrate 38.0 mg, 0.91 mmol, 2.0 eq.
  • Step 4 tert-butyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl] carbamate
  • DIPEA dimethylamine hydrochloride
  • HATU hydroxy-3-yl
  • 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]acetic acid (120.0 mg, 0.47 mmol, 1.0 eq.).
  • Step 6 2-[ 6-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl] amino]pyridazin-3-yl] -N,N-dimethyl-acetamide
  • Step 3 benzhydrylidene- [ 6-methyl-4-(oxetan-3-yl)pyridazin-3-yl] amine
  • BINAP (19.96 mg, 0.032 mmol, 0.10 eq.) and tris (dibenzylideneacetone)dipalladium (0) chlorofom adduct (16.59 mg, 0.016 mmol, 0.050 eq.) were added, the vial was sealed and the mixture was heated to 100 °C. Stirring was continued for 16 hours. The mixture was cooled to 23 °C and concentrated.
  • Step 4 (3-methyl-6, 7-dihydro-5H-pyrrolo[2,3-c]pyridazin-7-ium-5-yl)methanol; 2,2,2- trijluoroacetate
  • Step 5 l-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3- c pyridazin- 7-yl) benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

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Abstract

L'invention concerne un composé de formule (I) dans laquelle L, A1, R1, R2 et R3 sont tels que définis dans la description et dans les revendications. Le composé de formule (I) peut être utilisé en tant que médicament.
EP23840681.3A 2022-12-27 2023-12-22 Nouveaux dérivés de benzimidazole Pending EP4642773A1 (fr)

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