EP4642535A1 - Benzimidazole derivatives useful as sik modulators - Google Patents

Benzimidazole derivatives useful as sik modulators

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Publication number
EP4642535A1
EP4642535A1 EP23840680.5A EP23840680A EP4642535A1 EP 4642535 A1 EP4642535 A1 EP 4642535A1 EP 23840680 A EP23840680 A EP 23840680A EP 4642535 A1 EP4642535 A1 EP 4642535A1
Authority
EP
European Patent Office
Prior art keywords
methyl
benzimidazol
pyrazol
pyridine
carbonitrile
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
EP23840680.5A
Other languages
German (de)
French (fr)
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 EP4642535A1 publication Critical patent/EP4642535A1/en
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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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 heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 ;
  • R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 6 ; each instance of R 4 is individually selected from cyano, alkyl, alkoxy, halogen, haloalkoxy and haloalkyl; each instance of R 5 is individually selected from alkyl and dialkylaminocarbonyl; each instance of R 6 is individually selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl; and 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 (cAMP-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 cAMP-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 HD AC 4/5 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 SIK1 -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 cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic cytoplasmic
  • 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, piperidinyl, 1- piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-l-yl, [3 -oxo-piperazin- 1-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)- 2,3,3a,5,6,
  • heterocycloalkyloxy denotes a “oxy” group linked to a “heterocylcoalkyl” group.
  • heterocycloalkylalkyl denotes an “alkyl” group wherein at least one hydrogen atom of alkyl has been replaced by a “heterocylcoalkyl” group.
  • heteroaryl signifies an 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, benzotriazolyl, 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-pyri
  • heteroaryl pyrazolyl and pyridazinyl, more particularly pyrazol-l-yl, pyrazol-4-yl and pyridazin-3-yl.
  • heteroaryl is “N-heteroaryl”.
  • heteroarylamino alone or in combination, denotes an “amino” group wherein one of the hydrogen atoms of amino is replaced by a “heteroaryl” group.
  • 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.
  • oxy signifies the -O- group.
  • 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.
  • 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.
  • amino alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).
  • alkylamino is an alkyl group linked to a -NH- group.
  • dialkylamino denotes two alkyl groups linked to a -N- atom. Examples of a” dialkylamino” group are for instance dimethylamino, diethylamino and (methyl)(ethyl)amino.
  • dialkylaminocarbonyl alone or in combination, denotes a “carbonyl” group linked to an “dialkylamino” group.
  • dialkylaminoalkoxy denotes an “alkoxy” group wherein at least one hydrogen atom of alkoxy has been replaced with a “dialkylamino” group.
  • dialkylaminoalkyl denotes an “alkyl” group wherein at least one hydrogen atom of alkyl has been replaced with a “dialkylamino” 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, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene
  • 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.
  • Particular pharmaceutically acceptable salts of the compound of the present invention are the salts formed with formic acid.
  • 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), carbobenzyl oxy (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 selected from pyrazolyl and pyridinyl, wherein pyrazolyl and pyridinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 1 is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ;
  • R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 ;
  • R 2 is hydrogen, methoxy, fluoro, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 ;
  • R 3 is hydrogen, alkyl, dialkylaminoalkyl, piperidyl, oxetanyl or pyridazinyl; wherein piperidyl, oxetanyl and pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 6 ;
  • R 3 is hydrogen, methyl, dimethylaminoethyl, piperidyl, oxetanyl or pyridazinyl; wherein piperidyl, oxetanyl and pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 6 ;
  • R 4 is at each instance independently selected from cyano, alkyl, haloalkoxy and haloalkyl;
  • R 4 is at each instance independently selected from cyano, methyl, difluoromethoxy, difluoromethyl and trifluoroethyl;
  • R 5 is at each instance independently selected from methyl and dimethylaminocarbonyl
  • R 6 is at each instance individually selected from alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dialkylaminocarbonyl;
  • R 6 is at each instance individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dimethylaminocarbonyl;
  • the invention further relates to a compound of formula (I) selected from
  • 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)
  • R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.
  • 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; R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.
  • One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (lie) wherein L, R 2 and R 3 are as described herein; R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular from cyano, difluoromethoxy, difluoromethyl 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 L, R 1 , R 2 , R 4 and R 5 are as described herein; and R 6 is at each instance individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dimethylaminocarbonyl .
  • 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 R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyl oxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 as described herein; pyrazole of R 1 is substituted with R 4 and R 4 ’, wherein R 4 and R 4 ’ are individually selected from cyano, alkyl, haloalkoxy and haloalkyl; L is -NH-; R3 is pyridazinyl, wherein pyridazinyl is optionally substituted with one, two or three R 6 groups, wherein R 5 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloal
  • the compound of formula (I-a‘) is a compound of formula (I), wherein R 3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyl oxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 as described herein; pyrazole of R 1 is substituted with R 4 and R 4 ’, wherein R 4 and R 4 ’ are individually selected from cyano, alkyl, haloalkoxy and haloalkyl; R 2 is pyridazinyl, wherein pyridazinyl of R 2 is optionally substituted with one, two or three R 5 groups, wherein R 5 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl
  • R2/R3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy.
  • R5/R6 is is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy,
  • Step A 6-chloro-2-fluoro-pyridine-3-carbonitrile 1 can be reacted with a substituted pyrazole 2 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 (for instance DMF, DMA, NMP, DMSO or THF, MeTHF) at temperatures ranging from about -10 °C to about 120 °C to yield intermediate 3.
  • a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH
  • a suitable polar solvent for instance DMF, DMA, NMP, DMSO or THF, MeTHF
  • Step B Intermediates 3 and 4 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 temperatures ranging from about -10 °C to about 120 °C to yield the regioisomeric compounds I-a and I-a’ which can be separated 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
  • intermediates 3 and 4 can be reacted under Buchwald-Hartwig coupling conditions using a suitable base (such as for instance CS2CO3 K2CO3 or K3PO4), and as suitable palladium catalyst (such as for instance t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance t-amyl alcohol) at between around 80 °C to around 90 °C to yield the regioisomeric 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 t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf
  • a suitable solvent such as for instance t-amyl alcohol
  • Step A (4-bromo-5-fluoro-2-nitro-phenyl)amine 5 and alcohol 6 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 7.
  • 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 7 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 - 50 °C to about 120 °C to yield the diamino intermediate 8.
  • 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 7 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 8.
  • a catalyst such as for instance Pd on charcoal
  • a suitable polar protic solvent such as for instance MeOH or EtOH
  • Step C The diamino intermediate 8 can be cyclized in the presence of orthoformate (such as for instance trimethylorthoformate of triethylorthoformate) which can be used as the reaction solvent to yield the benzimidazol intermediate 9.
  • orthoformate such as for instance trimethylorthoformate of triethylorthoformate
  • Scheme 3 In scheme 3, the synthesis of a compound of formula (4) is described wherein R 2 is selected from hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino and heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 as described herein; pyridazinyl is optionally substituted with one, two or three R 6 groups, wherein R 6 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl.
  • R 2 is selected from hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino and heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected
  • Step A Intermediate 10 and SEM-C1 can be reacted in the presence of a suitable organic or mineral base (such as for instance NaH, CS2CO3 or DBU) in a suitable polar solvent (such as for instance DMF, DMA or NMP) at temperatures ranging from about -50 °C to about 120 °C to yield the regioisomeric intermediates 11-a and 11-b.
  • a suitable organic or mineral base such as for instance NaH, CS2CO3 or DBU
  • a suitable polar solvent such as for instance DMF, DMA or NMP
  • Step B Introduction of the aminopyridazine 12 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 t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance 1,4-di oxane) at between around 80 °C to around 90 °C to yield intermediates 13-a and 13-b.
  • a suitable base such as for instance CS2CO3 K2CO3 or K3PO4
  • suitable palladium catalyst such as for instance t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf
  • a suitable solvent such as for instance 1,4-di oxane
  • Step C The regioi someric mixture of intermediates 13-a and 13-b can be combined with a strong acid (such as for instance TFA) with or without a suitable solvent (such as for instance DCM) to yield intermediate 4.
  • a strong acid such as for instance TFA
  • a suitable solvent such as for instance DCM
  • the compound of formula (I-b) or (I-b’) is a compound of formula (I), wherein R 1 is heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R 4 ; R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyl oxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 ; R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 6 ; L is absent, -O- or -NH-.
  • Step A 2,6-dichloronicotinonitrile 14 and intermediate 15 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 temperatures ranging from about -10 °C to about 120 °C to yield the regioisomeric intermediates 16-a and 16-b.
  • 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 B A Palladium-catalyzed cross-coupling reaction ( Suzuki -Miy aura) between intermediate (16-a) and/or (16-b) and the corresponding aryl boronic acid R1B(OH)2 or aryl pinacol borane RIBpin, a Pd catalyst (such as for instance P(Phs)4 or Pd(dppf)C12-CH2C12 or other suitable Pd catalysts) and a suitable base (K3PO4, CS2CO3, K2CO3, Na2COs) in a suitable solvent (such as for instance a mixture of 1,4-di oxane and water) while heating (e.g.
  • the compound of formula (I-c) or (I-c’) is a compound of formula (I), wherein R 1 is heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R 4 as described herein; R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R 5 as described herein; R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R 6 ; pyridazinyl is optionally substituted with one, two or three R 6 groups, wherein R 6 is at each instance individually selected from alkyl,
  • Step A Introduction of the aminopyridazine 12 on intermediates 17-a and 17-b (as single compounds or as regioisomeric mixture of both compounds) 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 t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance 1,4-di oxane) at between around 80 °C to around 90 °C to yield compound of formula (I-c) and (I-c’) or a regioisomeric mixture thereof 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 t-Buxphos-Pd-G
  • the invention thus also relates to a process for the preparation of a compound according to the invention, comprising one of the following steps:
  • step (c) the reaction of a compound of formula (Cl) or (C2) with a compound of formula (C3) in presence of a suitable solvent, a suitable base and a suitable catalyst, wherein Xi is halogen, OMs or OTs, in particular halogen; X2 is halogen, in particular chloro; L, R 1 , R 2 , R 3 and R 6 are as described herein;
  • the solvent can be for example a polar solvent, in particular DMF, DMA, NMP, DMSO or THF, more particular DMSO;
  • the base can be for example an organic or a mineral base, in particular DIPEA, DBU, K2CO3, CS2CO3 or NaH, more particular K2CO3;
  • step (a) is performed at a temperature from about 0 °C to about 120 °C, in particular from about 50 °C to about 80 °C;
  • reaction of step (a) is performed during about 1 hour to about 48 hours, in particular during about 2 hours and about 24 hours, more particular from about 2 hours to about 16 hours;
  • step (a) is performed in presence of DMSO and in presence of K2CO3, at a temperature from about 50 °C to about 80 °C, during about 2 hours to about 24 hours;
  • the solvent can be for example water, 1,4-di oxane or a mixture thereof, in particular a mixture of water and 1,4-di oxane;
  • the base can be for example K3PO4, CS2CO3, K2CO3, Na2CO3, in particular K2CO3;
  • the catalyst can be for example a Pd catalyst, in particular Pd(PPh3)2Ch, Pd(PPh3)4, Pd(dppf)C12-CH2C12; or Pd(Oac)2 or Pd2(dba)3 and phospine ligands; more particular Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH2Cl 2 ;
  • step (b) is performed at a temperature from about 60 °C to about 120 °C, in particular from about 80 °C to about 110 °C;
  • reaction of step (b) is performed during about 1 hour to about 48 hours, in particular during about 2 hours and about 24 hours, more particular from about 4 hours to about 16 hours;
  • the reaction of step (b) is performed in presence of a mixture of water and 1,4-di oxane, in presence of K2CO3, at a temperature from about 80 °C to about 120 °C, during about 2 hours to about 48 hours.
  • the solvent can be for example water, 1,4-di oxane or a mixture thereof, in particular 1,4-di oxane or a mixture of water and 1,4-di oxane;
  • the base can be for instance K2CO3, CS2CO3 or K3PO4, in particular K2CO3;
  • the catalyst can be for example a Pd catalyst, in particular t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf);
  • step (c) is performed at a temperature from about 60 °C to about 120 °C, in particular from about 80 °C to about 100 °C;
  • reaction of step (c) is performed during about 1 hour to about 48 hours, in particular during about 2 hours and about 24 hours, more particular from about 4 hours to about 16 hours;
  • step (c) is performed in presence of a mixture of water and 1,4-di oxane, in presence of K2CO3, at a temperature from about 80 °C to about 120 °C, during about 2 hours to about 48 hours.
  • the invention also relates to a compound according to the invention when manufactured by the process as described herein.
  • 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
  • Ts tosylate TsOH tosylic acid UV ultraviolet
  • Step 2 lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine
  • Step 3 2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl pyridine-3-carbonitrile
  • Step 2 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile;formic acid
  • Example 3 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
  • Crude 2 from Example 2, step 2 was further purified by preparative HPLC (ACS-WH-GX-F), water / FA - ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid (25 mg, 0.06 mmol, 8% yield) as yellow solid.
  • Step 3 2-[ ( 6-bromo-3H-benzimidazol-5-yl)oxy ] ethyl-dimethyl-amine
  • Step 4 2-[ 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl ] oxyethyl-dimethyl-amine
  • Step 5 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine
  • Step 6 dimethyl- [2- [[ 6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5- yl] oxy ] ethyl amine
  • Step 7 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl -6-[ 6-[ 2 -(dimethylamino) ethoxy ]-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
  • Step 1 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole
  • Step 2 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2, 2-trifluoroethyl)pyr azole
  • Step 3 2-chloro-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile
  • Step 4 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ 3-methyl-l-(2, 2, 2- trijluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;formic acid
  • Step 1 tert-butyl 3-hydr oxy-5-methyl-pyr azole- 1 -carboxylate
  • Step 2 tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-l-carboxylate
  • acetonitrile 250 mL
  • 2-chloro-2,2-difluoro-acetyl)oxysodium 14.38 g, 94.34 mmol, 1.1 eq.
  • CS2CO3 CS2CO3
  • Step 4 6-chloro-2-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl ]pyridine-3-carbonitrile
  • a mixture of 6-chloro-2-fluoro-pyridine-3-carbonitrile (280 mg, 1.79 mmol, 1.0 eq.), 3- (difluoromethoxy)-5-methyl-lH-pyrazole (265 mg, 1.79 mmol, 1.0 eq.) and potassium carbonate (742 mg, 5.37 mmol, 3.0 eq.) in DMSO (6 mL) was stirred at 25 °C for 2.5 hours.
  • LCMS showed a little the starting material was remained and 67% of desired mass was detected.
  • Step 5 6-( 6-bromobenzimidazol-l -yl)-2-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl ]pyridine-3- carbonitrile
  • Step 6 ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate
  • Step 8 3-(benzhydrylideneamino)-N,N, 6-trimethyl-pyridazine-4-carboxamide
  • DIPEA 1,3-bis(trimethoxy)-2-(trimethoxy)-2-(trimethoxy)-2-(trimethoxy)-2-(trimethoxy)-2-(trimethoxy)-2-(trimethoxy)-2-(trimethoxy)-2-(trimethoxysilyl)
  • HATU 7.22 g, 9.45 mmol, 3.0 eq.
  • dimethylamine hydrochloride 514 mg, 6.3 mmol, 2.0 eq.
  • Step 9 3-amino-N,N, 6-trimethyl-pyridazine-4-carboxamide
  • hydroxylamine hydrochloride 161 mg, 2.32 mmol, 2.0 eq.
  • sodium acetate 0.22 mL, 2.9 mmol, 2.5 eq.
  • Step 10 3-[[ 3-[5-cyano-6-[ 3 -(difluoromethoxy) -5 -me thy l-pyr azol- 1-y I ]-2-pyridyl Jbenzimidazol- 5-yl (amino J-N,N, 6-trimethyl-pyridazine-4-carboxamide formic acid
  • Step 1 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethyl)-5-methyl- pyrazol-l-yl]pyridine-3-carbonitrile
  • Step 2 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile
  • Step 1 tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l-carboxylate
  • Step 4 N-[ 6-[ [ 1 -(oxetan-3-yl)-4-piperidyl oxy ]pyridazin-3-yl -l, 1-diphenyl-methanimine
  • Step 5 6-[[ l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine
  • Step 6 5-bromo-6-fluoro-lH-benzimidazole A mixture of 4-bromo-5-fluoro-benzene-l,2-diamine (4.0 g, 19.51 mmol, 1.0 eq.) in formic acid (33 mL, 883.5 mmol, 45 eq.) was stirred at 100 °C for 16 hours. The reaction mixture was concentrated and the resulting oil was partitioned between EtOAc (200mL) and sat. aq. NaHCCh (500 mL).
  • Step 7 6-(5-bromo-6-fluoro-benzimidazol-l-yl)-2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l- yl ]pyridine-3-carbonitrile and 6-( 6-bromo-5-fluoro-benzimidazol-l-yl)-2-[ 3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile
  • Step 8 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-fluoro-5-[[6-[[ l-(oxetan-3-yl)-4- piperidyl oxy ]pyridazin-3-yl amino ]benzimidazol-l-yl pyridine-3-carbonitrile formic acid
  • Step 4 tert-butyl N- [6- [2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3-yl] carbamate
  • Step 5 6-[ 2-(3-methoxyazetidin-l-yl)ethyl ]pyridazin-3-amine
  • Step 6 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-fluoro-5-[ [ 6-[ 2-(3-methoxyazetidin-l- yl)ethyl ]pyridazin-3-yl amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile
  • Step 1 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline
  • THF 90 mL
  • sodium hydride 60% in oil
  • 4-bromo-5-fluoro-2-nitro-aniline 9.0 g, 38.3 mmol, 1.0 eq.
  • Step 4 6-[ 6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl ]-2-[ 3 -(difluoromethoxy) -5 -me thy l- pyrazol-l-yl]pyridine-3-carbonitrile and 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2- [3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile
  • reaction mixture was cooled to RT, poured into H2O (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated.
  • 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 7 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid
  • Step 4 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-l-yl]-2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile
  • Step 5 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-(3-methyloxetan-3-yl)oxy-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
  • Step 3 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
  • Step 4 6-chloro-2-[ 2-(difluoromethoxy)-5-methyl-4-pyridyl ]pyridine-3-carbonitrile
  • Step 5 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]methoxy]ethyl-trimethyl-silane and 2- [[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl] methoxy] ethyl-trimethyl-silane
  • Step 6 N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine andN-(6-methylpyridazin-3-yl)-6-(oxetan-3- yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine
  • Step 7 N-( 6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-lH-benzimidazol-5-amine
  • Step 8 2-[ 2-(difluoromethoxy)-5-methyl-4-pyridyl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid
  • Example 20 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-l- yl] pyridine-3-carbonitrile
  • 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (Example 8, step 4) (100 mg, 0.35 mmol, 1.0 eq.) and 5-(oxetan-3-yloxy)-lH-benzimidazole (87 mg, 0.46 mmol, 1.3 eq.) in DMSO (3 mL) was added K2CO3 (145.35 mg, 1.05 mmol, 3.0 eq.).
  • Step 1 tert-butyl N-[l-(oxetan-3-yl)-4-piperidyl] carbamate
  • Step 5 N-[ l-(oxetan-3-yl)-4-piperidyl]-lH-benzimidazol-5-amine
  • tBuXPhosPdG3 (23 mg, 0.03 mmol, 0.2 eq.) was added and the reaction mixture was stirred at 80 °C for 16 hours under N2. The reaction mixture was cooled to RT, poured into sat. aqueous NH4CI (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated.
  • Example 22 - Phosphorylation assay SIK1-3 In the presence of SIK2 (resp. SIK1 or SIK3) and ATP the CHK-peptide (KKKVSRSGLYRSPSMPENLNRPR with C-terminal arginine amide modification) were phosphorylated at one of the four feasible serine’s. Only one phosphorylation is observed under the assay conditions. 60 nl of each compound dilution series (12 point; dilution factor 3, generally 30 pM to 170 pM) in DMSO were transferred by acoustic dispensing to the assay plate and 30 minutes pre-incubated (ambient temperature) after the addition of 5 pl SIK1 (5 nM) resp.
  • Samples were aspirated by vacuum for max. 600ms and loaded to C4-cartridge (Agilent; #G9203A) for 3000ms@1.5ml/min with 0.1% formic acid in water. Afterwards samples were transferred to the API5000 (API6500+) or QToF mass spectrometer for 4000ms@1.25ml/min with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned for additional 500ms with 0.1% formic acid in water.
  • VCap 3000V; Drying & Sheath gas: 340 °C@81/min; Nebulizer: 60psig; Nozzle Voltage: 2000V; Fragmentor: 130V; Skimmer: 35V; Octi RF Vpp: 700V; Ref masses on@5spectra/s
  • Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.
  • Capsules containing the following ingredients can be manufactured in a conventional manner: The components are sieved and mixed and filled into capsules of size 2.
  • Injection solutions can have the following composition: The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

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Abstract

The invention relates to a compound of formula (I), (I) wherein L, R1, R2 and R3 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

BENZIMIDAZOLE DERIVATIVES USEFUL AS SIK MODULATORS
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
R1 is heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R4;
R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5;
R3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6; each instance of R4 is individually selected from cyano, alkyl, alkoxy, halogen, haloalkoxy and haloalkyl; each instance of R5 is individually selected from alkyl and dialkylaminocarbonyl; each instance of R6 is individually selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl; and L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof.
Salt-inducible kinases (SIK) 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 (cAMP-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. 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).
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 HD AC 4/5 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”.
Strikingly, the inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-resolution phenotype. This comes with an increase in IL- 10 (by interfering with the SIK-CRTC3 pathway) and a concomitant decrease in TNF-a, IL- 12 and IL-6 (by interfering with the SIK-HDAC4/5 and NF- KB pathway). The high levels of IL- 10 and low levels of pro-inflammatory cytokines upon SIK inhibition will promote resolution of inflammation. The exploration of the SIK pathway has initially been described in macrophages (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34): 12468-73) and the therapeutic potential of pan-SIK inhibitors has been confirmed in a mouse LPS (lipopolysaccharide) challenge model (Sundberg et al., ACS Chem Biol. 2016 Aug 19; 1 l(8):2105-l 1) and in colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct
20;27(l l): 1821 -1831). 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-
Jun;296: 100428). Importantly, SIK1 is poorly expressed in macrophages and one embodiment of the invention are SIK2/3 inhibitors sparing SIK1, thus limiting potential SIK1 -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.
Diseases with a proven link to IL-10 and TNF-a are IBD. 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. In addition, 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.
All three 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.
In addition to their physiological roles, reports have linked dysregulation of SIK expression to a few diseases. For example, SIK2 has been described as a risk locus for primary sclerosing cholangitis, a fibrotic disease regularly associated with IBD. In addition, 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).
As of today many diseases caused by dysregulation of the innate immune system lack efficient therapies and there is a high unmet medical need for new therapies. The present invention relates to a novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases. In addition to inflammation, 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.
In the present description the term “alkyl”, alone or in combination, 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).
The term “heterocycloalkyl”, alone or in combination, 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). Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-3-yl, piperidinyl, 1- piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-l-yl, [3 -oxo-piperazin- 1-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)- 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro- lH-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-3-yl), (6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2-oxa-5,8- diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5-yl), (2- azabicyclo[2.2.1]heptan-2-yl), 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]hexan-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, (2-oxo-l- piperidyl), (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl), pyrrolidin-l-yl, 2-oxo-pyrimidin-4- yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-l -piperidyl), 2-oxo-4- piperidyl, 5-oxo-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, (7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6- yl] and [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-l-yl], Particular examples of “heterocycloalkyl” are piperidinyl and oxetanyl, more particularly 4-piperidyl and oxetan-3-yl. In a particular embodiment, heterocycloalkyl is “N-heterocycloalkyl”.
The term “heterocycloalkyloxy”, alone or in combination, denotes a “oxy” group linked to a “heterocylcoalkyl” group.
The term “heterocycloalkylalkyl”, alone or in combination, denotes an “alkyl” group wherein at least one hydrogen atom of alkyl has been replaced by a “heterocylcoalkyl” group.
The term “heteroaryl”, alone or in combination, signifies an 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). Examples of heteroaryl 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, benzotriazolyl, 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-pyridyl. pyrimidin-2-yl, pyrimidin-5-yl, (l,3,4-oxadiazol-2-yl), (l,3,4-thiadiazol-2-yl), (l,2,4-triazin-3-yl), 2-oxo- pyrimidin-4-yl, ( 1 -m ethyl -2-oxo-3 -pyridyl) and (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl). Particular examples of “heteroaryl” are pyrazolyl and pyridazinyl, more particularly pyrazol-l-yl, pyrazol-4-yl and pyridazin-3-yl. In one particular embodiment, heteroaryl is “N-heteroaryl”.
The term “heteroarylamino”, alone or in combination, denotes an “amino” group wherein one of the hydrogen atoms of amino is replaced by a “heteroaryl” group.
The term “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. Particular examples of “alkoxy” are methoxy and ethoxy.
The term “oxy”, alone or in combination, signifies the -O- group. The term “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.
The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine. The term “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.
The term “haloalkyl”, alone or in combination, 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.
The term “haloalkoxy”, alone or in combination, 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.
The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.
The term “carbonyl”, alone or in combination, signifies the -C(O)- group.
The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).
The term “alkylamino” is an alkyl group linked to a -NH- group. The term “dialkylamino” denotes two alkyl groups linked to a -N- atom. Examples of a” dialkylamino” group are for instance dimethylamino, diethylamino and (methyl)(ethyl)amino.
The term “dialkylaminocarbonyl”, alone or in combination, denotes a “carbonyl” group linked to an “dialkylamino” group.
The term “dialkylaminoalkoxy”, alone or in combination, denotes an “alkoxy” group wherein at least one hydrogen atom of alkoxy has been replaced with a “dialkylamino” group.
The term “dialkylaminoalkyl”, alone or in combination, denotes an “alkyl” group wherein at least one hydrogen atom of alkyl has been replaced with a “dialkylamino” group. The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “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, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of 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. Particular pharmaceutically acceptable salts of the compound of the present invention are the salts formed with formic acid.
The term “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.
If 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, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyl oxy (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.
The term “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.
Furthermore, 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).
If desired, 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.
In the embodiments, where an optically pure enantiomer is provided, 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 2H, 3H, 13C, 14C and 18F. For example the structures wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a 13C- or 14C- enriched carbon are within the scope of this invention.
The invention thus relates to:
A compound according to the invention, wherein R1 is selected from pyrazolyl and pyridinyl, wherein pyrazolyl and pyridinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R4;
A compound according to the invention, wherein R1 is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from R4;
A compound according to the invention, wherein R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5;
A compound according to the invention, wherein R2 is hydrogen, methoxy, fluoro, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5;
A compound according to the invention, wherein R3 is hydrogen, alkyl, dialkylaminoalkyl, piperidyl, oxetanyl or pyridazinyl; wherein piperidyl, oxetanyl and pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6;
A compound according to the invention, wherein R3 is hydrogen, methyl, dimethylaminoethyl, piperidyl, oxetanyl or pyridazinyl; wherein piperidyl, oxetanyl and pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6;
A compound according to the invention, wherein R4 is at each instance independently selected from cyano, alkyl, haloalkoxy and haloalkyl;
A compound according to the invention, wherein R4 is at each instance independently selected from cyano, methyl, difluoromethoxy, difluoromethyl and trifluoroethyl;
A compound according to the invention, wherein R5 is at each instance independently selected from methyl and dimethylaminocarbonyl; A compound according to the invention, wherein R6 is at each instance individually selected from alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dialkylaminocarbonyl;
A compound according to the invention, wherein R6 is at each instance individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dimethylaminocarbonyl;
A compound according to the invention, wherein L is -NH-;
A compound according to the invention, wherein L is absent;
A compound according to the invention, wherein L is -O-;
A compound according to the invention, wherein the compound of formula (I) is present as free base; and
A pharmaceutically acceptable salt of the compound according to formula (I) as described herein.
The invention further relates to a compound of formula (I) selected from
2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l -yl]-2-[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l -yl]-2-[5-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;
3-[[l-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3- yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-l- yl)ethyl]pyridazin-3-yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-
3 -yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-
3 -yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile; 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-l- yl]pyridine-3 -carbonitrile; and
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[[l-(oxetan-3-yl)-4- piperidyl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.
The invention further relates in particular to a compound of formula (I) selected from
2-[3-(difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l -yl]-2-[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l -yl]-2-[5-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
2-[3-(difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difhioromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan- 3 -yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile; and
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.
One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (Ila)
wherein L, R2 and R3 are as described herein; R4 is selected from cyano, haloalkyl and haloalkoxy, in particular from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.
One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (lib) wherein L, R2 and R3 are as described herein; R4 is selected from cyano, haloalkyl and haloalkoxy, in particular from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.
One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (lie) wherein L, R2 and R3 are as described herein; R4 is selected from cyano, haloalkyl and haloalkoxy, in particular from cyano, difluoromethoxy, difluoromethyl 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 L, R1, R2, R4 and R5 are as described herein; and R6 is at each instance individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dimethylaminocarbonyl .
General synthetic schemes
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.
Scheme 1
In scheme 1, the synthesis of a compound of formula (I-a) or (I-a’) is described. The compound of formula (I-a) is a compound of formula (I), wherein R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyl oxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5 as described herein; pyrazole of R1 is substituted with R4 and R4’, wherein R4 and R4’ are individually selected from cyano, alkyl, haloalkoxy and haloalkyl; L is -NH-; R3 is pyridazinyl, wherein pyridazinyl is optionally substituted with one, two or three R6 groups, wherein R5 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl. The compound of formula (I-a‘) is a compound of formula (I), wherein R3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyl oxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5 as described herein; pyrazole of R1 is substituted with R4 and R4’, wherein R4 and R4’ are individually selected from cyano, alkyl, haloalkoxy and haloalkyl; R2 is pyridazinyl, wherein pyridazinyl of R2 is optionally substituted with one, two or three R5 groups, wherein R5 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl. In the scheme below, R2/R3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy. In the scheme below, R5/R6 is is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy,
(alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl.
Step A: 6-chloro-2-fluoro-pyridine-3-carbonitrile 1 can be reacted with a substituted pyrazole 2 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 (for instance DMF, DMA, NMP, DMSO or THF, MeTHF) at temperatures ranging from about -10 °C to about 120 °C to yield intermediate 3.
Step B: Intermediates 3 and 4 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 temperatures ranging from about -10 °C to about 120 °C to yield the regioisomeric compounds I-a and I-a’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC.
Alternatively, intermediates 3 and 4 can be reacted under Buchwald-Hartwig coupling conditions using a suitable base (such as for instance CS2CO3 K2CO3 or K3PO4), and as suitable palladium catalyst (such as for instance t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance t-amyl alcohol) at between around 80 °C to around 90 °C to yield the regioisomeric compounds I-a and I-a’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC.
Scheme 2
In scheme 2, the synthesis of a compound of formula (8) is described wherein A is selected from alkyl, dialkylaminoalkyl, heteroaryl and heterocycloalkyl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R5 as described herein.
Step A: (4-bromo-5-fluoro-2-nitro-phenyl)amine 5 and alcohol 6 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 7.
Step B: The nitro group of intermediate 7 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 - 50 °C to about 120 °C to yield the diamino intermediate 8.
Alternatively, the nitro group of intermediate 7 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 8.
Step C: The diamino intermediate 8 can be cyclized in the presence of orthoformate (such as for instance trimethylorthoformate of triethylorthoformate) which can be used as the reaction solvent to yield the benzimidazol intermediate 9.
Scheme 3 In scheme 3, the synthesis of a compound of formula (4) is described wherein R2 is selected from hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino and heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5 as described herein; pyridazinyl is optionally substituted with one, two or three R6 groups, wherein R6 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl.
Step A: Intermediate 10 and SEM-C1 can be reacted in the presence of a suitable organic or mineral base (such as for instance NaH, CS2CO3 or DBU) in a suitable polar solvent (such as for instance DMF, DMA or NMP) at temperatures ranging from about -50 °C to about 120 °C to yield the regioisomeric intermediates 11-a and 11-b.
Step B: Introduction of the aminopyridazine 12 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 t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance 1,4-di oxane) at between around 80 °C to around 90 °C to yield intermediates 13-a and 13-b.
Step C: The regioi someric mixture of intermediates 13-a and 13-b can be combined with a strong acid (such as for instance TFA) with or without a suitable solvent (such as for instance DCM) to yield intermediate 4.
Scheme 4
In scheme 4, the synthesis of a compound of formula (I-b) or (I-b’) is described. The compound of formula (I-b) or (I-b’) is a compound of formula (I), wherein R1 is heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R4; R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyl oxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5; R3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6; L is absent, -O- or -NH-.
Step A: 2,6-dichloronicotinonitrile 14 and intermediate 15 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 temperatures ranging from about -10 °C to about 120 °C to yield the regioisomeric intermediates 16-a and 16-b.
Step B: A Palladium-catalyzed cross-coupling reaction ( Suzuki -Miy aura) between intermediate (16-a) and/or (16-b) and the corresponding aryl boronic acid R1B(OH)2 or aryl pinacol borane RIBpin, a Pd catalyst (such as for instance P(Phs)4 or Pd(dppf)C12-CH2C12 or other suitable Pd catalysts) and a suitable base (K3PO4, CS2CO3, K2CO3, Na2COs) in a suitable solvent (such as for instance a mixture of 1,4-di oxane and water) while heating (e.g. at a temperature between around 80 °C to around 110 °C or via microwave irradiation at a temperature between around 80 °C to around 120 °C) yields a regioisomeric mixture of compounds of formula (I-a) and (I-b') which can be separated by flash column chromatography or preparative HPLC or preparative TLC.
Scheme 5
In scheme 5, the synthesis of a compound of formula (I-c) or (I-c’) is described. The compound of formula (I-c) or (I-c’) is a compound of formula (I), wherein R1 is heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R4 as described herein; R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5 as described herein; R3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6; pyridazinyl is optionally substituted with one, two or three R6 groups, wherein R6 is at each instance individually selected from alkyl, heterocycloalkyl, heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl.
Step A: Introduction of the aminopyridazine 12 on intermediates 17-a and 17-b (as single compounds or as regioisomeric mixture of both compounds) 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 t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance 1,4-di oxane) at between around 80 °C to around 90 °C to yield compound of formula (I-c) and (I-c’) or a regioisomeric mixture thereof which can be separated by flash column chromatography or preparative HPLC or preparative TLC.
The invention thus also relates to a process for the preparation of a compound according to the invention, comprising one of the following steps:
(a) the reaction of a compound of formula (Al) with a compound of formula (A2) in presence or a suitable solvent and in presence of a suitable base;
(b) the reaction of a compound of formula (Bl) with a compound of formula (B2)
R1B(OH)2, RI Bpin or R1BF3K, neopentyl glycol (B2) in presence of a suitable solvent and a suitable catalyst, or
(c) the reaction of a compound of formula (Cl) or (C2) with a compound of formula (C3) in presence of a suitable solvent, a suitable base and a suitable catalyst, wherein Xi is halogen, OMs or OTs, in particular halogen; X2 is halogen, in particular chloro; L, R1, R2, R3 and R6 are as described herein; In step (a), the solvent can be for example a polar solvent, in particular DMF, DMA, NMP, DMSO or THF, more particular DMSO;
In step (a), the base can be for example an organic or a mineral base, in particular DIPEA, DBU, K2CO3, CS2CO3 or NaH, more particular K2CO3;
Conveniently, the reaction of step (a) is performed at a temperature from about 0 °C to about 120 °C, in particular from about 50 °C to about 80 °C;
Conveniently, the reaction of step (a) is performed during about 1 hour to about 48 hours, in particular during about 2 hours and about 24 hours, more particular from about 2 hours to about 16 hours;
Conveniently, the reaction of step (a) is performed in presence of DMSO and in presence of K2CO3, at a temperature from about 50 °C to about 80 °C, during about 2 hours to about 24 hours;
In step (b), the solvent can be for example water, 1,4-di oxane or a mixture thereof, in particular a mixture of water and 1,4-di oxane;
In step (b), the base can be for example K3PO4, CS2CO3, K2CO3, Na2CO3, in particular K2CO3;
In step (b), the catalyst can be for example a Pd catalyst, in particular Pd(PPh3)2Ch, Pd(PPh3)4, Pd(dppf)C12-CH2C12; or Pd(Oac)2 or Pd2(dba)3 and phospine ligands; more particular Pd(PPh3)4, Pd(dppf)Cl2 CH2Cl2;
Conveniently, the reaction of step (b) is performed at a temperature from about 60 °C to about 120 °C, in particular from about 80 °C to about 110 °C;
Conveniently, the reaction of step (b) is performed during about 1 hour to about 48 hours, in particular during about 2 hours and about 24 hours, more particular from about 4 hours to about 16 hours;
Conveniently, the reaction of step (b) is performed in presence of a mixture of water and 1,4-di oxane, in presence of K2CO3, at a temperature from about 80 °C to about 120 °C, during about 2 hours to about 48 hours. In step (c), the solvent can be for example water, 1,4-di oxane or a mixture thereof, in particular 1,4-di oxane or a mixture of water and 1,4-di oxane;
In step (c), the base can be for instance K2CO3, CS2CO3 or K3PO4, in particular K2CO3;
In step (c), the catalyst can be for example a Pd catalyst, in particular t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf);
Conveniently, the reaction of step (c) is performed at a temperature from about 60 °C to about 120 °C, in particular from about 80 °C to about 100 °C;
Conveniently, the reaction of step (c) is performed during about 1 hour to about 48 hours, in particular during about 2 hours and about 24 hours, more particular from about 4 hours to about 16 hours;
Conveniently, the reaction of step (c) is performed in presence of a mixture of water and 1,4-di oxane, in presence of K2CO3, at a temperature from about 80 °C to about 120 °C, during about 2 hours to about 48 hours.
The invention also relates to a compound according to the invention when manufactured by the process as described herein.
The invention also relates in particular to:
A compound of formula (I) as describe herein or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance;
A pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier;
The use of 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);
The use of 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 compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for use in 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); and
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.
Pharmaceutical Compositions
Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, 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. 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. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, 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).
The invention will now be illustrated by the following examples which have no limiting character. Examples
Abbreviations
[tBuBrettPhos Pd(allyl)]OTf allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl- 1,1’ -biphenyl )palladium(II) triflate (CAS # 1798782-15-6)
ACN acetonitrile
ATP adenosine triphosphate aq. aqueous
Boc tert-butyl oxycarbonyl
CAS chemical abstracts service dba dibenzylideneacetone
DCM dichloromethane
DIPEA 7V,7V-diisopropylethylamine
DMF N,N -dimethylformamide
DMSO dimethyl sulfoxide dppf 1,1’ -ferrocenediyl -bis(diphenylphosphine) eq. equivalents
ESI electrospray ionization
EtOAc ethyl acetate
EtOH ethanol
FA formic acid
HATU (l-[bis(dimethylamino)methylene]-U/-l,2,3-triazolo[4,5-
Z>]pyridinium 3 -oxide hexafluorophosphate
HPLC high pressure liquid chromatography iPrOH iso-propanol
LCMS high-performance liquid chromatography - mass spectrometry MeOH methanol
Ms mesylate
NMR nuclear magnetic resonance NPLC normal phase liquid chromatography PE petroleum ether psi pounds per square inch QToF quadrupole time of flight
Rf retention factor
RT room temperature sat. saturated tBuXPhosPdG3 [(2-Di-tert-butylphosphino-2’ ,4’ ,6’ -triisopropyl- 1,1’ -biphenyl)-2-
(2’ -amino- 1,1’ -biphenyl)] palladium(II) methanesulfonate (CAS
# 1447963-75-8)
Tf triflyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
Ts tosylate TsOH tosylic acid UV ultraviolet
XantPhos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) Example 1 2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl] pyridine-3-carbonitrile Step 1: 6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)nicotinonitrile
To a stirred solution of 6-chloro-2-fluoro-nicotinonitrile (250 mg, 1.60 mmol, 1.0 eq.) at RT in N,N-dimethylformamide (4 mL) under an argon atmosphere were added 5-methyl-lH-pyrazole- 3 -carbonitrile (205 mg, 1.92 mmol, 1.2 eq.) and K2CO3 (221 mg, 1.60 mmol, 1.0 eq.). Stirring at RT was continued for 2 hours 30 minutes. The mixture was diluted with H2O (16 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried (MgSCU), filtered and concentrated. The crude product was purified by flash chromatography (silica gel (20 g), 50% EtOAc in n-heptane) to give 6-chloro-2-(3-cyano-5- methyl-pyrazol-l-yl)nicotinonitrile (84 mg, 0.346 mmol, 22% yield) as a white solid. ESI pos [M+H]+ 244.0
Step 2: lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine
A mixture of lH-benzimidazol-5-ylamine (2 g, 15.02 mmol, 1.0 eq.) and 3-chloro-6-methyl- pyridazine (2.32 g, 18.02 mmol, 1.2 eq.) in iPrOH (120 mL) under an argon atmosphere was heated to 120 °C (oil bath temperature). Stirring at reflux was continued for 3 x 9 hours (reaction stopped at the end of the day, not left overnight. The next day some iPrOH is added as some solvent gets out the flask during the strong refluxing. The mixture was cooled to RT and the solid was collected by filtration, washed with iPrOH and dried to give lH-benzimidazol-5-yl-(6- m ethyl pyridazin-3-yl)amine (2.516 g, 11.18 mmol, 74% yield) as a light brown solid. ESI pos [M+H]+ 226.1
Step 3: 2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl pyridine-3-carbonitrile
To a stirred solution of 6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)nicotinonitrile (79 mg, 0.324 mmol, 1.0 eq.) in dimethyl sulfoxide (3 mL) at RT under an argon atmosphere were added 1H- benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (81 mg, 0.324 mmol, 1.0 eq.) and 1,8- diazabicyclo[5.4.0]undec-7-ene (74 mg, 73 uL, 0.486 mmol, 1.5 eq.). The mixture was heated to 85 °C and stirring at that temperature was continued for 1 hour 30 minutes. The mixture was cooled to RT, diluted with EtOAc (15 mL) and washed with H2O (15 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (MgSO4), filtered and concentrated. The residual yellow solid was purified by flash chromatography (silica gel, 20 g, 0% to 15% MeOH in DCM) to give a light yellow solid containing a mixture of both regioisomers. This mixture was further purified by preparative HPLC (Gemini NX, 12 nm, 5 pm, 100 x 30 mm, ACN / Water+0.1% TEA) to give 2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyridine-3 -carbonitrile (13 mg, 0.030 mmol, 9% yield) as a light yellow solid. ESI pos [M+H]+ 433.2 Example 2 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile Step 1: 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile
To a solution of 6-chloro-2-fluoro-pyridine-3-carbonitrile (1.0 g, 6.39 mmol, 1.0 eq.) in DMSO (10 mL) was added 3-(difluoromethyl)-5-methyl-lH-pyrazole (844 mg, 6.39 mmol, 1.0 eq.) and K2CO3 (2.477 mg, 19.16 mmol, 3.0 eq.) and stirred at 25 °C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed by brine, dried (ISfeSCL), filtered and concentrated. The crude was purified by flash chromatography (silica gel, 20 g, 30% EtOAc in petroleum ether) to give 6-chloro-2-[3- (difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (800 mg, 2.98 mmol, 42% yield) as white solid. ESI pos [M+H]+ 268.9 1H NMR (400 MHz, CDCI3) 5 = 8.13 (d, J= 8.2 Hz, 1H), 7.45 (d, J= 8.2 Hz, 1H), 6.75 (t, J= 54.6 Hz, 1H), 6.52 (s, 1H), 2.65 (s, 3H).
Step 2: 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile;formic acid
A mixture of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (180 mg, 0.67 mmol, 1.0 eq.) , N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (151 mg, 0.67 mmol, 1.0 eq.), K2CO3 (278 mg, 2.01 mmol, 3.0 eq.) in DMSO (1 mL) was stirred at 50 °C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by preparative NPLC (ACSWH-PREP-NPLC-A, hexane-EtOH) to give 2 batches: crude 1 and crude 2.
Crude 1 was further purified by preparative HPLC (ACS-WH-GX-F), ACN / Water + 0.1% FA) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid (27 mg, 0.06 mmol, 9% yield) as a yellow solid. ESI pos [M+H]+ 457.9 JH NMR (400 MHz, CD3OD) 5 = 8.94 (br s, 1H), 8.56 (d, J= 8.6 Hz, 1H), 8.26 (s, 1H), 8.13 (d, J= 8.9 Hz, 1H), 8.08 (d, J= 8.6 Hz, 1H), 7.63 (dd, J= 2.0, 9.0 Hz, 1H), 7.36 (d, J= 92 Hz, 1H), 7.12 (d, J= 9.2 Hz, 1H), 6.83 (t, J= 54.5 Hz, 1H), 6.64 (s, 1H), 2.62 (s, 3H), 2.53 (s, 3H).
Example 3 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile Crude 2 from Example 2, step 2, was further purified by preparative HPLC (ACS-WH-GX-F), water / FA - ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid (25 mg, 0.06 mmol, 8% yield) as yellow solid. ESI pos [M+H]+ 457.9
'HNMR (400 MHz, CD3OD) 5 = 8.93 (d, J= 1.7 Hz, 1H), 8.86 (s, 1H), 8.63 (d, J= 8.4 Hz, 1H), 8.10 (d, J= 8.6 Hz, 1H), 7.71 (d, J= 8.7 Hz, 1H), 7.49 (dd, J= 2.1, 8.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.15 (d, J= 92 Hz, 1H), 6.83 (t, J= 54.5 Hz, 1H), 6.60 (s, 1H), 2.62 (s, 3H), 2.55 (s, 3H).
Example 4
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: 2-(5-amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine
To a solution of 2-(dimethylamino)ethanol (2.21 g, 2.5 mL, 24.82 mmol, 1.8 eq.) in dry THF (50 mL) at 0 °C was added NaH (993 mg, 24.82 mmol, 1.8 eq.). The ice bath was removed and the mixture was stirred at RT for 30 minutes. The reaction mixture was cooled to 0 °C and (4- bromo-5-fluoro-2-nitro-phenyl)amine (3.24 g, 13.79 mmol, 1.0 eq.) was added and the mixture was allowed to warm up to RT and stirred for 12 hours. The reaction was cooled to 0 °C and quenched with NH4CI sat. sol. (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer were dried (MgSCU), filtered and concentrated. The crude product was purified by flash chromatography (SiNEE, 50 g, 0% to 10% MeOH in DCM) to give 2-(5-amino-2-bromo-4- nitro-phenoxy)ethyl-dimethyl-amine (4.068 g, 13.38 mmol, 97% yield). ESI pos [M+H]+ 306.1
Step 2: 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethyl-amine
2-(5-amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine (4.52 g, 13.38 mmol, 1.000 eq.) was dissolved in ethanol (189.4 mL) under Ar. Activated zinc (zinc was suspended in IM HC1, stirred for 30 minutes, filtered, washed with EtOH and dried in vacuo) (8.74 g, 133.75 mmol, 10.0 eq.) was added and the reaction mixture was cooled to 0 °C. A solution containing acetic acid (5.62 g, 5.36 mL, 93.63 mmol, 7.0 eq.) in ethanol (50 mL) was added dropwise while the temperature was kept under 5 °C. The reaction mixture allowed to warm to RT and stirred for 2 hours. The reaction mixture was filtered, the filter cake was washed with EtOH and the solution was evaporated to dryness. The crude product was dissolved in 2 N ISfeCCL sol. (50 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried (MgSCU), filtered and concentrated. The crude product was purified by flash chromatography (SiNEE, 50 g, 0% to 10% MeOH in DCM) to give 2-(4,5-diamino-2-bromo-phenoxy)ethyl- dimethyl-amine (3.24 g, 11.82 mmol, 84% yield). ESI pos [M+H]+ 274.2
Step 3: 2-[ ( 6-bromo-3H-benzimidazol-5-yl)oxy ] ethyl-dimethyl-amine
A solution of 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethyl-amine (3.24 g, 11.82 mmol, 1.0 eq.) in trimethyl orthoformate (93.56 g, 96.45 mL, 881.62 mmol, 74.6 eq.) was stirred at 120 °C for 3 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50 mL) and H2O (30 mL) was added. The organic layer was washed with brine (20 mL), dried (MgSCU), filtered and concentrated. The crude product was purified by flash chromatography (SiNEE, 50 g, 0% to 30% MeOH in DCM) to give 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl- dimethyl-amine (984 mg, 3.464 mmol, 29% yield). ESI pos [M+H]+ 284.2
Step 4: 2-[ 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl ] oxyethyl-dimethyl-amine
To the solution of 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethyl-amine (805 mg, 2.69 mmol, 1.0 eq.) in DMF (6 mL) at 0 °C was added NaH (96.89 mg, 4.04 mmol, 1.500 eq.) in portions. The resulting mixture was stirred at 0 °C for 15 minutes. 2- (trimethylsilyl)ethoxymethyl chloride (747 mg, 796 uL, 4.04 mmol, 1.5 eq.) was added dropwise and the temperature was kept below 5 °C. The reaction mixture was allowed to warm to RT and was stirred for 2 hours. The reaction mixture was cooled to 0 °C, quenched with sat. NaHCCL sol. (10 mL) and extracted wit DCM (30 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried (MgSCh), filtered and concentrated to give a mixture of 2-[6-bromo-3- (2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine and 2-[6-bromo-l- (2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-N,N-dimethyl-ethanamine (455 mg, 1.10 mmol, 41% yield) which was used without further purification. ESI pos [M+H]+ 416.3
Step 5: 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine
Ar was bubbled for 5 minutes through a suspension of a mixture of 2-[6-bromo-3-(2- trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine and 2-[6-bromo-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-N,N-dimethyl-ethanamine (401 mg, 0.968 mmol, 1.0 eq.), (6-methylpyridazin-3-yl)amine (211 mg, 1.94 mmol, 2.0 eq.) and CS2CO3 (946 mg, 2.9 mmol, 3.0 eq.) at RT in dry 1,4-dioxane (14 mL). Then [tBuBrettPhos Pd(allyl)]OTf (151 mg, 0.194 mmol, 0.2 eq.) was added, the vial was capped and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled, concentrated and purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give a mixture of 6-[2- (dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-[2-(dimethylamino)ethoxy]-N-(6- methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (330 mg, 0.746 mmol, 77% yield). ESI pos [M+H]+ 443.5
Step 6: dimethyl- [2- [[ 6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5- yl] oxy ] ethyl amine
A solution of a mixture of 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-[2-(dimethylamino)ethoxy]-N-(6- methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (330 mg, 0.746 mmol, 1.0 eq.) in TFA (4.88 g, 3.3 mL, 42.83 mmol, 57 eq.) was stirred for 1 hour at RT. The reaction mixture was concentrated to dryness, dissolved in with DCM (30 mL) and washed with 2 N Na2CC>3 sol. (10 mL). The organic layer was washed with brine (10 mL), dried (MgSCh), filtered and concentrated. The crude product was purified by flash chromatography (SiNLL, 20 g, 0% to 10% MeOH in DCM) to give dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H- benzimidazol-5-yl]oxy]ethyl]amine (160 mg, 0.513 mmol, 69% yield). ESI pos [M+H]+ 313.3
Step 7: 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl -6-[ 6-[ 2 -(dimethylamino) ethoxy ]-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]nicotinonitrile (50 mg, 0.186 mmol, 1.0 eq.) and dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5- yl]oxy]ethyl]amine (61 mg, 0.195 mmol, 1.05 eq.) in DMSO (1.5 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (31 mg, 31 uL, 0.205 mmol, 1.1 eq.) and the solution was stirred at 80 °C for 3 hours. The reaction was cooled to RT and diluted with DCM (10 mL) and H2O (10 mL). The organic layer was washed with brine (5 mL), dried over MgSCh, filtered and concentrated. The crude product was purified by flash chromatography chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give a mixture of 2-[3-(difluoromethyl)-5-methyl- pyrazol-l-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]pyridine-3 -carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[2-
(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3- carbonitrile. The isomers were separated by preparative HPLC (YMC-Triart Cl 8, 12 nm, 5 pm, 100 x 30 mm, ACN / Water + 0.1% FA) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6- [6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3- carbonitrile;formic acid (18 mg, 0.033 mmol, 18% yield) as a yellow solid. ESI pos [M+H]+ 545.2. 'H NMR (600 MHz, DMSO-d6) 8 = 9.04 (s, 1 H), 8.79 (s, 1 H), 8.80 (d, J =7.9 Hz, 1 H), 8.56 (br s, 1 H), 8.29 (d, J =8.7 Hz, 1 H), 7.92 (s, 1 H), 7.36 (d, J =9.1 Hz, 1 H), 7.19 - 7.30 (m, 1 H), 7.01 - 7.22 (m, 2 H), 6.76 (s, 1 H), 4.19 (br s, 2 H), 2.64 - 2.94 (m, 2 H), 2.60 (s, 3 H), 2.49
- 2.49 (m, 3 H), 2.29 (br s, 3 H).
Example 5 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
Separation of the isomers in Example 5, step 7, gave 2-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyridine-3-carbonitrile;formic acid (13 mg, 0.024 mmol, 13% yield) as a yellow solid. ESI pos [M+H]+ 545.2
JH NMR (600 MHz, DMSO-d6) 8 = 9.20 (s, 1 H), 9.06 (s, 1 H), 8.81 (d, =8.7 Hz, 1 H), 8.60 (s, 1 H), 8.25 (d, J =8.7 Hz, 1 H), 7.55 (s, 1 H), 7.32 (d, J =9.1 Hz, 1 H), 7.17 (d, J =9.1 Hz, 1 H), 7.01 - 7.22 (m, 1 H), 6.68 (s, 1 H), 4.27 (t, J =5.6 Hz, 2 H), 2.67 - 2.81 (m, 2 H), 2.58 (s, 3 H), 2.50 (s, 3 H), 2.31 (br s, 5 H).
Example 6
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile
Step 1: 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole
A mixture of 4-bromo-3 -methyl pyrazole (15.0 g, 93.17 mmol, 1.0 eq.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.71 g, 97.83 mmol, 1.05 eq.) and CS2CO3 (25.33 g, 186.34 mmol, 2.0 eq.) in DMF (150 mL) was stirred at 100 °C for 12 hours. The reaction mixture was filtered and the filtrate was diluted with H2O (250 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (3 x 250 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 4-bromo-3 -methyl- 1 -(2,2,2- trifluoroethyl)pyrazole and 4-bromo-5-methyl-l-(2,2,2-trifluoroethyl)pyrazole (2: 1 ratio) (19.5 g, 80.24 mmol, 86% yield) as colorless oil. ESI pos [M+H]+ 242.9 'HNMR (400 MHz, DMSO-d6) 8 = 8.00 (s, 1H), 5.09 - 4.99 (m, 2H), 2.14 (s, 3H).
Step 2: 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2, 2-trifluoroethyl)pyr azole
A 2:1 mixture of 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-l- (2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (200 mL). Potassium acetate (5.66 mL, 90.53 mmol, 2.0 eq.) and bis(pinacolato)diboron (13.79 g, 54.32 mmol, 1.2 eq., CAS: 73183-34-3) were added followed by Pd(dppf)C12.CH2C12 (3.7 g, 4.53 mmol, 0.1 eq.). The mixture was stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was cooled to RT and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 3-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole and 5-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole which was further purified by preparative HPLC (Welch Ultimate XB-SiOH 10 pm, 250*70 mm, Hexane-EtOH) to give a mixture of 3 -methyl-4-(4,4,5, 5-tetram ethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -(2,2,2- trifluoroethyl)pyrazole and 5-methyl -4-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)-l -(2,2,2- trifhioroethyl)pyrazole (3:1 ratio) (6.0 g, 20.68 mmol, 46% yield). ESI pos [M+H]+ 291.1
Step 3: 2-chloro-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile
To a solution of 2,6-dichloronicotinonitrile (100 mg, 0.58 mmol, 1.0 eq.) and N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (130 mg, 0.58 mmol, 1.0 eq.) in DMSO (2 mL) was added diisopropylethylamine (0.2 mL, 1.16 mmol, 2.0 eq.). The mixture was stirred at 130 °C for 12 hours. The mixture was cooled to RT and H2O (20 mL) was added. The mixture was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM) and further purified by preparative HPLC (Welch Ultimate XB- SiOH 10 pm, 250 x 70 mm, hexane-EtOH) to give 2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile (90 mg, 0.25 mmol, 34% yield) as a yellow solid. ESI pos [M+H]+ 362.1
'HNMR (400 MHz, DMSO-d6) 8 = 9.43 (s, 1H), 9.12 (s, 1H), 8.66 (d, J= 8.5 Hz, 1H), 8.52 (d, J= 1.9 Hz, 1H), 8.28 (d, J= 8.9 Hz, 1H), 8.21 (d, J= 8.6 Hz, 1H), 7.58 (dd, J= 2.2, 8.9 Hz, 1H), 7.34 (s, 1H), 7.13 (s, 1H), 2.54 (s, 3H). Step 4: 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ 3-methyl-l-(2, 2, 2- trijluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;formic acid
To a solution of a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2- trifluoroethyl)pyrazole and 5-methyl-4-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)-l -(2,2,2- trifluoroethyl)pyrazole (3:1 ratio) (221 mg, 0.76 mmol, 1.1 eq.) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was added 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]pyridine-3 -carbonitrile (250 mg, 0.69 mmol, 1.0 eq.), potassium carbonate (191 mg, 1.38 mmol, 2.0 eq.) and Pd(dppf)C12-CH2C12 (56 mg, 0.07 mmol, 0.1 eq.) and the mixture was stirred at 100 °C under N2 atmosphere for 12 hours. The mixture was concentrated and the residue was purified by reversed phase flash chromatography (0% to 30% ACN in water + 0.1 FA) to give a mixture of 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile and 6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3- carbonitrile (147 mg, 0.30 mmol, 43% yield) as an off-white solid. The isomers were separated by preparative SFC (Column: Phenomenex Luna Cl 8, 10 pm, 150 x 25 mm) to give 6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4- yl]pyridine-3 -carbonitrile (25 mg, 0.050 mmol, 7% yield) as a yellow solid . ESI pos [M+H]+ 489.9.
'HNMR (400 MHz, DMSO-d6) 8 = 9.25 (s, 1H), 9.06 (s, 1H), 8.60 - 8.54 (m, 2H), 8.46 (d, J= 1.6 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H), 8.04 (d, J= 8.7 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.34 (d, J= 9.0 Hz, 1H), 7.09 (d, J= 9.0 Hz, 1H), 5.30 - 5.20 (m, 2H), 2.48 (br s, 3H), 2.46 (s, 3H). Example 7
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile Separation of the isomers in Example 6, step 4, gave 6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3- carbonitrile;formic acid (4 mg, 0.001 mmol, 1% yield) as a yellow solid. ESI pos [M+H]+ 490.0. 'HNMR (400 MHz, DMSO-d6) 8 = 9.25 (s, 1H), 9.09 (s, 1H), 8.58 (d, J= 8.6 Hz, 1H), 8.42 (d, .7= 2.0 Hz, 1H), 8.23 (d, J= 9.0 Hz, 1H), 8.18 (s, 1H), 8.06 (d, J= 8.8 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.34 (d, J= 9.0 Hz, 1H), 7.08 (d, J= 9.1 Hz, 1H), 5.33 - 5.23 (m, 2H), 2.59 (s, 3H), 2.48 (br s, 3H).
Example 8 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol- 5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide
Step 1: tert-butyl 3-hydr oxy-5-methyl-pyr azole- 1 -carboxylate
To a solution of 5-methyl-lH-pyrazol-3-ol (5.0 g, 50.97 mmol, 1.0 eq.) in DCM (50 mL) was added di-t-butyldi carbonate (11.72 mL, 50.97 mmol, 1.0 eq.) and triethylamine (7.81 mL, 56.07 mmol, 1.1 eq.) and the reaction was stirred at RT for 18 hours. The reaction solution was poured into water (150 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over ISfeSCL, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM) to give tert-butyl 3- hydroxy-5-methyl-pyrazole-l -carboxylate (9.8 g, 49.44 mmol, 90% yield) as yellow solid. ESI pos [M-C4H8+H]+ 143.0.
'H NMR (400 MHz, DMSO-d6) 8 = 10.68 (d, J = 3.5 Hz, 1H), 5.70 (d, J = 0.9 Hz, 1H), 2.37 (d, J = 0.6 Hz, 3H), 1.52 (s, 9H).
Step 2: tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-l-carboxylate To a solution of tert-butyl 3-hydroxy-5-methyl-pyrazole-l-carboxylate (17.0 g, 85.76 mmol, 1.0 eq.) in acetonitrile (250 mL) was added (2-chloro-2,2-difluoro-acetyl)oxysodium (14.38 g, 94.34 mmol, 1.1 eq.) and CS2CO3 (55.89 g, 171.53 mmol, 2.0 eq.). The reaction was stirred at 80 °C for 12 hours. The mixture was filtered and the cake was washed with acetonitrile (4 x 50 mL). The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether) to give tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-l- carboxylate (14.0 g, 56.4 mmol, 66% yield) as colorless oil. ESI pos [M-C4H8+H]+ 193.0
'HNMR (400 MHz, CD3OD) 5 = 7.38 - 6.84 (m, 1H), 5.97 (s, 1H), 2.46 (d, J = 0.7 Hz, 3H), 1.59 (s, 9H). Step 3: 3-(difluoromethoxy)-5-methyl-lH-pyrazole
To a solution of tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-l-carboxylate (12.5 g, 50.36 mmol, 1.0 eq.) in DCM (30 mL) was added HC1 in dioxane 4M (31.25 mL, 125.0 mmol, 2.48 eq.) and the mixture was stirred at RT for 24 hours. The reaction mixture was concentrated to give 3-(difluoromethoxy)-5-methyl-lH-pyrazole (7.4 g, 49.96 mmol, 95% yield) as colorless oil. ESI pos [M-C4H8+H]+ 149.1. 'HNMR (400 MHz, CDCI3) 5 = 13.40 (s, 1H), 6.68 (t, J = 72.1 Hz, 1H), 5.85 (s, 1H), 2.41 (s, 3H).
Step 4: 6-chloro-2-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl ]pyridine-3-carbonitrile A mixture of 6-chloro-2-fluoro-pyridine-3-carbonitrile (280 mg, 1.79 mmol, 1.0 eq.), 3- (difluoromethoxy)-5-methyl-lH-pyrazole (265 mg, 1.79 mmol, 1.0 eq.) and potassium carbonate (742 mg, 5.37 mmol, 3.0 eq.) in DMSO (6 mL) was stirred at 25 °C for 2.5 hours. LCMS showed a little the starting material was remained and 67% of desired mass was detected. The mixture was poured into water (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (silica gel, 0% to 50% EtAOc in petroleum ether) give 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3- carbonitrile (270 mg, 0.95 mmol, 53% yield) as white solid. ESI pos [M+H]+ 285.0. JH NMR (400 MHz, CDC13) 8 = 8.05 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.34-6.98 (t, 1H), 5.95 (s, 1H), 2.65 (s, 3H).
Step 5: 6-( 6-bromobenzimidazol-l -yl)-2-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl ]pyridine-3- carbonitrile
A mixture of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (310 mg, 1.09 mmol, 1.0 eq.), 5-bromo-lH-benzimidazole (215 mg, 1.09 mmol, 1.0 eq.) and potassium carbonate (452 mg, 3.27 mmol, 3.0 eq.) in DMSO (6 mL) was stirred at 25 °C for 1 hour. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 10% to 40% EtOAc in petroleum ether) to give 6-(5-bromobenzimidazol-l-yl)-2-[3- (difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (135.0 mg, 0.3 mmol, 27.84% yield) as white solid: ESI pos [M+H]+ 445.1. ‘HNMR (400 MHz, DMSO-d6) 5 = 9.18 (s, 1H), 8.77 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 3.4, 8.6 Hz, 2H), 8.04 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 1.8, 8.7 Hz, 1H), 7.36 (t, J = 72.8 Hz, 1H), 6.35 (s, 1H), 2.53 (s, 3H) and 6-(6- bromobenzimidazol-l-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (125.0 mg, 0.28 mmol, 25.78% yield) as white solid. ESI pos [M+H]+ 445.1. ‘HNMR (400 MHz, DMSO-d6) 5 = 9.17 (s, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.54 - 7.16 (m, 1H), 6.38 (s, 1H), 2.57 (s, 3H).
Step 6: ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate
To a solution of ethyl 3-chloro-6-methyl-pyridazine-4-carboxylate (50 mg, 0.25 mmol, 1.0 eq.) and diphenylmethanimine (0.06 mL, 0.37 mmol, 1.5 eq.) in 1,4-dioxane (1 mL) were added CS2CO3 (244 mg, 0.75 mmol, 3.0 eq.) and Xantphos Pd G4 (21 mg, 0.02 mmol, 0.1 eq.). The mixture was bubbled with N2 and stirred at 100 °C for 16 hours under N2. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentracted. The crude was purified by preparative TLC (EtOAc) to give ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4- carboxylate (60 mg, 0.17 mmol, 70% yield) as a yellow oil. ESI pos [M+H]+ 346.1. 1 H NMR (400 MHz, CDCI3) 8 = 7.93 - 7.10 (m, 8H), 4.30 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.30 - 1.27 (m, 3H).
Step 7: 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid
To a mixture of ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (1.4 g, 4.05 mmol, 1.0 eq.) in a mixture of THF (5 mL) / methanol (5 mL) / H2O (2.5 mL) was added LiOH (243 mg, 10.14 mmol, 2.5 eq.). The mixture was stirred at RT for 1 hour. The mixture was concentrated to give 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid (1.2 g, 3.78 mmol, 93% yield) as yellow solid. The crude product was used directly in the next step without further purification. ESI pos [M+H]+ 318.0.
Step 8: 3-(benzhydrylideneamino)-N,N, 6-trimethyl-pyridazine-4-carboxamide To a solution of 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid (1.00 g, 3.15 mmol, 1.0 eq.) in DMF (15 mL) were added DIPEA (1.65 mL, 9.45 mmol, 3.0 eq.), HATU (2.22 g, 9.45 mmol, 3.0 eq.) and dimethylamine hydrochloride (514 mg, 6.3 mmol, 2.0 eq.). The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentracted to give (3-(benzhydrylideneamino)-N,N,6-trimethyl- pyridazine-4-carboxamide (1.09 mg, 3.15 mmol, quant, yield)) which was used in the next step without further purification. ESI pos [M+H]+ 345.1.
Step 9: 3-amino-N,N, 6-trimethyl-pyridazine-4-carboxamide To a solution of 3-(benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (400 mg, 1.16 mmol, 1.0 eq.) in methanol (20 mL) was added hydroxylamine hydrochloride (161 mg, 2.32 mmol, 2.0 eq.), sodium acetate (0.22 mL, 2.9 mmol, 2.5 eq.) and the mixture was stirred at RT for 2 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (30 mL) and washed with H2O (20 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases was washed by brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (EtOAc) to give 3- amino-N,N,6-trimethyl-pyridazine-4-carboxamide (199 mg, 1.10 mmol, 95% yield) as brown solid. ESI pos [M+H]+ 181.1. XH NMR (400 MHz, CDCI3) 6 = 6.92 (s, 1H), 5.42 (br s, 2H), 3.04 (br s, 3H), 2.94 (br s, 3H), 2.50 (s, 3H).
Step 10: 3-[[ 3-[5-cyano-6-[ 3 -(difluoromethoxy) -5 -me thy l-pyr azol- 1-y I ]-2-pyridyl Jbenzimidazol- 5-yl (amino J-N,N, 6-trimethyl-pyridazine-4-carboxamide formic acid
^-OH o
A mixture of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (41 mg, 0.22 mmol, 2.0 eq.) and 6-(6-bromobenzimidazol-l-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3- carbonitrile (50 mg, 0.11 mmol, 1.0 eq.) and cesium carbonate (110 mg, 0.34 mmol, 3.0 eq.) in 1,4-dioxane (2 mL) was bubbled with N2 for 3 minutes. [tBuBrettPhos Pd(allyl)]OTf (18 mg, 0.02 mmol, 0.2 eq.) was added and the mixture was stirred at 80 °C for 2 hours. The solution was filtered and the filtrate was concentrated and the residue was purified by preparative HPLC (Phenomenex luna C18 10 pm, 150 mm x 25mm, water + 0.1% FA - ACN) to give 3-[[3-[5- cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]amino]- N,N,6-trimethyl-pyridazine-4-carboxamide;formic acid (23 mg, 0.04 mmol, 37% yield) as yellow solid. ESI pos [M+H]+ 545.2.
'H NMR (400 MHz, DMSO-d6) 8 = 9.02 (s, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7.33 (s, 1H), 7.53 - 7.17 (t, 1H), 6.27 (s, 1H), 2.97 (s, 3H), 2.87 (s, 3H), 2.54 (s, 3H), 2.52 (s, 3H). Example 9 3-[[l-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol- 5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide
A mixture of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (40 mg, 0.22 mmol, 2.0 eq.), 6-(5-bromobenzimidazol-l-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3- carbonitrile (50 mg, 0.11 mmol, 1.0 eq.) and cesium carbonate (110 mg, 0.34 mmol, 3.0 eq.) in 1,4-di oxane (2 mL) was bubbled with N2 for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (18 mg, 0.02 mmol, 0.2 eq.) was added and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 10 pm, 150 mm x 25mm, water + 0.1% FA - ACN) to give 3-[[l-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;formic acid (33 mg, 0.06 mmol, 53% yield) as yellow solid. ESI pos [M+H]+ 545.2.
'H NMR (400 MHz, DMSO-d6) 5 = 9.10 (s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J= 1.8 Hz, 1H), 8.16 (dd, J= 8.8, 12.6 Hz, 2H), 7.58 (dd, J= 2.0, 8.9 Hz, 1H), 7.34 (s, 1H), 7.55 - 7.19 (t, 1H), 6.35 (s, 1H), 2.99 (s, 3H), 2.90 (s, 3H), 2.58 (s, 3H), 2.52 (s, 3H). Example 10
2- [3-(difluoromethyl)-5-methyl-pyrazol- 1-yl] -6- [5- [(6-methylpyridazin-3-yl)amino] -6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethyl)-5-methyl- pyrazol-l-yl]pyridine-3-carbonitrile
To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (200 mg, 0.74 mmol, 1.0 eq., prepared in 0, step 1) in DMSO (3 mL) was added 5-bromo-6- (oxetan-3-yloxy)-lH-benzimidazole (200 mg, 0.74 mmol, 1.0 eq.; prepared in Example 14, step 3), K2CO3 (308.68 mg, 2.23 mmol, 3.0 eq.) and the mixture was stirred at RT for 1 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (3 x 5 mL), dried over anhydrous ISfeSCU, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10: 1) to give: 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethyl)-5-methyl- pyrazol-l-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 18% yield) as white solid; ESI pos [M+H]+ 502.7; 'HNMR (400 MHz, CDCI3) 8 = 8.47 (s, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.12 (s, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.33 (s, 1H), 6.83 (t, J= 54.6 Hz, 1H), 6.64 (s, 1H), 5.22 (quin, J= 5.7 Hz, 1H), 4.94 - 4.90 (m, 2H), 4.89 - 4.84 (m, 2H), 2.60 (s, 3H); and 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]pyridine-3 -carbonitrile (80 mg, 0.16 mmol, 20% yield); ESI pos [M+H]+ 502.7. 1 H NMR (400 MHz, CDCI3) 6 = 8.59 (s, 1H), 8.41 (d, J= 8.4 Hz, 1H), 8.35 (s, 1H), 7.66 (d, J= 8.4 Hz, 1H), 6.96 (s, 1H), 6.80 (br t, J= 54.6 Hz, 1H), 6.62 (s, 1H), 5.38 - 5.31 (m, 1H), 5.09 (br t, J= 6.7 Hz, 2H), 4.93 - 4.89 (m, 2H), 2.69 (s, 3H).
Step 2: 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile
To a solution of 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 1.0 eq.) in 1,4-dioxane (3 mL) was added 3-amino-6-methylpyridazine (18 mg, 0.17 mmol, 1.2 eq.), CS2CO3 (136.49 mg, 0.42 mmol, 3.0 eq.) and the mixture was bubbled with N2 for lOmin. [tBuBrettPhos Pd(allyl)]OTf (22 mg, 0.03 mmol, 0.2 eq.) was added and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL) was added. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (ACS-WH-GX-F, water + 0.1% FA - ACN) to give 2- [3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid (15 mg, 0.03 mmol, 20% yield) as white solid. ESI pos [M+H]+ 529.9.
'HNMR (400 MHz, DMSO-d6) 8 = 9.05 (s, 1H), 8.87 (s, 1H), 8.81 (d, J= 8.6 Hz, 1H), 8.38 (s, 1H), 8.29 (d, J= 8.7 Hz, 1H), 7.42 (s, 1H), 7.37 (s, 2H), 7.15 (t, J= 54.2 Hz, 1H), 6.82 (s, 1H), 5.28 (quin, J= 5.4 Hz, 1H), 4.79 - 4.75 (m, 2H), 4.75 - 4.71 (m, 2H), 2.55 (s, 6H).
Example 11
2- [3-(difluoromethyl)-5-methyl-pyrazol- 1-yl] -6- [6- [(6-methylpyridazin-3-yl)amino] -5- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile The title compound was prepared in analogy to Example 10, step 2, using 6-[6-bromo-5-(oxetan- 3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (Example 10, step 1) (80 mg, 0.16 mmol, 1.0 eq.), 1,4-dioxane (3 mL), 3-amino-6- methylpyridazine (21 mg, 0.19 mmol, 1.2 eq.), CS2CO3 (155.99 mg, 0.48 mmol, 3.0 eq.) and [tBuBrettPhos Pd(allyl)]OTf (25 mg, 0.03 mmol, 0.2 eq.) to give 2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-l- yl]pyridine-3 -carbonitrile (19.5 mg, 0.04 mmol, 21.92% yield) as white solid. ESI pos [M+H]+ 529.9.
'HNMR (400 MHz, DMSO-d6) 8 = 9.28 (s, 1H), 9.03 (s, 1H), 8.79 (d, J= 8.6 Hz, 1H), 8.41 (s, 1H), 8.22 (d, J= 8.7 Hz, 1H), 7.32 (s, 2H), 7.24 - 6.95 (m, 2H), 6.66 (s, 1H), 5.45 (quin, J= 5.3 Hz, 1H), 5.02 (t, J= 6.7 Hz, 2H), 4.72 (dd, J= 5.1, 7.2 Hz, 2H), 2.55 (s, 3H), 2.48 (br s, 3H).
Example 12
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l-carboxylate
To the solution of l-Boc-4-hydroxypiperidine (1621 mg, 8.05 mmol, 1.2 eq.) in THF at 0 °C under N2 (15 mL) was added NaH (60% in oil) (537 mg, 13.43 mmol, 2.0 eq.) in portions. The reaction mixture was stirred at 0 °C for 30 minutes. 3,6-dichloropyridazine (1.0 g, 6.71 mmol, 1.0 eq.) was added at 0 °C and the reaction mixture was allowed to reach RT and stirred for 2 hours. The reaction mixture was poured into sat. NH4CI aqueous solution (100 mL) and was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography chromatography (silica gel, 15% EtAOc in petroleum ether) to give tert-butyl 4-(6- chloropyridazin-3-yl)oxypiperidine-l -carboxylate (1.8 mg, 5.74 mmol, 85% yield) as white solid. ESI pos [M+H]+ 314.2.
'H NMR (400 MHz, CDCI3) 8 = 7.38 (d, J = 92 Hz, 1H), 6.94 (d, J= 9.2 Hz, 1H), 5.44 (tt, J = 3.9, 8.1 Hz, 1H), 3.90 - 3.75 (m, 2H), 3.31 - 3.22 (m, 2H), 2.12 - 2.04 (m, 2H), 1.83 - 1.68 (m, 2H), 1.48 (s, 9H).
Step 2: 3-chloro-6-(4-piperidyloxy)pyridazine;hydrochloride
CI H To a solution of tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l -carboxylate (300 mg, 0.96 mmol, 1.0 eq.) in DCM (3 mL) was added HC1 4M in dioxane (1.0 mL, 4.0 mmol, 4.18 eq.). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated to give 3- chloro-6-(4-piperidyloxy)pyridazine;hydrochloride (200 mg, 0.8 mmol, 98% yield) as white solid. ESI pos [M+H]+ 214.2. 'H NMR (400 MHz, DMSO-d6) 8 = 8.92 (br s, 2H), 7.83 (d, J = 9.3 Hz, 1H), 7.36 (d, J = 9.3 Hz, 1H), 5.40 (tt, J = 3.7, 7.8 Hz, 1H), 3.24 (br s, 2H), 3.17 - 3.07 (m, 2H), 2.20 (ddd, J= 3.3, 6.9, 10.2 Hz, 2H), 2.01 - 1.90 (m, 2H).
Step 3: 3-chloro-6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine
A solution of 3-chloro-6-(4-piperidyloxy)pyridazine (150 mg, 0.7 mmol, 1.0 eq.) and 3- oxetanone (152 mg, 2.11 mmol, 3.0 eq.) in MeOH (3 mL) was stirred at RT for 10 minutes. NaBHsCN (88 mg, 1.4 mmol, 2.0 eq.) was added and the mixture was stirred at RT for 1 hour. The reaction mixture was poured into water (lOmL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over ISfeSCU, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH 10: 1) to give 3-chloro-6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazine (160 mg, 0.59 mmol, 84% yield) as white solid. ESI pos [M+H]+ 270.1. 'HNMR (400 MHz, DMSO-d6) 6 = 7.78 (d, J= 9.3 Hz, 1H), 7.31 (d, J= 9.3 Hz, 1H), 5.16 (td, J = 4.3, 8.3 Hz, 1H), 4.53 (t, J= 6.4 Hz, 2H), 4.46 - 4.39 (m, 2H), 3.42 (t, J = 6.4 Hz, 1H), 2.61 - 2.54 (m, 2H), 2.15 - 2.00 (m, 4H), 1.78 - 1.67 (m, 2H).
Step 4: N-[ 6-[ [ 1 -(oxetan-3-yl)-4-piperidyl oxy ]pyridazin-3-yl -l, 1-diphenyl-methanimine
To a solution of diphenylmethanimine (0.12 mL, 0.72 mmol, 1.5 eq.) and 3-chloro-6-[[l- (oxetan-3-yl)-4-piperidyl]oxy]pyridazine (130 mg, 0.48 mmol, 1.0 eq.) in 1,4-dioxane (4 mL) were added CS2CO3 (314 mg, 0.96 mmol, 2.0 eq.) and Xantphos Pd G4 (23 mg, 0.02 mmol, 0.05 eq.). The mixture was bubbled with N2 for 10 minutes and stirred at 100 °C for 16 hours under N2. The reaction mixture was poured into water (30mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over ISfeSCU, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH 10: 1) to give N-[6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazin-3-yl]-l,l-diphenyl-methanimine (120 mg, 0.29 mmol, 60% yield) as white solid. ESI pos [M+H]+ 415.3.
'H NMR (400 MHz, DMSO-d6) 6 = 7.73 - 7.68 (m, 2H), 7.59 (d, J= 7.4 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.36 - 7.32 (m, 3H), 7.17 - 7.13 (m, 2H), 7.10 (s, 1H), 7.11 - 7.07 (m, 1H), 7.03 - 6.98 (m, 1H), 5.07 - 4.97 (m, 1H), 4.52 (t, J= 6.5 Hz, 2H), 4.44 - 4.38 (m, 2H), 3.43 - 3.35 (m, 2H), 2.08 - 1.96 (m, 4H), 1.68 - 1.57 (m, 2H).
Step 5: 6-[[ l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine
To a solution of N-[6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-l,l-diphenyl- methanimine (400 mg, 0.97 mmol, 1.0 eq.) in MeOH (8 mL) was added sodium acetate (0.18 mL, 2.41 mmol, 2.5 eq.) and hydroxylamine hydrochloride (134 mg, 1.93 mmol, 2.0 eq.) and the reaction mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated and the residue was purified by preparative TLC (DCM/MeOH 10: 1) to give 6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazin-3 -amine (180 mg, 0.72 mmol, 75% yield) as white solid. ESI pos [M+H]+ 251.1.
JH NMR (400 MHz, DMSO-d6) 8 = 6.87 - 6.78 (m, 2H), 5.85 (s, 2H), 4.94 (tt, J= 4.1, 8.5 Hz, 1H), 4.55 - 4.50 (m, 2H), 4.42 (t, J= 6.1 Hz, 2H), 2.10 - 1.94 (m, 4H), 1.64 (dtd, J= 3.5, 9.1, 12.5 Hz, 2H)
Step 6: 5-bromo-6-fluoro-lH-benzimidazole A mixture of 4-bromo-5-fluoro-benzene-l,2-diamine (4.0 g, 19.51 mmol, 1.0 eq.) in formic acid (33 mL, 883.5 mmol, 45 eq.) was stirred at 100 °C for 16 hours. The reaction mixture was concentrated and the resulting oil was partitioned between EtOAc (200mL) and sat. aq. NaHCCh (500 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give 5-bromo-6-fluoro-lH- benzimidazole (4.0 g, 18.6 mmol, 95% yield) as a brown solid which was used without further purification. ESI pos [M+H]+ 217.0.
Step 7: 6-(5-bromo-6-fluoro-benzimidazol-l-yl)-2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l- yl ]pyridine-3-carbonitrile and 6-( 6-bromo-5-fluoro-benzimidazol-l-yl)-2-[ 3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile
To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (0, step 1) (400 mg, 1.49 mmol, 1.0 eq.) in DMSO (5 mL) were added 5-bromo-6-fluoro-lH- benzimidazole (320 mg, 1.49 mmol, 1.0 eq.) and K2CO3 (617 mg, 4.47 mmol, 3.0 eq.) and the mixture was stirred at RT for 1 hour. The mixture reaction was poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether) to give a mixture of 6-(5-bromo-6- fluoro-benzimidazol-l-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-l-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]pyridine-3 -carbonitrile (400 mg, 0.89 mmol, 42% yield) as a yellow solid. ESI pos [M+H]+ 448.8.
Step 8: 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-fluoro-5-[[6-[[ l-(oxetan-3-yl)-4- piperidyl oxy ]pyridazin-3-yl amino ]benzimidazol-l-yl pyridine-3-carbonitrile formic acid
To a suspension of 6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine (34 mg, 0.13 mmol, 1.2 eq.) in 1,4-dioxane (2 mL) was added a mixture of 6-(5-bromo-6-fluoro-benzimidazol-l-yl)- 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro- benzimidazol-l-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), CS2CO3 (109 mg, 0.34 mmol, 3.0 eq.) and [tBuBrettPhos Pd(allyl)]OTf (17 mg, 0.02 mmol, 0.2 eq.). The mixture was bubbled with N2 for 10 minutes stirred at 80 °C for 2 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by prep-HPLC (ACS-WH-GX-F, water +0.1%FA- ACN) to give 2-[3-(difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[[l-(oxetan-3-yl)- 4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid (28 mg, 0.05 mmol, 41% yield) as white solid. ESI pos [M+H]+ 617.3.
'H NMR (400 MHz, DMSO-d6) 5 = 9.16 (s, 1H), 8.88 - 8.79 (m, 3H), 8.30 (d, J= 8.6 Hz, 1H), 8.09 (d, J = 11.7 Hz, 1H), 7.45 (br d, = 9.4 Hz, 1H), 7.28 - 6.98 (m, 2H), 6.79 (s, 1H), 5.17 -
5.00 (m, 1H), 4.86 - 4.64 (m, 1H), 4.62 - 4.36 (m, 4H), 3.51 - 3.34 (m, 2H), 2.58 (s, 3H), 2.16 - 1.98 (m, 4H), 1.79 - 1.62 (m, 2H).
Example 13 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-l- yl)ethyl] pyridazin-3-yl] amino] benzimidazol- 1-yl] pyridine-3-carbonitrile
Step 1: 3-methoxyazetidine;hydrochloride
CI H
To a solution of tert-butyl 3 -methoxyazetidine- 1 -carboxylate (1.5 mg, 8.01 mmol, 1.0 eq.) in 1,4- dioxane (10 mL) were added HC1 4M in dioxane (10 mL, 40.0 mmol, 5.0 eq.). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated to give 3- methoxyazetidine (600 mg, 6.89 mmol, 86% yield) as a light yellow oil which was used in the next step without further purification.
Step 2: 3-chloro-6-vinyl-pyridazine
A solution of 3,6-dichloropyridazine (2.0 g, 13.42 mmol, 1.0 eq.) and vinylboronic acid pinacol ester (2.1 g, 13.42 mmol, 1.0 eq.) in a mixture of 1,4-dioxane (20 mL) and H2O (8 mL) was bubbled with N2 for 10 minutes. Pd(dppf)C12»DCM (1.1 g, 1.34 mmol, 0.1 eq.) and K2CO3 (5.6 g, 40.27 mmol, 3.0 eq.) were added and the suspension was stirred at 100 °C for 4 h under N2. The mixture was cooled to RT and poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over ISfeSCL, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 30% EtOAc in petroleum ether) to afford 3-chloro-6-vinyl-pyridazine (1.0 g, 7.11 mmol, 53% yield) as white solid. ESI pos [M+H]+ 141.0 Step 3: tert-butyl N-(6-vinylpyridazin-3-yl)carbamate
A suspension of 3-chloro-6-vinyl-pyridazine (700 mg, 4.98 mmol, 1.0 eq.), tert-butyl carbamate (875 mg, 7.47 mmol, 1.5 eq.) and CS2CO3 (3.2 g, 9.96 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) was bubbled with N2 for 10 min. Pd2(dba)s (456 mg, 0.5 mmol, 0.1 eq.) and Xantphos (577 mg, 1.0 mmol, 0.2 eq.) were added and the reaction mixture was stirred at 90 °C for 3 hours under N2. The reaction mixture was cooled to RT, poured into sat. NH4CI (200 mL) and extracted with EtAOAc (3 x 100 mL). The combined organic layers were dried over ISfeSCL, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0% to 60% EtOAc in petroleum ether) to give tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (1.10 g, 4.97 mmol, 99% yield) as light yellow gum. ESI pos [M+H]+ 166.0.
'H NMR (400 MHz, CDCI3) 8 = 8.20 (d, J= 9.4 Hz, 1H), 7.95 (br s, 1H), 7.59 (d, J= 9.3 Hz, 1H), 6.99 (dd, J= 11.1, 17.8 Hz, 1H), 6.10 (d, J= 17.9 Hz, 1H), 5.58 (d, J= 11.1 Hz, 1H), 1.55 (s, 9H).
Step 4: tert-butyl N- [6- [2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3-yl] carbamate
To a solution of tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (1.10 g, 4.97 mmol, 1.0 eq.) and 3 -methoxyazetidine hydrochloride (1.23 g, 9.94 mmol, 2.0 eq.) in MeOH (10 mL) was added acetic acid (940 pL, 14.91 mmol, 3.0 eq.). The mixture was stirred at 65 °C for 16 houra under N2. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Phenom enex luna C18 15 qm, 150 mm x 40 mm, water + 0.1% FA - ACN) to give tert-butyl N-[6-[2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3-yl]carbamate (840 mg, 2.72 mmol, 55% yield) as colorless gum. ESI pos [M+H]+ 309.1. 'HNMR (400 MHz, CDC13) 6 = 8.43 (s, 1H), 8.17 (d, J= 9.3 Hz, 1H), 7.88 (br d, J= 1.4 Hz, 1H), 7.37 (d, J= 9.3 Hz, 1H), 4.23 - 4.16 (m, 1H), 4.14 - 4.08 (m, 2H), 3.38 - 3.31 (m, 4H), 3.27 (s, 3H), 3.16 - 3.10 (m, 2H), 1.54 (s, 9H).
Step 5: 6-[ 2-(3-methoxyazetidin-l-yl)ethyl ]pyridazin-3-amine
To a solution of tert-butyl N-[6-[2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3-yl]carbamate (200 mg, 0.65 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (2.0 mL, 25.92 mmol, 40 eq.) and the mixture was stirred at RT for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Phenomenex luna C18 10 pm, 150 mm x 25mm, water + 0.1% FA - ACN) to give 6-[2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3 -amine (120.0 mg, 0.58 mmol, 89 % yield) as white solid. ESI pos [M+H]+ 209.0.
'H NMR (400 MHz, CD3OD) 5 = 7.74 (d, J= 9.4 Hz, 1H), 7.48 (d, J= 9.5 Hz, 1H), 4.59 - 4.38 (m, 2H), 4.31 (quin, J= 5.3 Hz, 1H), 4.21 - 3.90 (m, 2H), 3.68 (br t, J= 7.0 Hz, 2H), 3.35 (s, 3H), 3.13 (t, J = 7.0 Hz, 2H)
Step 6: 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-fluoro-5-[ [ 6-[ 2-(3-methoxyazetidin-l- yl)ethyl ]pyridazin-3-yl amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile
To a solution of a mixture of 6-(5-bromo-6-fluoro-benzimidazol-l-yl)-2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-l-yl)-2-[3- (difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (50 mg, 0.110 mmol, 1.0 eq., prepared in Example 12, step 7) in 1,4-di oxane (2 mL) was added 6-[2-(3-methoxyazetidin-l- yl)ethyl]pyridazin-3-amine;2,2,2-trifluoroacetic acid (72 mg, 0.220 mmol, 2.0 eq.) and CS2CO3 (109 mg, 0.340 mmol, 3 eq.). The mixture was bubbled with N2 for 10 minutes followed by the addition of [tBuBrettPhos Pd(allyl)]OTf (9 mg, 0.010 mmol, 0.10 eq.). The mixture was stirred at 80 °C for 2 hours. The mixture cooled to RT, poured into sat. aqueous NH4CI (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over ISfeSCU, filtered and concentrated. The residue was purified by preparative HPLC(Phenomenex luna C18 10 pm, 150 mm x 25mm, water + 0.1% FA - ACN) to give a mixture of 2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3- yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile and 2-[5-(difluoromethyl)-3-methyl-pyrazol- l-yl]-6-[5-fluoro-6-[[6-[2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-l- yl]pyridine-3 -carbonitrile as a yellow solid. The mixture was purified by SFC (Daicel Chiral OD 10 pm 250mm x 30mm, 0.1% NH4OH in EtOH) followed by preparative HPLC (Waters Xbridge 5 pm 150 x25mm, water + 0.1% NH4HCO3 - ACN) to give 2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-l-yl)ethyl]pyridazin-3- yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile (7 mg, 0.01 mmol, 8% yield) as a yellow solid. ESI pos [M+H]+ 217.0.
'HNMR (400 MHz, CDCI3) 8 = 8.63 (d, J= 7.5 Hz, 1H), 8.61 (s, 1H), 8.39 (d, J= 8.4 Hz, 1H), 7.90 (d, J= 10.9 Hz, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.36 (d, J= 9.0 Hz, 1H), 7.05 (d, J= 9.0 Hz, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 6.66 (s, 1H), 6.60 (s, 1H), 4.56 - 4.43 (m, 2H), 4.39 - 4.32 (m, 1H), 3.83 - 3.68 (m, 4H), 3.36 (t, J= 7.4 Hz, 2H), 3.32 (s, 3H), 2.65 (s, 3H).
Example 14
2- [3-(difluoromethoxy)-5-methyl-pyrazol- 1-yl] -6- [6- [(6-methylpyridazin-3-yl)amino] -5- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline To a solution of oxetan-3-ol (4.26 g, 57.46 mmol, 1.5 eq.) in THF (90 mL) under N2 cooled to 0 °C was added sodium hydride (60% in oil) (2.3 g, 57.61 mmol, 1.5 eq.) in portions and the mixture was stirred at 0 °C for 30 minutes. 4-bromo-5-fluoro-2-nitro-aniline (9.0 g, 38.3 mmol, 1.0 eq.) was added and the reaction mixture was allowed to warm to RT and was stirred at RT for 12 hours. The reaction was quenched with H2O (100 mL) which formed a precipitate. The mixture was filtered and the filter cake was dried under reduced pressure to give 4-bromo-2- nitro-5-(oxetan-3-yloxy)aniline (4.0 g, 13.84 mmol, 36% yield). The filtrate was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over ISfeSCU, filtered and concentrated. The residue was triturated in a mixture of petrol ether / EtOAc (10: 1, 30 mL) at RT for 30 minutes. The mixture was filtered and the filter cake was dried under reduced pressure to give 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (7.0 g, 24.21 mmol, 63% yield) as yellow solid. ESI pos [M+H]+ 289.0.
‘H NMR (400 MHz, DMSO-d6) 5 = 8.16 (s, 1H), 7.56 (s, 2H), 6.21 (s, 1H), 5.31 (q, J = 5.4 Hz, 1H), 4.93 (t, J= 6.8 Hz, 2H), 4.59 (dd, J= 5.2, 7.6 Hz, 2H).
Step 2: 4-bromo-5-(oxetan-3-yloxy)benzene-l,2-diamine
To a solution of 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (10.5 g, 36.32 mmol, 1.0 eq.) in EtOH (120 mL) under N2 was added Fe (10.14 g, 181.61 mmol, 5.0 eq.), NH4C1 (19.43 g, 363.22 mmol, 10.0 eq.) and H2O (40 mL). The reaction mixture was stirred under N2 at 50 °C for 12 hours. The reaction mixture was cooled to RT and filtered. The filtrate was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated to give 4-bromo-5-(oxetan-3-yloxy)benzene-l,2-diamine (9.4 g, 36.28 mmol, quant, yield) as black solid. ESI pos [M+H]+ 259.0.
Step 3: 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole;formic acid
A solution of 4-bromo-5-(oxetan-3-yloxy)benzene-l,2-diamine (9.0 g, 34.74 mmol, 1.0 eq.) and formic acid (8.0 mL, 41463.19 mmol, 1193.68 eq.) in triethyl orthoformate (80 mL) was stirred at 80 °C for 12 hours. The reaction mixture was cooled to RT and concentrated. The residue was purified by preparative HPLC (Phenom enex luna C18 10 pm, 150 mm x 40mm, water + 0.1% FA - ACN) to give 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (8.6 g, 31.96 mmol, 91% yield) as a white solid. ESI pos [M+H]+ 270.9.
'HNMR (400 MHz, CDCI3) 5 = 8.16 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 6.80 (s, 1H), 5.29 (td, J = 5.6, 11.2 Hz, 1H), 5.04 (t, J= 6.8 Hz, 2H), 4.95 - 4.84 (m, 2H).
Step 4: 6-[ 6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl ]-2-[ 3 -(difluoromethoxy) -5 -me thy l- pyrazol-l-yl]pyridine-3-carbonitrile and 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2- [3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile
To a colorless solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3- carbonitrile (350 mg, 1.23 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-(oxetan-3- yloxy)-lH-benzimidazole (331 mg, 1.23 mmol, 1.0 eq.), N,N-diisopropylethylamine (0.64 mL, 3.69 mmol, 3.0 eq.) and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to RT, poured into H2O (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH=9: 1, Rf=0.60/0.65) to give 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethoxy)-5-methyl- pyrazol-l-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 11% yield) as light yellow solid; ESI pos [M+H]+ 519.0. 'HNMR (400 MHz, DMSO-d6) 8 = 9.07 (s, 1H), 8.79 (d, J= 8.4 Hz, 1H), 8.18 (d, J= 8.6 Hz, 1H), 8.11 (s, 1H), 7.57 -7.20 (t, 1H), 7.48 (s, 1H), 6.39 (s, 1H), 5.32 (quin, J = 5.4 Hz, 1H), 4.82 (t, J= 6.7 Hz, 2H), 4.64 (dd, J= 5.0, 7.2 Hz, 2H), 3.33 (s, 3H); and 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethoxy)-5-methyl- pyrazol-l-yl]pyridine-3-carbonitrile (30 mg, 0.06 mmol, 5% yield) as light yellow solid. ESI pos [M+H]+ 519.0 Step 5: 2-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl ]-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]-5- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid
A solution of 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethoxy)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile (30 mg, 0.06 mmol, 1.0 eq.) and 3-amino-6- methylpyridazine (13 mg, 0.12 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) was bubbled with N2 for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (9 mg, 0.01 mmol, 0.2 eq.) and CS2CO3 (57 mg, 0.17 mmol, 3.0 eq.) were added and the reaction mixture was stirred at 80 °C for 2 hours under N2. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Phenom enex Synergi Cl 8 10 pm, 150 mm x 25mm, 0.1% FA in water - ACN) to give 2-[3-(difluoromethoxy)-5-methyl- pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-l- yl]pyridine-3-carbonitrile;formic acid (11 mg, 0.02 mmol, 35% yield) as an off white solid. ESI pos [M+H]+ 546.2.
'HNMR (400 MHz, DMSO-d6) 5 = 9.31 - 9.27 (m, 1H), 9.00 (s, 1H), 8.75 (d, J= 8.6 Hz, 1H), 8.46 - 8.41 (m, 1H), 8.11 (d, J= 8.6 Hz, 1H), 7.54 -7.17 (t, 1H), 7.37 - 7.33 (m, 2H), 7.08 (s, 1H), 6.25 (s, 1H), 5.48 - 5.42 (m, 1H), 5.02 (t, J= 6.5 Hz, 2H), 4.74 - 4.70 (m, 2H), 3.32 (s, 3H), 2.55 (br s, 3H)
Example 15
2- [3-(difluoromethoxy)-5-methyl-pyrazol- 1-yl] -6- [5- [(6-methylpyridazin-3-yl)amino] -6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile A solution of 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-[3-(difluoromethoxy)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile (50 mg, 0.1 mmol, 1.0 eq.) and 3-amino-6- methylpyridazine (21 mg, 0.19 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) was bubbled with N2 for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (15 mg, 0.02 mmol, 0.2 eq.) and CS2CO3 (94.48 mg, 0.29 mmol, 3.0 eq.) were added and the reaction mixture was stirred at 80 °C for 2 hours under N2. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude was purified by preparative HPLC (Phenomenex Synergi C18 10 pm, 150 mm x 25mm, 0.1% FA in water - ACN) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin- 3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid (22 mg, 0.04 mmol, 42% yield) as a light yellow solid. ESI pos [M+H]+ 546.2.
'HNMR (400 MHz, DMSO-d6) 8 = 9.00 (s, 1H), 8.89 - 8.86 (m, 1H), 8.76 (d, J= 8.6 Hz, 1H), 8.39 (s, 1H), 8.20 - 8.17 (m, 1H), 7.58 -7.22 (t, 1H), 7.42 - 7.37 (m, 3H), 6.39 (s, 1H), 5.32 (quin, J= 5.4 Hz, 1H), 4.86 - 4.81 (m, 2H), 4.78 - 4.73 (m, 2H), 3.29 - 3.22 (m, 3H), 2.54 (br s, 3H).
Example 16
2- [3-(difluoromethoxy)-5-methyl-pyrazol- 1-yl] -6- 16-met hoxy-5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: 4-bromo-5-methoxy-2-nitro-aniline
To a solution of 5-methoxy-2-nitroaniline (10.0 g, 59.47 mmol, 1.0 eq.) in acetonitrile (150 mL) was added NBS (11.6 g, 65.42 mmol, 1.1 eq.) in portions under N2 at RT and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was poured into sat. ISfeSCL solution (300 mL) under vigorous stirring and H2O (500 mL) was added. The resulting precipitate was filtered and the filter cake was dried to give 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.62 mmol, 88% yield) as a yellow solid. ESI pos [M+H]+ 249.1.
'HNMR (400 MHz, CDCI3) 8 = 8.36 (s, 1H), 6.25 (br s, 2H), 6.18 (s, 1H), 3.92 (s, 3H)
Step 2: 4-bromo-5-methoxy-benzene-l,2-diamine
To a solution of 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.6 mmol, 1.0 eq.) in a mixture of DCM (260 mL) and MeOH (260 mL) was added sat. NH4CI (520 mL, 1052 mmol, 20.0 eq.) at at RT and the mixture was bubbled with N2 for 10 minutes. Zn (34.4 g, 527 mmol, 10.0 eq.) was added in portions at RT and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved with DCM (600mL) and washed with brine (3 x 200 mL). The combined organic phases were concentrated to give 4-bromo-5-methoxy-benzene-l,2-diamine (11.0 g, 50.68 mmol, 96% yield) as black solid which was used without further purification. ESI pos [M+H]+ 217.0. 'H NMR (400 MHz, DMSO-de) 6 = 6.66 (s, 1H), 6.34 (s, 1H), 4.79 - 4.13 (m, 4H), 3.63 (s, 3H).
Step 3: 5-bromo-6-methoxy-lH-benzimidazole
To a solution of 4-bromo-5-methoxy-benzene-l,2-diamine (11.0 g, 50.7 mmol, 1.0 eq.) in trimethyl orthoformate (200 mL, 507 mmol, 10.0 eq.) was added formic acid (10.0 mL, 265 mmol, 5.2 eq.) and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (400mL) and washed with sat. NaHCCh (300mL). Then the organic phase was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (silica gel, EtOAc) to give 5-bromo-6-methoxy-lH-benzimidazole (9.6 g, 42.3 mmol, 83% yield) as a yellow solid. ESI pos [M+H]+ 227.0. 'H NMR (400 MHz, DMSO-d6) 8 = 12.53 - 12.20 (m, 1H), 8.14 (br s, 1H), 7.90 - 7.68 (m, 1H), 7.40 - 7.09 (m, 1H), 3.86 (s, 3H).
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
To a solution of 2-(trimethylsilyl)ethoxymethyl chloride (3.27 mL, 18.5 mmol, 1.4 eq.) in DMF (60 mL) was added sodium hydride (60% in oil) (635 mg, 15.9 mmol, 1.2 eq.) in portions at 0 °C. After addition, the mixture was allowed to reach RT and was stirred for 1 hour. The mixture was cooled to 0°C and 5-bromo-6-methoxy-lH-benzimidazole (3.0 g, 13.2 mmol, 1.0 eq.) was added. The mixture was allowed to reach RT and was stirred for 16 hours. The mixture was poured into sat. aqueous NH4CI (300 mL), extracted with EtOAc (3 x 100 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 2- [(5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane and 2-[(6-bromo-5- methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (2.8 g, 7.84 mmol, 59% yield) as a yellow oil. ESI pos [M+H]+ 357.0.
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
A solution of a mixture of 2-[(5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl- silane and 2-[(6-bromo-5-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (2.8 g, 7.84 mmol, 1.0 eq.), 3-amino-6-methylpyridazine (1.71 g, 15.7 mmol, 2.0 eq.) and CS2CO3 (7.66 g, 23.5 mmol, 3.0 eq.) in 1,4-dioxane (50 mL) was bubbled with N2 for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (613 mg, 0.78 mmol, 0.1 eq.) was added and the mixture was stirred at 80 °C for 4 hours under N2. The mixture was poured into sat. aqueous NH4CI (300 mL), extracted with EtOAc (3 x 100 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether) to give a mixture of 6-m ethoxy-N-(6-m ethyl pyridazin-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, 7.78 mmol, 94% yield) as yellow oil. ESI pos [M+H]+ 386.1.
Step 6: 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine
To a solution of a mixture of 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-m ethoxy-N-(6-m ethyl pyridazin-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. The mixture was concentrated and the resulting gum was dissolved in MeOH (10 mL). Aqueous NH3 (10%) (10 mL) was added carefully until pH 7 and the resulting yellow precipitate was filtered. The filter cake was washed with PE (3 x 10 mL) and dried to give 6-methoxy-N-(6-methylpyridazin- 3-yl)-lH-benzimidazol-5-amine (1.0 g, 3.92 mmol, 52% yield) as yellow solid. The combined filtrates were concentrated and the resulting residue was purified by preparative HPLC (Kromasil Eternity XT 10 pm, 250 mm x 80 mm, 0.1% NH4HCO3 in water - ACN) to give 6-methoxy-N- (6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (0.5 g, 1.96 mmol, 26% yield) as yellow solid. ESI pos [M+H]+ 256.1. XH NMR (400 MHz, CD3OD) 5 = 8.61 (s, 1H), 8.36 (s, 1H), 7.41 (d, J= 9.3 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.26 (s, 1H), 3.98 (s, 3H), 2.54 (s, 3H).
Step 7: 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid
^-OH O
To a solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (100 mg, 0.35 mmol, 1.0 eq.), 6-methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (90 mg, 0.35 mmol, 1.0 eq.) in DMSO (2 mL) was added K2CO3 (136 mg, 1.05 mmol, 3.0 eq.). Then the reaction mixture was stirred at 50 °C 16 hours. The reaction mixture was cooled to RT and diluted with H2O (20 mL) and EtOAc (10 mL). The resulting mixture of regioisomers was filtered. The filter cake was dissolved in DMSO (2 mL) and purified by preparative HPLC (ACS-WH-GX-F, 0,1% FA in water - ACN) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l- yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3- carbonitrile;formic acid (18 mg, 0.04 mmol, 10% yield)as white solid. ESI pos [M+H]+ 504.2. 'H NMR (400 MHz, DMSO-d6) 8 = 8.97 (s, 1H), 8.87 - 8.83 (m, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H), 7.36 - 7.32 (m, 2H), 7.19 (s, 1H), 6.35 (s, 1H), 3.92 (s, 3H), 2.62 (s, 3H), 2.48 (br s, 3H). Example 17
2- [3-(difluoromethoxy)-5-methyl-pyrazol- 1-yl] -6- 15-met hoxy-6- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile The aqueous layer from the work-up in Example 16, step 7, was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane: methanol= 10: 1) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-methoxy-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile (9 mg, 0.02 mmol, 5% yield) as yellow solid. ESI pos [M+H]+ 504.2.
'HNMR (400 MHz, DMSO-d6) 8 = 9.26 (d, J= 8.1 Hz, 1H), 8.97 (s, 1H), 8.73 (d, J= 8.6 Hz, 1H), 8.42 (s, 1H), 8.10 (d, J= 8.6 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 7.31 - 7.28 (m, 2H), 7.16 (s, 1H), 6.24 (s, 1H), 3.96 (s, 3H), 2.55 (s, 3H), 2.46 (s, 3H). Example 18
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile Step 1: 4-bromo-5-(3-methyloxetan-3-yl)oxy-2-nitro-aniline
[-0 Br O - 1 tv 0=N NH2 b-
To a solution of 3 -methyl ox etan-3 -ol (742 mg, 8.43 mmol, 1.1 eq.) in THF (80 mL) was added sodium hydride (60% in oil) (460 mg, 11.49 mmol, 1.5 eq.) in portions at RT under N2. The mixture was stirred at 70 °C for 1 hour under N2. The reaction mixture was cooled to RT and a solution of 4-bromo-5-fhroro-2-nitro-aniline (1.80 g, 7.66 mmol, 1.0 eq.) in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at 50 °C for 16 h under N2. The mixture was poured into water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over ISfeSCL, filtered and concentrated. The crude was purified by flash chromatography (silica gel, 0% to 75% EtOAc in petroleum ether) to give 4-bromo-5-(3-methyloxetan-3-yl)oxy-2-nitro-aniline (700 mg, 2.31 mmol, 30% yield) as yellow solid. ESI pos [M+H]+ 303.0.
'HNMR (400 MHz, CDCI3) 8 = 8.41 (s, 1H), 6.33 - 6.03 (m, 2H), 5.61 (s, 1H), 4.99 (d, J= 6.8 Hz, 2H), 4.65 (d, J= 7.5 Hz, 3H), 1.85 (s, 3H).
Step 2: 4-bromo-5-(3-methyloxetan-3-yl)oxy-benzene-l, 2-diamine
To a solution of 4-bromo-5-(3-methyloxetan-3-yl)oxy-2-nitro-aniline (700 mg, 2.31 mmol, 1.0 eq.) in EtOH (40 mL) were added iron (645 mg, 11.55 mmol, 5.0 eq.), NH4CI (1.24 g, 23.09 mmol, 10 eq.) and H2O (20 mL). The suspension was stirred at 50 °C for 2 hours under N2. MeOH (100 mL) was added and the mixture was stirred at 50 °C for 30 minutes. The mixture was filtered while hot and the filtrate was concentrated and diluted with H2O (50 ml) and EtOAc (100 mL). The aqueous layers was extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with sat. NaHCOs solution (3 x 50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (SiO2, 20 g, EtOAc) to give 4-bromo-5-(3-methyloxetan-3-yl)oxy-benzene-l, 2-diamine (370 mg, 1.35 mmol, 59% yield) as dark green solid. ESI pos [M+H]+ 272.9. 'H NMR (400 MHz, CDCI3) 6 = 6.94 (s, 1H), 6.08 (s, 1H), 4.97 (d, J= 6.5 Hz, 2H), 4.50 (d, J= 7.1 Hz, 2H), 3.92 - 2.91 (m, 4H), 1.72 (s, 3H).
Step 3: 5-bromo-6-(3-methyloxetan-3-yl)oxy-lH-benzimidazole
To a solution of 4-bromo-5-(3-methyloxetan-3-yl)oxy-benzene-l,2-diamine (370 mg, 1.35 mmol, 1.0 eq.) in EtOH (10 mL) were added trimethyl orthoformate (1.44 g, 13.55 mmol, 10 eq.) and TsOH (23 mg, 0.14 mmol, 0.1 eq.). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to RT and quenched with sat. NaHCCL (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (SiCL, 20 g, 10% MeOH in EtOAc) to give 5-bromo-6-(3-methyloxetan-3-yl)oxy-lH-benzimidazole (300 mg, 1.06 mmol, 78% yield) as a brown solid. ESI pos [M+H]+ 282.9
Step 4: 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-l-yl]-2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile
To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (Example 2, step 1) (237 mg, 0.88 mmol, 1.0 eq.) in DMSO (10 mL) were added 5-bromo-6-(3- methyloxetan-3-yl)oxy-lH-benzimidazole (250 mg, 0.88 mmol, 1.0 eq.) and K2CO3 (366 mg, 2.65 mmol, 3.0 eq.) and the suspension was stirred at RT for 2 hours. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude was purified by preparative NPLC (Welch Ultimate XB-SiOH 10 pm, 250 mm x 70 mm, hexane-EtOH) to give 6-[6- bromo-5-(3-methyloxetan-3-yl)oxy-benzimidazol-l-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol- l-yl]pyridine-3 -carbonitrile (100 mg, 0.19 mmol, 22% yield) as an off-white solid: ESI pos [M+H]+ 515.1; 'H NMR (400 MHz, CDCI3) 8 = 8.60 (br s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 6.97 - 6.65 (m, 2H), 6.62 (s, 1H), 5.06 (d, J = 6.7 Hz, 2H), 4.69 (d, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.86 (s, 3H); and 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-l-yl]-2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 22% yield) as yellow oil. ESI pos [M+H]+ 515.1;
‘HNMR (400 MHz, CDCI3) 6 = 8.50 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 6.80 (t, J = 54.6 Hz, 1H), 6.62 (s, 1H), 4.97 (d, J = 6.6 Hz, 2H), 4.47 (d, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.75 (s, 3H).
Step 5: 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[ 6-(3-methyloxetan-3-yl)oxy-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile
To a solution of 3-amino-6-methylpyridazine (42 mg, 0.39 mmol, 2.0 eq.) in 1,4-dioxane (5 mL) were added 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-l-yl]-2-[3-(difluoromethyl)- 5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 1.0 eq.), and CS2CO3 (190 mg, 0.58 mmol, 3.0 eq.). The reaction mixture was bubbles with N2 for 10 min. [tBuBrettPhos Pd(allyl)]OTf (15 mg, 0.02 mmol, 0.1 eq.) was added and the suspension was stirred at 80 °C for 1 hour under N2. The mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC ( Phenomenex C18 3 pm, 75 mm x 30mm, 0.1% FA in water - ACN followed by preparative TLC (DCM / MeOH 10: 1, Rf = 0.4) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbonitrile (24 mg, 0.04 mmol, 23% yield) as yellow solid. ESI pos [M+H]+ 544.1.
'HNMR (400 MHz, CDC13) 5 = 8.55 (s, 1H), 8.48 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.28 (br s, 1H), 7.25 - 7.21 (m, 1H), 7.15 - 7.10 (m, 1H), 6.96 - 6.66 (m, 1H), 6.62 (s, 1H), 4.96 (d, J = 6.6 Hz, 2H), 4.48 (d, J = 7.0 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H), 1.74 (s, 3H). Example 19
2- [2-(difluoromethoxy)-5-methyl-4-pyridyl] -6- [5- [(6-methylpyridazin-3-yl)amino] -6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: 4-bromo-5-methyl-pyridin-2-ol
A mixture of 4-bromo-2-chloro-5-methylpyridine (4.0 g, 19.37 mmol, 1.0 eq.) and t-BuONa (11.17 g, 116.24 mmol, 6.0 eq.) in tert-butanol (80 mL) was stirred at 120 °C for 24 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reversed-phase HPLC (Phenomenex Synergi C18 10 pm, 150 mm x 25 mm, 0.1% FA in water - ACN) to give 4-bromo-5-methyl-pyridin-2-ol (3.5 g, 18.62 mmol, 96% yield) as yellow solid. ESI pos [M+H]+ 188.1.
Step 2: 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine
A mixture of (2-chloro-2,2-difhioro-acetyl)oxysodium (10.4 g, 31.9 mmol, 3.0 eq.), CS2CO3 (13.9 g, 42.6 mmol, 4.0 eq.) and 4-bromo-5-methyl-pyridin-2-ol (2.0 g, 10.6 mmol, 1.0 eq.) in DMF (40 mL) was stirred at 100 °C for 12 hours. The reaction mixture was filtered and the filtrate was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 20% EtOAc in petroleum ether) to give a 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (450 mg, 1.89 mmol, 18% yield) as a colorless oil. ESI pos [M+H]+ 237.7.
Step 3: 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
A mixture of 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (400 mg, 1.68 mmol, 1.0 eq.), bis(pinacolato)diboron (1.71 mg, 6.72 mmol, 4.0 eq.), potassium acetate (330 mg, 3.36 mmol, 2.0 eq.) and [l,r-bis(diphenylphosphino)ferrocene]palladium,(II) chloride (137 mg, 0.17 mmol, 0.1 eq.) in 1,4-dioxane (20 mL) was stirred at 80 °C under N2 for 2 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated. The residue was purified by column on silica (silica gel, 20% to 50% EtOAc in petroleum ether) to give 2-(difluoromethoxy)-5-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (260 g, 0.912 mmol, 54% yield) as a yellow solid. ESI pos [M+H]+ 286.1.
Step 4: 6-chloro-2-[ 2-(difluoromethoxy)-5-methyl-4-pyridyl ]pyridine-3-carbonitrile
To a solution of 2-bromo-6-chloro-pyridine-3 -carbonitrile (100 mg, 0.460 mmol, 1.0 eq.) in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL) was added 2-(difluoromethoxy)-5-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.31 g, 4.60 mmol, 10 eq.), Na2COs (146.22 mg, 1.38 mmol, 3 eq.) and l,l'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (38 mg, 0.050 mmol, 0.10 eq.). The mixture was bubbled with nitrogen for 10 minutes and stirred at 60 °C for 2 hours under N2. The mixture was poured into sat. NH4CI solution (50 mL) and was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex luna Cl 8 10 pm, 150 mm x 25mm, 0.225% FA in water - ACN) to give 6-chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]pyridine-3-carbonitrile (50 mg, 0.17 mmol, 37% yield) as a white solid. ESI pos [M+H]+ 296.2. 'HNMR (400 MHz, CD3OD) 5 = 8.33 (d, J= 8.4 Hz, 1H), 8.26 (s, 1H), 7.76 (s, 1H), 7.74 - 7.39 (m, 1H), 7.08 (s, 1H), 2.21 (s, 3H).
Step 5: 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]methoxy]ethyl-trimethyl-silane and 2- [[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl] methoxy] ethyl-trimethyl-silane
To a solution of 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (4.5 g, 16.7 mmol, 1.0 eq.) in DMF (80 mL) at 0 °C was added sodium hydride (60% in oil) (0.80 g, 20.1 mmol, 1.2 eq.) in portions. The mixture was allowed to reach RT and stirred at RT for 1 hour. The mixture was cooled to 0 °C and 2-(trimethylsilyl)ethoxymethyl chloride (4.44 mL, 25.1 mmol, 1.5 eq.) was added dropwise. The mixture was stirred at RT for 16 hours. The mixture was poured into saturated NH4CI aqueous solution (400 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in EtOAc) to give a mixture of 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]methoxy]ethyl- trimethyl-silane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]methoxy]ethyl -trimethyl- silane (2.0 g, 5.01 mmol, 30% yield) as a yellow oil. ESI pos [M+H]+ 401.0.
Step 6: N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine andN-(6-methylpyridazin-3-yl)-6-(oxetan-3- yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine
To a yellow solution of a mixture of 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l- yl]methoxy]ethyl-trimethyl-silane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l- yl]methoxy]ethyl-trimethyl-silane (2.0 mg, 5.01 mmol, 1.0 eq.) in 1,4-dioxane (40 mL) was added 3-amino-6-methylpyridazine (1.1 g, 10.02 mmol, 2.0 eq.) and CS2CO3 (4.9 g, 15.02 mmol, 3.0 eq.). The reaction mixture was bubbled with N2 for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (783 mg, 1.0 mmol, 0.20 eq.) was added and the mixture was stirred at 80 °C for 4 hours. The mixture was poured into saturated NH4CI aqueous solution (200 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 15% MeOH in EtOAc) to give a mixture of N-(6-methylpyridazin-3 -yl)-6-(ox etan-3 -yl oxy)- 1 -(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-m ethyl pyridazin-3 -yl)-6-(oxetan-3- yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (1.5 g, 3.51 mmol, 70% yield) as light yellow oil. ESI pos [M+H]+ 428.1
Step 7: N-( 6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-lH-benzimidazol-5-amine
A solution of a mixture of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-m ethyl pyridazin-3 -yl)-6-(oxetan-3 - yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (1.5 g, 3.51 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 129.8 mmol, 37 eq.) was stirred at RT for 3 hours. The mixture was concentrated and the residue was dissolved in H2O (30 mL) and acetonitrile (10 mL) at RT. The solution was lyophilized to give a yellow solid which was purified by flash chromatography chromatography (silica gel, 0% to 105 MeOH in EtOAc) to give N-(6-m ethyl pyridazin-3 -yl)-6- (oxetan-3-yloxy)-lH-benzimidazol-5-amine (1.0 g, 3.36 mmol, 96% yield) as a yellow solid. ESI pos [M+H]+ 298.1.
'HNMR (400 MHz, CD3OD) 5 = 8.97 (br s, 1H), 8.64 (br s, 1H), 7.79 - 7.69 (m, 2H), 7.01 (s, 1H), 5.49 (br s, 1H), 5.13 - 5.05 (m, 2H), 4.79 (br d, J= 3.5 Hz, 2H), 2.66 - 2.61 (m, 3H). Step 8: 2-[ 2-(difluoromethoxy)-5-methyl-4-pyridyl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile;formic acid
To a solution of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-lH-benzimidazol-5-amine (60 mg, 0.2 mmol, 1.2 eq.) in t-amyl alcohol (1.0 mL) was added 6-chloro-2-[2-(difluoromethoxy)-5- methyl-4-pyridyl]pyridine-3-carbonitrile (50 mg, 0.17 mmol, 1.0 eq.) and K3PO4 (108 mg, 0.51 mmol, 3.0 eq.). The mixture was bubbled with N2 for 10 mintes. tBuXPhosPdG3 (13 mg, 0.02 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 2 hours under N2. The reaction mixture was cooled to RT, poured into sat. NH4CI solution (30 mL), and was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH 10:1) to give a mixture of 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[6-[(6-methylpyridazin-3- yl)amino]-5-(oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile and 2-[3- (difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile (20 mg, 0.04 mmol, 21% yield) The mixture of regioisomers was purified by preparative HPLC (Phenomenex Luna Cl 8 10 pm 150 mm x 25mm, 0.225% FA in water - ACN) to give 2-[2-(difluoromethoxy)-5-methyl-4- pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3- carbonitrile;formic acid (2.29 mg, 0.0 mmol, 2.25% yield) (LCMS: WUX002952-507-P1F2; HNMR: WUX002952-507-P1B) as light yellow solid. ESI pos [M+H]+ 557.3.
'H NMR (400 MHz, DMSO-d6) 5 = 9.11 (s, 1H), 8.87 - 8.84 (m, 1H), 8.74 (d, J= 8.8 Hz, 1H), 8.44 (s, 1H), 8.36 - 8.30 (m, 2H), 7.82 (t, J= 72.8 Hz, 1H), 7.51 (s, 1H), 7.47 (s, 1H), 7.37 - 7.34 (m, 2H), 5.18 - 5.11 (m, 1H), 4.67 - 4.62 (m, 2H), 4.60 - 4.56 (m, 2H), 2.54 (s, 3H), 2.27 (s, 3H). Example 20 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-l- yl] pyridine-3-carbonitrile To a solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (Example 8, step 4) (100 mg, 0.35 mmol, 1.0 eq.) and 5-(oxetan-3-yloxy)-lH-benzimidazole (87 mg, 0.46 mmol, 1.3 eq.) in DMSO (3 mL) was added K2CO3 (145.35 mg, 1.05 mmol, 3.0 eq.). The reaction was stirred at 80 °C for 16 hours. The mixture was cooled to RT, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Cl 8 10 pm 150 mm x 25mm, 0.225% FA in water - ACN) followed by SFC (Daicel ChiralPak IG 10 pm 250 mm x 30 mm, 0.1% NH4OH - EtOH) to give 2-[3-(difluoromethoxy)-5-methyl- pyrazol-l-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3-carbonitrile (5 mg, 0.01 mmol, 3% yield) as yellow solid. ESI pos [M+H]+ 439.1.
'H NMR (400 MHz, METHANOL-d4) 5 = 8.90 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.20 - 8.05 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.45 - 6.97 (m, 3H), 6.14 (s, 1H), 5.43 - 5.31 (m, 1H), 5.06 (t, J =
6.7 Hz, 2H), 4.73 (dd, J = 5.1, 7.2 Hz, 3H), 2.61 (s, 3H).
Example 21 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[[l-(oxetan-3-yl)-4- piperidyl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile
Step 1: tert-butyl N-[l-(oxetan-3-yl)-4-piperidyl] carbamate
To a solution of tert-butyl N-(4-piperidyl)carbamate (5.0 g, 24.97 mmol, 1.0 eq.) in DCM (250 mL) were added 3-oxetanone (5.4 g, 74.94 mmol, 3.0 eq.) and acetic acid (1.05 g, 17.48 mmol, 0.7 eq.) and the mixture was stirred at RT for 10 minutes. Sodium tri acetoxyb orohydri de (15.9 g, 75.02 mmol, 3.0 eq.) was added and the mixture was stirred at RT for 16 hours. The reaction mixture was diluted with sat. aq. NaHCCL solution (200 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with H2O (100 mL) and brine (3 x 50mL), dried over Na2SO4, filtered and concentrated. The crude was purified by flash (silica gel, 0% to 10 % MeOH in EtOAc) to give tert-butyl N-[l-(oxetan-3-yl)-4-piperidyl]carbamate (5.4 g, 21.07 mmol, 84% yield) as a white solid. ESI pos [M+H]+ 257.1.
'HNMR (400 MHz, CDCI3) 8 = 4.67 - 4.61 (m, 2H), 4.60 - 4.55 (m, 2H), 4.47 (br s, 1H), 3.52 - 3.37 (m, 2H), 2.66 (br d, J= 11.4 Hz, 2H), 2.01 - 1.86 (m, 4H), 1.44 (s, 11H). Step 2: l-(oxetan-3-yl)piperidin-4-amine;dihydrochloride
To a solution of tert-butyl N-[l-(oxetan-3-yl)-4-piperidyl]carbamate (5.4 g, 21.1 mmol, 1.0 eq.) in DCM (40 mL) and MeOH (20 mL) was added HC1 4M in dioxane (32 mL, 128 mmol, 6.1 eq.). The reaction mixture was stirred at RT for 4 hours to give a white suspension. The reaction mixture was concentrated to give l-(oxetan-3-yl)piperidin-4-amine;dihydrochloride (4.8 g, 21.0 mmol, 99% yield) as a white solid which was used without further purification. ESI pos [M+H]+ 157.1.
Step 3: 4-nitro-Nl-[l-(oxetan-3-yl)-4-piperidyl]benzene-l,3-diamine
To a suspension of l-(oxetan-3-yl)piperidin-4-amine;dihydrochloride (3.24 g, 14.1 mmol, 1.1 eq.) in DMSO (20 mL) was added K2CO3 (5.33 g, 38.6 mmol, 3.0 eq.) and stirred at RT for 5 minutes. 5-fluoro-2-nitroaniline (2.0 g, 12.8 mmol, 1.0 eq.) was added and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to RT, poured into sat. aqueous NH4CI (300 mL) under vigorous stirring and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over ISfeSCU, filtered and concentrated. The crude was purified by flash chromatography (silica gel, 0% to 10% MeOH in EtOAc) to give 4-nitro-Nl-[l-(oxetan-3-yl)-4-piperidyl]benzene-l,3-diamine (1.4 g, 4.79 mmol, 37% yield) as a yellow solid. ESI pos [M+H]+ 293.0.
'H NMR (400 MHz, DMSO-d6) 8 = 7.71 (d, J= 9.5 Hz, 1H), 7.28 (br s, 2H), 6.84 (br d, J= 7.5 Hz, 1H), 6.02 (dd, J= 2.0, 9.5 Hz, 1H), 5.88 (d, J= 1.8 Hz, 1H), 4.57 - 4.47 (m, 2H), 4.41 (t, J= 6.0 Hz, 2H), 3.38 (br t, J= 6.4 Hz, 1H), 3.25 - 3.15 (m, 1H), 2.67 (br d, J= 11.1 Hz, 2H), 1.94 - 1.83 (m, 4H), 1.51 - 1.37 (m, 2H). Step 4: N4-[ l-(oxetan-3-yl)-4-piperidyl] benzene- 1,2, 4-triamine
To a solution of 4-nitro-Nl-[l-(oxetan-3-yl)-4-piperidyl]benzene-l,3-diamine (100 mg, 0.34 mmol, 1.0 eq.) in MeOH (15 mL) was added Fe (191 mg, 3.42 mmol, 10 eq.), NH4CI (366 mg, 6.84 mmol, 20 eq.) and H2O (5 mL) and the reaction mixture was stirred at 50 °C for 2 hours under N2. The reaction was cooled to RT and diluted with MeOH (10 mL). Aqueous NH3 (10%) (0.5 mL) was added and the mixture was stirred at 30 °C for 10 minutes. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was dried over Na2SO4, filtered and concentrated to give N4-[l-(oxetan-3-yl)-4- piperidyl]benzene- 1,2, 4-triamine (100 mg, 0.38 mmol, quant, yield) as a dark brown solid which was used without further purification. TLC: DCM / MeOH 10: 1, Rf = 0.20.
Step 5: N-[ l-(oxetan-3-yl)-4-piperidyl]-lH-benzimidazol-5-amine
To a solution of N4-[l-(oxetan-3-yl)-4-piperidyl]benzene-l, 2, 4-triamine (100 mg, 0.38 mmol, 1.0 eq.) in EtOH (2 mL) was added TsOH (7 mg, 0.04 mmol, 0.1 eq.) and trimethoxymethane (417 pL, 3.81 mmol, 10 eq.) and the reaction mixture was stirred at 80 °C for 2 hours under N2. The reaction mixture was cooled to RT and concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 15 pm 150 mm x 40 mm, 0.1% NH4OH in water - ACN to give N-[l-(oxetan-3-yl)-4-piperidyl]-lH-benzimidazol-5-amine (35 mg, 0.13 mmol, 34% yield) as a brown solid. ESI pos [M+H]+ 273.1. Step 6: 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[[ l-(oxetan-3-yl)-4- piperidyl amino ]benzimidazol-l-yl ]pyridine-3-carbonitrile
To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine-3-carbonitrile (Example 2, step 1) (48 mg, 0.18 mmol, 1.2 eq.) in t-amyl alcohol (2.0 mL) were added N-[l- (oxetan-3-yl)-4-piperidyl]-lH-benzimidazol-5-amine (40 mg, 0.15 mmol, 1.0 eq.) and K3PO4 (94 mg, 0.44 mmol, 3.0 eq.). The reaction mixture was bubbled with N2 for 10 minutes. tBuXPhosPdG3 (23 mg, 0.03 mmol, 0.2 eq.) was added and the reaction mixture was stirred at 80 °C for 16 hours under N2. The reaction mixture was cooled to RT, poured into sat. aqueous NH4CI (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give a mixture of 2-[3-(difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[[l-(oxetan- 3-yl)-4-piperidyl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-6-[6-[[l-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-l-yl]pyridine-3- carbonitrile (20 mg, 0.04 mmol, 27% yield) as a yellow oil. The mixture of isomers was purified by SFC (DAICEL CHIRALCEL OD 10 pm, 250 mm x 30 mm, 0.1% NH4OH in MeOH - ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[[l-(oxetan-3-yl)-4- piperidyl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile (6 mg, 0.01 mmol, 29% yield) as a yellow solid. ESI pos [M+H]+ 505.1.
'HNMR (400 MHz, DMSO-d6) 8 = 8.98 (s, 1H), 8.72 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.93 (br d, J = 8.9 Hz, 1H), 7.11 (br t, J = 54.0 Hz, 1H), 6.87 (s, 1H), 6.76 (br s, 2H), 5.54 (br d, J = 8.0 Hz, 1H), 4.53 (br t, J = 6.3 Hz, 2H), 4.42 (br t, J = 6.0 Hz, 2H), 3.39 (br s, 1H), 2.67 (br s, 5H), 2.55 (s, 3H), 1.98 - 1.89 (m, 4H).
Example 22 - Phosphorylation assay SIK1-3: In the presence of SIK2 (resp. SIK1 or SIK3) and ATP the CHK-peptide (KKKVSRSGLYRSPSMPENLNRPR with C-terminal arginine amide modification) were phosphorylated at one of the four feasible serine’s. Only one phosphorylation is observed under the assay conditions. 60 nl of each compound dilution series (12 point; dilution factor 3, generally 30 pM to 170 pM) in DMSO were transferred by acoustic dispensing to the assay plate and 30 minutes pre-incubated (ambient temperature) after the addition of 5 pl SIK1 (5 nM) resp. 5 pl SIK2 (0.5 nM) or 7 pl SIK3 (1.5 nM) in assay-buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 5 pl for SIK1 & SIK2, respectively 3 pl for SIK3 of a 10 pM CHK-peptide solution and 100 pM ATP solution in assay-buffer were added and incubated ambient for 45 minutes. 40 pl of 0.125% formic acid in water were added to quench the reaction. RapidFire (RF) Mass Spectrometry was utilized for data generation as described below. The multiple charged species (3-5 charges) for the phosphorylated and non-phosphorylated form measured by MRM (Multiple Reaction Monitoring; API5000 or 6500+) or EIC (Extracted Ion Current; QToF) were summed up and the ratio calculated (sum phosphorylated species / sum all species) for data evaluation. Normalization was performed by Genedata software based on the non-inhibition control DMSO and the commercially available SIK inhibitor @ IpM YKL-05- 099 (CAS number 1936529-65-5). The results of the assay are expressed in half-maximal inhibitory concentrations (IC50s) and are summarized below in Table 1.
RapidFire Setup:
Samples were aspirated by vacuum for max. 600ms and loaded to C4-cartridge (Agilent; #G9203A) for 3000ms@1.5ml/min with 0.1% formic acid in water. Afterwards samples were transferred to the API5000 (API6500+) or QToF mass spectrometer for 4000ms@1.25ml/min with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned for additional 500ms with 0.1% formic acid in water.
MS-Setup Sciex API5000/API6500+:
All MS analyses using the following MS-setup in MRM mode: Electrospray positive; Ion Spray Voltage: 4000V; Temperature: 550 °C; Collision Gas: 5; Curtain Gas: 15; Gas 1 : 40; Gas 2: 42; EP: 10. DP = declustering potential; CE = collision energy; CXP = cell exit potential.
MS-Setup Agilent QToF 6545
All MS analyses using the following MS-setup in Mode MS: Dual AJS Electrospray positive;
VCap: 3000V; Drying & Sheath gas: 340 °C@81/min; Nebulizer: 60psig; Nozzle Voltage: 2000V; Fragmentor: 130V; Skimmer: 35V; Octi RF Vpp: 700V; Ref masses on@5spectra/s
Table 1: IC50 values for inhibition of SIK1, SIK2 and SIK3:
Example A
Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a conventional manner: The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition: The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

Claims
1. A compound of formula (I) wherein
R1 is heteroaryl optionally substituted with 1, 2 or 3 substituents individually selected from R4;
R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5;
R3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6; each instance of R4 is individually selected from cyano, alkyl, alkoxy, halogen, haloalkoxy and haloalkyl; each instance of R5 is individually selected from alkyl and dialkylaminocarbonyl; each instance of R6 is individually selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl; and
L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R1 is selected from pyrazolyl and pyridinyl, wherein pyrazolyl and pyridinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R4.
3. The compound according to claim 1 or 2, wherein R1 is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from R4.
4. The compound according to any one of claims 1 to 3, wherein R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5.
5. The compound according to any one of claims 1 to 4, wherein R2 is hydrogen, methoxy, fluoro, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R5.
6. The compound according to any one of claims 1 to 5, wherein R3 is hydrogen, alkyl, dialkylaminoalkyl, piperidyl, oxetanyl or pyridazinyl; wherein piperidyl, oxetanyl and pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6.
7. The compound according to any one of claims 1 to 6, wherein R3 is hydrogen, methyl, dimethylaminoethyl, piperidyl, oxetanyl or pyridazinyl; wherein piperidyl, oxetanyl and pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R6.
8. The compound according to any one of claims 1 to 7, wherein R4 is at each instance individually selected from cyano, alkyl, haloalkoxy and haloalkyl.
9. The compound according to any one of claims 1 to 8, wherein R4 is at each instance independently selected from cyano, methyl, difluoromethoxy, difluoromethyl and trifluoroethyl.
10. The compound according to any one of claims 1 to 9, wherein R5 is at each instance independently selected from methyl and dimethylaminocarbonyl.
11. The compound according to any one of claims 1 to 10, wherein R6 is at each instance individually selected from alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dialkylaminocarbonyl.
12. The compound according to any one of claims 1 to 11, wherein R6 is at each instance individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dimethylaminocarbonyl.
13. The compound according to any one of claims 1 to 12, wherein L is -NH-.
14. The compound of formula (I) according to any one of claims 1 to 13, selected from 2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-[5-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;
3-[[l-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-l- yl)ethyl]pyridazin-3-yl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-l- yl]pyridine-3 -carbonitrile; and
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[[l-(oxetan-3-yl)-4- piperidyl]amino]benzimidazol-l-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.
15. The compound of formula (I) according to any one of claims 1 to 14, selected from
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-[5-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;
2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6- (oxetan-3-yloxy)benzimidazol-l-yl]pyridine-3 -carbonitrile;
2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile; and 2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3 -carbonitrile; or a pharmaceutically acceptable salt thereof.
16. A process for the preparation of a compound according to any one of claims 1 to 15, comprising one of the following steps: (a) the reaction of a compound of formula (Al) with a compound of formula (A2) in presence or a suitable solvent and in presence of a suitable base; (b) the reaction of a compound of formula (Bl) with a compound of formula (B2)
R1B(OH)2,
RI Bpin or R1BF3K, neopentyl glycol (B2) in presence of a suitable solvent and a suitable catalyst, or (c) the reaction of a compound of formula (Cl) or (C2) with a compound of formula (C3) in presence of a suitable solvent, a suitable base and a suitable catalyst, wherein Xi is halogen, OMs or OTs, in particular halogen; X2 is halogen, in particular chloro; L, R1, R2, R3 and R6 are as defined in any one of claims 1 to 13.
17. A compound according to any one of claims 1 to 15 when manufactured according to a process of claim 16.
18. A compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.
19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.
20. The use of a compound of formula (I) according to any one of claims 1 to 15 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.
21. The use of a compound of formula (I) according to any one of claims 1 to 15 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.
22. A compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, for use in 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 gl omerul onephriti s .
23. 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) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
24. The invention as hereinbefore described.
EP23840680.5A 2022-12-27 2023-12-22 Benzimidazole derivatives useful as sik modulators Pending EP4642535A1 (en)

Applications Claiming Priority (2)

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EP22216694 2022-12-27
PCT/EP2023/087526 WO2024141443A1 (en) 2022-12-27 2023-12-22 Benzimidazole derivatives useful as sik modulators

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WO (1) WO2024141443A1 (en)

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GB201702947D0 (en) * 2017-02-23 2017-04-12 Domainex Ltd Novel compounds
CN119604503A (en) * 2022-07-01 2025-03-11 豪夫迈·罗氏有限公司 Imidazolo[4,5-B]pyridine and pyrazolo[1,5-A]pyrimidine derivatives as SIK modulators for the treatment of rheumatoid arthritis
EP4547663A1 (en) * 2022-07-01 2025-05-07 F. Hoffmann-La Roche AG Imidazo[4,5-c]pyridine derivatives as sik modulators for the treatment of rheumatoid arthritis

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