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US20230100516A1 - Pyridazines - Google Patents

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Publication number
US20230100516A1
US20230100516A1 US17/934,625 US202217934625A US2023100516A1 US 20230100516 A1 US20230100516 A1 US 20230100516A1 US 202217934625 A US202217934625 A US 202217934625A US 2023100516 A1 US2023100516 A1 US 2023100516A1
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Prior art keywords
hplc
compound
mmol
group
lpa
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US17/934,625
Inventor
Christian Andreas KUTTRUFF
Tom Bretschneider
Cédrickx GODBOUT
Hannes Fiepko KOOLMAN
Domnic Martyres
Gerald Juergen Roth
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority to US17/934,625 priority Critical patent/US20230100516A1/en
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Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to novel pyridazines, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment and/or prevention of diseases and disorders mediated by Autotaxin.
  • ATX Autotaxin
  • LPC lysophosphatidylcholine
  • LPA bioactive lipid lysophosphatidic acid
  • LPA Receptors 1-6, LPAR1-6 six GPCRs
  • LPA acting on LPAR1
  • LPA induces lung fibroblast migration, proliferation and differentiation; modulates epithelial and endothelial barrier function; and promotes lung epithelial cell apoptosis
  • ATX inhibition, LPAR1 gene deletion and selective LPAR1 antagonists have been shown to be effective in pre-clinical models of fibrosis of the lung and skin (Tager A M, 2008; Swaney J, 2010, Casetelino F V, 2016).
  • Idiopathic Pulmonary Fibrosis (IPF) patients LPA levels in bronchoalveolar lavage fluid are increased (Tager et al., 2008, Nat. Med.) and increased concentrations of ATX were detected in human fibrotic lung tissue. (Oikonomou et al., 2012, AJRCMB). LPA levels are elevated in the exhaled breath condensate of IPF subjects (Montesi et al., 2014_BMCPM), and LPC is increased 2-fold in serum of stable IPF patients (Rindlisbacher et al., 2018, Resp. Res.).
  • ATX levels and/or increased levels of LPA, altered LPA receptor expression, and altered responses to LPA may affect a number of pathophysiological conditions related to ATX-LPA signaling.
  • Interstitial Lung Diseases are characterized by inflammation and fibrosis of the interstitium, the tissue and space between the air sacs of the lung (du Bois, Nat. Rev. Drug Discov. 2010, 9, 129-140).
  • An ILD may occur when an injury to the lungs triggers an abnormal healing response.
  • ILDs thus also include Progressive Fibrosing Interstitial Lung Diseases (PFILDs) wherein the response to lung injury becomes progressive, self-sustaining and independent of the original clinical association or trigger.
  • PFILDs Progressive Fibrosing Interstitial Lung Diseases
  • the most prominent PFs ILDs are Idiopathic Pulmonary Fibrosis (IPF) and Systemic Sclerosis-ILD (SSc-ILD).
  • IPF interstitial pneumonia
  • SSc Systemic Sclerosis
  • scleroderma is an immune-mediated rheumatic disease of complex aetiology. It is a multi-organ, heterogenic disease characterized by extensive fibrosis, vasculopathy and autoantibodies against various cellular antigens with high mortality. It is a rare disorder, an orphan disease with high unmet medical need.
  • the early clinical signs of SSc can be varied. Raynaud's phenomenon and gastro-oesophageal reflux are often present early in the disease (Rongioletti F, et al., J Eur Acad Dermatol Venereol 2015; 29: 2399-404).
  • SSc patients are classified into two major disease subsets: diffuse cutaneous systemic sclerosis, and limited cutaneous systemic sclerosis (LeRoy E C, et al., J Rheumatol 1988; 15:202-5).
  • SSc is currently considered as a manifestation of dysregulated or dysfunctional repair of connective tissue to injury (Denton C P et al., Lancet 2017; 390: 1685-99).
  • ATX inhibitors of various structural classes are reviewed in D. Castagna et al. (J. Med. Chem. 2016, 59, 5604-5621).
  • WO2014/139882 discloses compounds that are inhibitors of ATX, having the generalized structural formula
  • Example 2 therein is further disclosed in N. Desroy, et al (J. Med. Chem. 2017, 60, 3580-3590 as example 11) as a first-in-class ATX inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis.
  • ATX inhibitor BI-2545 (example 19) is disclosed that significantly reduces LPA levels in vivo.
  • the present invention provides novel pyridazines that are surprisingly potent inhibitors of autotaxin (Assay A), further characterized by
  • Compounds of the present invention are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signalling participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
  • ATX-LPA signalling has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression and tumor metastasis.
  • ATX is a soluble plasma protein, which is active in heparinized whole blood. Its substrate LPC is highly abundant, its concentration being in the ⁇ M range. Therefore, a whole blood assay at physiological substrate concentrations is a highly relevant assay, predictive for the efficacy of ATX inhibitors in vivo.
  • LPA reduction in vivo is determined by measuring the plasma concentration of LPA after oral dosage of the compounds of the present invention.
  • LPA is a very strong bioactive lipid, which efficiently activates downstream pathways via the LPA-receptors 1-6 in a concentration dependent manner.
  • the pronounced and sustained blockage of the LPA formation via ATX inhibition is assessed by measuring the extent of LPA reduction 8 hours after compound dosage.
  • a high reduction of plasma LPA at 8 h is therefore highly indicative for efficacy and sustained duration of action in vivo as well as sustained target engagement of the LPA receptors.
  • the present invention provides novel compounds according to formula (I)
  • Another embodiment of the present invention relates to a compound of formula (I), wherein A is pyridyl substituted with one or two members of the group consisting of F, F 1-3 -fluoro-C 1 -alkyl; and substituents E and K are defined as in the preceding embodiment.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein A is pyridyl substituted with one or two members of the group consisting of F, F 2 HC and F 3 C; and substituents E and K are defined as in the preceding embodiment.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group consisting of
  • Another embodiment of the present invention relates to a compound of formula (I), wherein E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of F, F 2 HC, and F 3 C; and substituents A and K are defined as in any of the preceding embodiments.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of F and F 3 C; and substituents A and K are defined as in any of the preceding embodiments.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein E is selected from the group consisting of
  • a further embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I according to the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • a further embodiment relates to a compound of formula (I) according to the present invention, for use as a medicament.
  • C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • groups like HO, H 2 N, (O)S, (O) 2 S, NC (cyano), HOOC, F 3 C or the like the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself.
  • aryl-C 1-3 -alkyl means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • aryl-C 1-3 -alkyl means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.
  • 3-carboxypropyl-group represents the following substituent:
  • the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
  • C 1-n -alkyl wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • C 1-5 -alkyl embraces the radicals H 3 C—, H 3 C—CH 2 —, H 3 C—CH 2 —CH 2 —, H 3 C—CH(CH 3 )—, H 3 C—CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH(CH 3 )—, H 3 C—CH(CH 3 )—CH 2 —, H 3 C—C(CH 3 ) 2 —, H 3 C—CH 2 —CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH(CH 3 )—, H 3 C—CH 2 —CH(CH 3 )—CH 2 —, H 3 C—CH(CH 3 )—CH 2 —CH 2 —, H 3 C—CH(CH 3 )—CH 2 —CH 2 —, H 3 C—CH 2 —C(CH 3 ) 2 —, H 3 C—C(CH 3 ) 2 —CH 2 —, H 3 C—CH(
  • halogen denotes chlorine, bromine, iodine, and fluorine.
  • halo added to an “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H 2 FC—, HF 2 C—, F 3 C—.
  • phenyl refers to the radical of the following ring
  • pyridinyl refers to the radical of the following ring
  • pyridazine refers to the following ring
  • oxetanyl refers to the following ring
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents.
  • Enantiomerically pure compounds of the present invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and/or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound forms a salt or a complex with an acid or a base.
  • acids forming a pharmaceutically acceptable salt with a parent compound containing a basic moiety include mineral or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.
  • Examples for cations and bases forming a pharmaceutically acceptable salt with a parent compound containing an acidic moiety include Na + , K + , Ca 2+ , Mg 2+ , NH 4 + , L-arginine, 2,2′-iminobisethanol, L-lysine, N-methyl-D-glucamine or tris(hydroxymethyl)-aminomethane.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoroacetate salts
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the present invention.
  • 5 nM recombinant ATX (Cayman Chemicals) was supplemented to 50 mM Tris buffer (pH 8.0) containing 3 mM KCl, 1 mM CaCl 2 ), 1 mM MgCl2 0.14 mM NaCl, and 0.1% bovine serum albumin.
  • Test compounds were dissolved in DMSO and tested in the range of 0.1 nM to 10 ⁇ M.
  • the enzymatic reaction (22.5 ⁇ L) was started by addition of 2.5 ⁇ L 10 ⁇ M 18:1 LPC (Avanti Lipids, Alabaster, Ala., USA).
  • test substance was solubilized in 0.5% natrosol supplemented with 0.015% Tween 80 for oral application to rats at a dose of 5 mg/kg.
  • Blood samples were collected before compound administration and 8 hours post application on ice using EDTA as coagulation agent. Subsequently, plasma was prepared by centrifugation and stored until analysis at ⁇ 20° C.
  • LPAs from plasma samples were extracted by using the procedure described by Scherer et al. (Clinical chemistry 2009, 55, 1218-22). 35 ⁇ L of heparinized plasma was mixed with 200 ⁇ L 40 mM disodium hydrogen phosphate buffer containing 30 mM citric acid (pH 4) and 1 ⁇ M 17:0 LPA (internal standard). Subsequently, 500 ⁇ L butanol was added and shaken vigorously for 10 min. Samples were centrifuged afterwards at 4000 rpm, 4° C., for 10 min. 500 ⁇ L of the organic upper phase was transferred to a fresh 96-deep-well plate and evaporated with a gentle nitrogen flow of 15 psi for 45 min. The resultant residual was dissolved in 100 ⁇ L ethanol prior to LC-MS analysis.
  • a Triple Quad 6500 (ABSciex, Toronto, Canada) was equipped with an Agilent 1290 LC system (Agilent, Santa Clara, Calif.) a CTC autosampler and an Atlantis 50 ⁇ 2.1-mm, 3- ⁇ m HILIC LC column (Waters, Elstree, UK).
  • Eluent A contained 0.2% formic acid and 50 mM ammonium formate in water
  • eluent B consisted of 0.2% formic acid in acetonitrile.
  • the LC gradient started from 95% solvent B and decreased within 1.5 min to 75% and within 0.2 min to 50% solvent B, with a further increase in the flow rate from 500 to 700 ⁇ L ⁇ min ⁇ 1 .
  • LPA depletion in percent was calculated based on the baseline LPA levels before test compound application.
  • the sum of LPA refers to the species 16:0; 18:0; 18:1; 18:2 and 20:4
  • the present invention is directed to compounds of general formula (I) which are useful in the prevention and/or treatment of a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA, including but not limited to the treatment and/or prevention of inflammatory conditions, fibrotic diseases, conditions of the respiratory system, renal conditions, liver conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection and conditions of the nervous system.
  • the compounds of general formula (I) are useful for the prevention and/or treatment of inflammatory conditions including, but not limited to Sjögren's syndrome, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematousus, inflammatory bowel disease, inflammatory airways diseases such as chronic obstructive pulmonary disease (COPD) and chronic asthma; fibrotic diseases including, but not limited to interstitial lung diseases (ILDs) including Progressive Fibrosing Interstitial Lung Diseases (PFILDs) such as idiopathic pulmonary fibrosis (IPF), and SSC-ILD, familial interstitial lung disease myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, collagen vascular disease including Systemic Sclerosis (SSc) and encapsulating peritonitis; conditions of the respiratory system including, but not limited to diffuse parenchymal lung diseases of different etiologies including iatrogenic drug
  • the present invention relates to a compound of general formula (I) for use as a medicament.
  • the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA.
  • the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA, including but not limited to inflammatory conditions, fibrotic diseases, conditions of the respiratory system, renal conditions, liver conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection and conditions of the nervous system.
  • a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA including but not limited to inflammatory conditions, fibrotic diseases, conditions of the respiratory system, renal conditions, liver conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection and conditions of the nervous system.
  • the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of inflammatory conditions including, but not limited to Sjögren's syndrome, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematousus, inflammatory bowel disease, inflammatory airways diseases such as chronic obstructive pulmonary disease (COPD) and chronic asthma; fibrotic diseases including, but not limited to interstitial lung diseases (ILDs) including Progressive Fibrosing Interstitial Lung Diseases (PFILDs) such as idiopathic pulmonary fibrosis (IPF), and SSC-ILD, familial interstitial lung disease myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, collagen vascular disease including Systemic Sclerosis (SSc) and encapsulating peritonitis; conditions of the respiratory system including, but not limited to diffuse parenchymal lung diseases of different eti
  • the present invention relates to a compound of general formula (I) for use in the treatment and/or prevention of above mentioned diseases and conditions.
  • the present invention relates to the use of a compound of general formula (I) for the preparation of a medicament for the treatment and/or prevention of above mentioned diseases and conditions.
  • the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula (I) to a human being.
  • Suitable preparations for administering the compounds of formula (I) will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • Compounds according to the present invention can be combined with other treatment options known to be used in the art so that at least two active compounds in effective amounts are used to treat an indication for which the present invention is useful at the same time.
  • combination therapy preferably includes the administration of two active compounds to the patient at the same time, it is not necessary that the compounds be administered to the patient at the same time, although effective amounts of the individual compounds will be present in the patient at the same time.
  • Compounds according to the present invention may be administered with one or more combination partners as otherwise described herein.
  • the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to treatment with one or more anti-inflammatory molecules from the list consisting of IL6 modulators, anti-IL6R modulators and IL13/IL-4 JAKi modulators.
  • the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to treatment with one or more anti-fibrotic molecules from the list consisting of CB2 agonists, TGF modulators, FGFR modulators, VEGFR inhibitors, PDGFR inhibitors, FGF modulators, avP6 integrin modulators, anti-CTGF antibodies, ROCK2 inhibitors, rhPTX-2 (Pentraxin-2), JNK1 inhibitors, LOXL2 inhibitors, Galectin3 inhibitors, MK2 inhibitors, Wnt pathway inhibitors, TGFR inhibitors, PDE4 modulators, TRPA1 inhibitors and microRNA modulators.
  • CB2 agonists CB2 agonists
  • TGF modulators FGFR modulators
  • VEGFR inhibitors VEGFR inhibitors
  • PDGFR inhibitors PDGFR inhibitors
  • FGF modulators avP6 integrin modulators
  • anti-CTGF antibodies
  • the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to nintedanib.
  • the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to pirfenidone.
  • the compounds according to the present invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.
  • Compounds of general formula (I) may be prepared by palladium-mediated Buchwald reactions or copper-mediated Ullmann reactions of pyridazinyl halogenides or triflates (II) with amines (III) wherein X is a leaving group which for example denotes Cl, Br, I or OTf (triflate).
  • Compounds of general formula (I) may alternatively be prepared by palladium-mediated Buchwald reactions or copper-mediated Ullmann reactions of pyridazinyl halogenides or triflates (VIII) with alcohols (VII) wherein X is a leaving group which for example denotes Cl, Br, I or OTf (triflate).
  • ambient temperature and “room temperature” are used interchangeably and designate a temperature of about 20° C.
  • Pd 2 (dba) 3 Tirs(dibenzylideneacetone)dipalladium(0) Pd/C palladium on activated carbon psi pounds per square inch PTK phase-transfer-cartridge RP reversed phase RT room temperature (about 20° C.) Rt retention time RUPHOS chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy- pallada- 1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)- cycle methyl-t-butyl ether adduct sat.
  • tert-Butyl 2-(4-cyanophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (example V.2) is diluted with 5 mL DCM and 300 ⁇ L (3.89 mmol) TFA is added. The reaction mixture is stirred at RT for 2 h and concentrated under reduced pressure to afford 0.26 g of the product.
  • reaction mixture is stirred under carbon monoxide atmosphere (5 bar) at 50° C. for 15 h.
  • the reaction mixture is filtered and the filtrate is evaporated in vacuo to provide the product.
  • the solution is degassed a few times.
  • the reaction solution is stirred at 80° C. overnight.
  • the reaction mixture is diluted with water and is extract with EE.
  • the organic layer is dried with MgSO 4 , is filtered over charcoal and is evaporated.
  • the residue is purified by HPLC to afford 15 mg of the product.
  • the solution is degassed a few times.
  • the reaction solution is stirred at 80° C. for 2 h.
  • another 481 mg (0.50 mmol) sodium-tert-butoxide are added and the reaction solution is stirred at 100° C. overnight.
  • the reaction solution is filtered and purified by HPLC to afford 14 mg of the product.
  • Analytical column Stable Bond (Agilent) 1.8 ⁇ m; 3.0 ⁇ 30 mm; column temperature: 60° C.
  • Analytical column XBridge (Waters) C18_3.0 ⁇ 30 mm_2.5 ⁇ m; column temperature: 60° C.
  • Analytical column Sunfire (Waters) 2.5 ⁇ m; 3.0 ⁇ 30 mm; column temperature: 60° C.

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Abstract

The present invention relates to novel pyridazines, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment and/or prevention of diseases and disorders mediated by Autotaxin.

Description

    FIELD OF THE INVENTION
  • The present invention relates to novel pyridazines, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment and/or prevention of diseases and disorders mediated by Autotaxin.
    • BACKGROUND OF THE INVENTION
  • Autotaxin (ATX; ENPP2) is a secreted enzyme responsible for hydrolysing lysophosphatidylcholine (LPC) to the bioactive lipid lysophosphatidic acid (LPA) through its lysophospholipase D activity. In turn, LPA exerts its effects by interacting with six GPCRs (LPA Receptors 1-6, LPAR1-6) (Houben A J, 2011). ATX-LPA signalling has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression and tumor metastasis. For example, LPA, acting on LPAR1, induces lung fibroblast migration, proliferation and differentiation; modulates epithelial and endothelial barrier function; and promotes lung epithelial cell apoptosis (Budd, 2013). ATX inhibition, LPAR1 gene deletion and selective LPAR1 antagonists have been shown to be effective in pre-clinical models of fibrosis of the lung and skin (Tager A M, 2008; Swaney J, 2010, Casetelino F V, 2016).
  • In Idiopathic Pulmonary Fibrosis (IPF) patients, LPA levels in bronchoalveolar lavage fluid are increased (Tager et al., 2008, Nat. Med.) and increased concentrations of ATX were detected in human fibrotic lung tissue. (Oikonomou et al., 2012, AJRCMB). LPA levels are elevated in the exhaled breath condensate of IPF subjects (Montesi et al., 2014_BMCPM), and LPC is increased 2-fold in serum of stable IPF patients (Rindlisbacher et al., 2018, Resp. Res.).
  • Therefore, increased ATX levels and/or increased levels of LPA, altered LPA receptor expression, and altered responses to LPA may affect a number of pathophysiological conditions related to ATX-LPA signaling.
  • Interstitial Lung Diseases (ILDs) are characterized by inflammation and fibrosis of the interstitium, the tissue and space between the air sacs of the lung (du Bois, Nat. Rev. Drug Discov. 2010, 9, 129-140). An ILD may occur when an injury to the lungs triggers an abnormal healing response. ILDs thus also include Progressive Fibrosing Interstitial Lung Diseases (PFILDs) wherein the response to lung injury becomes progressive, self-sustaining and independent of the original clinical association or trigger. The most prominent PFs ILDs are Idiopathic Pulmonary Fibrosis (IPF) and Systemic Sclerosis-ILD (SSc-ILD). IPF is a chronic fibrotic irreversible and ultimately fatal lung disease characterized by a progressive fibrosis in the interstitium in the lung, leading to a decreasing lung volume and progressive pulmonary insufficiency. IPF is also characterized by a specific histopathologic pattern known as usual interstitial pneumonia (UIP) (Raghu et al, Am. J. Respir. Crit. Care Med. 183: 788-824).
  • Systemic Sclerosis (SSc) also called scleroderma is an immune-mediated rheumatic disease of complex aetiology. It is a multi-organ, heterogenic disease characterized by extensive fibrosis, vasculopathy and autoantibodies against various cellular antigens with high mortality. It is a rare disorder, an orphan disease with high unmet medical need. The early clinical signs of SSc can be varied. Raynaud's phenomenon and gastro-oesophageal reflux are often present early in the disease (Rongioletti F, et al., J Eur Acad Dermatol Venereol 2015; 29: 2399-404). Some patients present with inflammatory skin disease, puffy and swollen fingers, musculoskeletal inflammation, or constitutional manifestations such as fatigue. Excess collagen deposition in the skin of patients makes the skin thick and tough. In some patients, organ-based manifestations of the disease, like lung fibrosis, pulmonary arterial hypertension, renal failure or gastrointestinal complication is observed. In addition, one of the most common manifestations of immune involvement is the presence of abnormal levels of autoimmune antibodies to the nucleus of one's own cells (anti-nuclear antibodies or ANA) that are seen in nearly everyone with SSc (Guiducci S et al., Isr Med Assoc J 2016; 18: 141-43). ILD and pulmonary arterial hypertension (PAH) are the most frequent causes of death in patients of SSc (Tyndall A J et al. Ann Rheum Dis 2010; 69: 1809-15).
  • SSc patients are classified into two major disease subsets: diffuse cutaneous systemic sclerosis, and limited cutaneous systemic sclerosis (LeRoy E C, et al., J Rheumatol 1988; 15:202-5). Three clinical features-excessive fibrosis (scarring), vasculopathy, and autoimmunity-appear to underlie the processes that result in the different manifestations that characterize SSc. SSc is currently considered as a manifestation of dysregulated or dysfunctional repair of connective tissue to injury (Denton C P et al., Lancet 2017; 390: 1685-99).
  • It is therefore desirable to provide potent ATX inhibitors.
  • ATX inhibitors of various structural classes are reviewed in D. Castagna et al. (J. Med. Chem. 2016, 59, 5604-5621). WO2014/139882 discloses compounds that are inhibitors of ATX, having the generalized structural formula
  • Figure US20230100516A1-20230330-C00001
  • Example 2 therein is further disclosed in N. Desroy, et al (J. Med. Chem. 2017, 60, 3580-3590 as example 11) as a first-in-class ATX inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis. In C. Kuttruff, et al. (ACS Med. Chem. Lett. 2017, 8, 1252-1257) ATX inhibitor BI-2545 (example 19) is disclosed that significantly reduces LPA levels in vivo.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention provides novel pyridazines that are surprisingly potent inhibitors of autotaxin (Assay A), further characterized by
      • high potency in human whole blood (Assay B), and
      • significant reduction in the plasma concentration levels of LPA in vivo over several hours (Assay C).
  • Compounds of the present invention are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signalling participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease. ATX-LPA signalling has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression and tumor metastasis.
  • Compounds of the invention are superior to those disclosed in the prior art in terms of the combination of the following parameters:
      • potency as inhibitors of ATX,
      • potency as inhibitors of ATX in human whole blood,
      • reducing the plasma concentration levels of LPA in vivo over several hours
  • ATX is a soluble plasma protein, which is active in heparinized whole blood. Its substrate LPC is highly abundant, its concentration being in the μM range. Therefore, a whole blood assay at physiological substrate concentrations is a highly relevant assay, predictive for the efficacy of ATX inhibitors in vivo.
  • LPA reduction in vivo is determined by measuring the plasma concentration of LPA after oral dosage of the compounds of the present invention. LPA is a very strong bioactive lipid, which efficiently activates downstream pathways via the LPA-receptors 1-6 in a concentration dependent manner. The pronounced and sustained blockage of the LPA formation via ATX inhibition is assessed by measuring the extent of LPA reduction 8 hours after compound dosage. A high reduction of plasma LPA at 8 h is therefore highly indicative for efficacy and sustained duration of action in vivo as well as sustained target engagement of the LPA receptors.
  • Compounds of the present invention differ structurally from examples 2 and 12 in WO2014/139882 and example 19 in ACS Med. Chem. Lett. 2017, 8, 1252-1257, in that they contain a central pyridazine core with substituents in the 3- and 6-positions. This structural difference unexpectedly leads to a superior combination of (i) inhibition of ATX, (ii) inhibition of ATX in human whole blood, and (iii) reduced plasma concentration levels of LPA in vivo over several hours.
  • Consequently, compounds of the present invention demonstrate high in vivo target engagement and can be expected to have higher efficacy in humans.
  • The present invention provides novel compounds according to formula (I)
  • Figure US20230100516A1-20230330-C00002
      • wherein
      • A is pyridyl substituted with one or two members of the group consisting of fluoro and F1-7-fluoro-C1-3-alkyl;
      • E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of fluoro and F1-7-fluoro-C1-3-alkyl;
      • K is selected from the group consisting of
  • Figure US20230100516A1-20230330-C00003
      • R3 is selected from the group consisting of R4(O)C—, oxetanyl, methyl, R5(O)C(CH3)N— and R5(O)CHN—;
      • R4 is methyl;
      • R5 is methyl.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein A is pyridyl substituted with one or two members of the group consisting of F, F1-3-fluoro-C1-alkyl; and substituents E and K are defined as in the preceding embodiment.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein A is pyridyl substituted with one or two members of the group consisting of F, F2HC and F3C; and substituents E and K are defined as in the preceding embodiment.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group consisting of
  • Figure US20230100516A1-20230330-C00004
  • and substituents A and K are defined as in any of the preceding embodiments.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of F, F2HC, and F3C; and substituents A and K are defined as in any of the preceding embodiments.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of F and F3C; and substituents A and K are defined as in any of the preceding embodiments.
  • Another embodiment of the present invention relates to a compound of formula (I), wherein E is selected from the group consisting of
  • Figure US20230100516A1-20230330-C00005
  • and substituents A and K are defined as in any of the preceding embodiments.
  • Preferred is a compound of formula (I), according to the present invention, selected from the group consisting of
  • Figure US20230100516A1-20230330-C00006
    Figure US20230100516A1-20230330-C00007
    Figure US20230100516A1-20230330-C00008
    Figure US20230100516A1-20230330-C00009
    Figure US20230100516A1-20230330-C00010
  • A further embodiment relates to a pharmaceutical composition comprising at least one compound of formula I according to the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • A further embodiment relates to a compound of formula (I) according to the present invention, for use as a medicament.
    • Used Terms and Definitions
  • Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
  • In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general in groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C1-3-alkyl” means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.
  • For example, the term “3-carboxypropyl-group” represents the following substituent:
  • Figure US20230100516A1-20230330-C00011
  • wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:
  • Figure US20230100516A1-20230330-C00012
  • The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • The term “substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
  • The term “C1-n-alkyl”, wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.
  • The term “halogen” denotes chlorine, bromine, iodine, and fluorine. By the term “halo” added to an “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC—, HF2C—, F3C—.
  • The term phenyl refers to the radical of the following ring
  • Figure US20230100516A1-20230330-C00013
  • The term pyridinyl refers to the radical of the following ring
  • Figure US20230100516A1-20230330-C00014
  • The term pyridazine refers to the following ring
  • Figure US20230100516A1-20230330-C00015
  • The term oxetanyl refers to the following ring
  • Figure US20230100516A1-20230330-C00016
  • Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents.
  • Enantiomerically pure compounds of the present invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and/or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.
  • Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.
  • The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • As used herein, “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound forms a salt or a complex with an acid or a base. Examples of acids forming a pharmaceutically acceptable salt with a parent compound containing a basic moiety include mineral or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.
  • Examples for cations and bases forming a pharmaceutically acceptable salt with a parent compound containing an acidic moiety include Na+, K+, Ca2+, Mg2+, NH4 +, L-arginine, 2,2′-iminobisethanol, L-lysine, N-methyl-D-glucamine or tris(hydroxymethyl)-aminomethane.
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoroacetate salts) also comprise a part of the present invention.
    • BIOLOGICAL ASSAYS
  • The biological activity of compounds was determined by the following methods:
    • Assay A: Biochemical ATX Assay
  • 5 nM recombinant ATX (Cayman Chemicals) was supplemented to 50 mM Tris buffer (pH 8.0) containing 3 mM KCl, 1 mM CaCl2), 1 mM MgCl2 0.14 mM NaCl, and 0.1% bovine serum albumin. Test compounds were dissolved in DMSO and tested in the range of 0.1 nM to 10 μM. The enzymatic reaction (22.5 μL) was started by addition of 2.5 μL 10 μM 18:1 LPC (Avanti Lipids, Alabaster, Ala., USA). After 2-h incubation at room temperature, the reaction was stopped by addition of 20 μL water containing 500 nM 20:4 LPA as internal standard and 100 μL 1-butanol for extracting LPA. Subsequently, the plates were centrifuged at 4000 rpm, 4° C., for 2 min. The resultant upper butanol phase was directly used for injection at a RapidFire system (Agilent).
  • The RapidFire autosampler was coupled to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). This system was equipped with a 10-μL loop, 5-μL Waters Atlantis HILIC cartridge (Waters, Elstree, UK), 90% acetonitrile containing 10 mM ammonium acetate as eluent A and 40% acetonitrile containing 10 mM ammoniumacetate as eluent B. For details see (Bretschneider et al., SLAS Discovery, 2017). 1 The MS was operated in negative mode with a source temperature of 550° C., curtain gas=35, gas 1=65, and gas 2=80. The following transitions and MS parameters (DP: declustering potential and CE: collision energy) for the respective LPAs were determined: 18:1 LPA at 435.2/152.8, DP=−40, CE=−28 and 20:4 LPA at 457.2/152.8, DP=−100, CE=−27).
  • The formation of 18:1 LPA was monitored and evaluated as ratio to 20:4 LPA.
  • TABLE 1
    Biological data for compounds for the
    invention as obtained in Assay A.
    Human ATX LPA
    Example IC50 [nM]
    1.1 3.4
    1.2 2.9
    1.3 1.5
    1.4 3.3
    1.5 3.9
    1.6 6.5
    1.7 1.6
    2.1 2.3
    2.2 3.0
    2.3 2.2
    2.4 1.9
    2.5 2.5
    2.6 1.8
    2.7 1.9
    2.8 2.0
    2.9 3.7
    2.10 1.8
    2.11 3.8
    2.12 3.5
    2.13 4.0
    2.14 4.4
    2.15 2.2
    2.16 10.4
    2.17 5.2
    2.18 9.2
    2.19 2.4
    2.20 2.9
    2.21 2.4
    2.22 6.2
    2.23 3.9
    3 2.9
    4 8.6
    5 7.0
    — —
    — —
    — —
  • TABLE 2
    Biological data for prior art compounds (examples
    2 and 12 in WO2014/139882) as obtained in Assay A.
    Example in Human ATX LPA
    WO2014/139882 IC50 [nM]
    2 5
    12 2
  • TABLE 3
    Biological data for prior art compounds (example 19 in ACS Med.
    Chem. Lett. 2017, 8, 1252-1257) as obtained in Assay A.
    Example in ACS Med. Chem. Human ATX LPA
    Lett. 2017, 8, 1252-1257 IC50 [nM]
    19 2.2
    • Assay B: Whole-Blood ATX Assay
  • 45 μL human whole-blood was supplemented with 5 μL of the test compound, dissolved in phosphate-buffered saline (concentration range 0.12 nM-100 μM). This mixture was incubated for 1 h at 37° C. and stopped by addition of 100 μL 40 mM disodium hydrogen phosphate buffer containing 30 mM citric acid (pH 4) and 1 μM 17:0 LPA (internal standard). LPA was extracted by addition of 500 μL 1-butanol, followed by 10-min centrifugation at 4000 rpm, 4° C. From the resultant organic supernatant, a 200 μL aliquot was transferred into a 96-deep-well plate and transferred to the RapidFire-based MS/MS measurement.
  • The RapidFire autosampler was coupled to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). This system was equipped with a 10-μL loop, 5-μL Waters Atlantis HILIC cartridge (Waters, Elstree, UK), 90% acetonitrile containing 10 mM ammonium acetate as eluent A and 40% acetonitrile containing 10 mM ammoniumacetate as eluent B. For details see (Bretschneider et al., SLAS Discovery, 2017, 22, 425-432). The MS was operated in negative mode with a source temperature of 550° C., curtain gas=35, gas 1=65, and gas 2=80. The following transitions and MS parameters (DP: declustering potential and CE: collision energy) for the respective LPAs were determined: 18:2 LPA at 433.2/152.8, DP=−150, CE=−27 and 17:0 LPA at 423.5/152.8, DP=−100.
  • The formation of 18:2 LPA was monitored and evaluated as ratio to 17:0 LPA.
  • TABLE 4
    Biological data for compounds for the
    invention as obtained in Assay B.
    Human whole blood LPA
    Example IC50 [nM]
    1.1 1.7
    1.2 1.0
    1.3 1.6
    1.4 2.8
    1.5 2.0
    1.6 8.7
    1.7 12.4
    2.1 4.7
    2.2 4.7
    2.3 4.4
    2.4 6.8
    2.5 4.0
    2.6 3.2
    2.7 7.0
    2.8 2.4
    2.9 4.1
    2.10 2.2
    2.11 4.0
    2.12 4.3
    2.13 4.1
    2.14 2.8
    2.15 9.3
    2.16 5.1
    2.17 3.5
    2.18 4.1
    2.19 2.0
    2.20 3.7
    2.21 1.4
    2.22 3.9
    2.23 3.6
    3 1.9
    4 7.1
    5 7.5
    — —
    — —
    — —
  • TABLE 5
    Biological data for prior art compounds (examples
    2 and 12 in WO2014/139882) as obtained in Assay B.
    Example in Human whole blood LPA
    WO2014/139882 IC50 [nM]
    2 370
    12 50
  • TABLE 6
    Biological data for prior art compounds (example 19 in ACS Med.
    Chem. Lett. 2017, 8, 1252-1257) as obtained in Assay B.
    Example in ACS Med. Chem. Lett. Human whole blood
    2017, 8, 1252-1257 LPA IC50 [nM]
    19 29
    • Assay C: In Vivo
  • The test substance was solubilized in 0.5% natrosol supplemented with 0.015% Tween 80 for oral application to rats at a dose of 5 mg/kg. Blood samples were collected before compound administration and 8 hours post application on ice using EDTA as coagulation agent. Subsequently, plasma was prepared by centrifugation and stored until analysis at −20° C.
  • LPAs from plasma samples were extracted by using the procedure described by Scherer et al. (Clinical chemistry 2009, 55, 1218-22). 35 μL of heparinized plasma was mixed with 200 μL 40 mM disodium hydrogen phosphate buffer containing 30 mM citric acid (pH 4) and 1 μM 17:0 LPA (internal standard). Subsequently, 500 μL butanol was added and shaken vigorously for 10 min. Samples were centrifuged afterwards at 4000 rpm, 4° C., for 10 min. 500 μL of the organic upper phase was transferred to a fresh 96-deep-well plate and evaporated with a gentle nitrogen flow of 15 psi for 45 min. The resultant residual was dissolved in 100 μL ethanol prior to LC-MS analysis.
    • LC-MS Method for the Analytic of In Vivo Samples
  • A Triple Quad 6500 (ABSciex, Toronto, Canada) was equipped with an Agilent 1290 LC system (Agilent, Santa Clara, Calif.) a CTC autosampler and an Atlantis 50×2.1-mm, 3-μm HILIC LC column (Waters, Elstree, UK). Eluent A contained 0.2% formic acid and 50 mM ammonium formate in water, whereas eluent B consisted of 0.2% formic acid in acetonitrile. The LC gradient started from 95% solvent B and decreased within 1.5 min to 75% and within 0.2 min to 50% solvent B, with a further increase in the flow rate from 500 to 700 μL·min−1. At 1.8 min, solvent B was set back to 95% and stayed constant for 0.7 min for re-equilibration of the column. The following LPA species were monitored (DP: declustering potential and CE: collision energy): 16:0 LPA at 409.2/152.8, DP=−150, CE=−28; 18:0 LPA at 437.3/152.8, DP=−60, CE=−28; 18:1 LPA at 435.2/152.8, DP=−40, CE=−28; 18:2 LPA at 433.2/152.8, DP=−150, CE=−28; 20:4 LPA at 457.2/152.8, DP=−100, CE=−29 and 17:0 LPA at 423.5/152.8, DP=−100, CE=−36. LPA depletion in percent was calculated based on the baseline LPA levels before test compound application. The sum of LPA refers to the species 16:0; 18:0; 18:1; 18:2 and 20:4
  • TABLE 7
    Biological data for compounds for the
    invention as obtained in Assay C.
    Example LPA reduction at 8 h [%]
    1.1 96.5
    1.2 96.7
    2.2 94.1
    2.5 95.9
    2.12 94.6
    3 99.9
  • TABLE 8
    Biological data for prior art compounds (examples
    2 and 12 in WO2014/139882) as obtained in Assay C.
    Example LPA reduction at 8 h [%]
    2 58.1
    12 60.3
  • TABLE 9
    Biological data for prior art compound (example 19 in ACS Med.
    Chem. Lett. 2017, 8, 1252-1257) as obtained in Assay C.
    Example LPA reduction at 8 h [%]
    19 40.7
    • Method of Treatment
  • The present invention is directed to compounds of general formula (I) which are useful in the prevention and/or treatment of a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA, including but not limited to the treatment and/or prevention of inflammatory conditions, fibrotic diseases, conditions of the respiratory system, renal conditions, liver conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection and conditions of the nervous system. The compounds of general formula (I) are useful for the prevention and/or treatment of inflammatory conditions including, but not limited to Sjögren's syndrome, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematousus, inflammatory bowel disease, inflammatory airways diseases such as chronic obstructive pulmonary disease (COPD) and chronic asthma; fibrotic diseases including, but not limited to interstitial lung diseases (ILDs) including Progressive Fibrosing Interstitial Lung Diseases (PFILDs) such as idiopathic pulmonary fibrosis (IPF), and SSC-ILD, familial interstitial lung disease myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, collagen vascular disease including Systemic Sclerosis (SSc) and encapsulating peritonitis; conditions of the respiratory system including, but not limited to diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), renal conditions including, but not limited to acute kidney injury and chronic renal disease with and without proteinuria including EndStage Renal Disease (ESRD, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases as well as acute and chronic kidney transplant rejection; liver conditions including, but not limited to liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, primary biliary cholangitis, non-alcoholic steatohepatitis and acute and chronic liver transplant rejection; vascular conditions including, but not limited to atherosclerosis, thrombotic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), endothelial dysfunction; cardiovascular conditions including, but not limited to acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage; cancer and cancer metastasis including, but not limited to breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof; ocular conditions including, but not limited to proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular oedema, central arterial/venous occlusion, traumatic injury, glaucoma; metabolic conditions including, but not limited to obesity, dyslipidaemia and diabetes; conditions of the nervous system including, but not limited to neuropathic pain, Alzheimer's disease, schizophrenia, neuro-inflammation (for example, astrogliosis), peripheral and/or autonomic (diabetic) neuropathies.
  • Accordingly, the present invention relates to a compound of general formula (I) for use as a medicament.
  • Furthermore, the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA.
  • Furthermore, the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of a disease and/or condition associated with or modulated by ATX and/or the biological activity of LPA, including but not limited to inflammatory conditions, fibrotic diseases, conditions of the respiratory system, renal conditions, liver conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection and conditions of the nervous system.
  • Furthermore, the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of inflammatory conditions including, but not limited to Sjögren's syndrome, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematousus, inflammatory bowel disease, inflammatory airways diseases such as chronic obstructive pulmonary disease (COPD) and chronic asthma; fibrotic diseases including, but not limited to interstitial lung diseases (ILDs) including Progressive Fibrosing Interstitial Lung Diseases (PFILDs) such as idiopathic pulmonary fibrosis (IPF), and SSC-ILD, familial interstitial lung disease myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, collagen vascular disease including Systemic Sclerosis (SSc) and encapsulating peritonitis; conditions of the respiratory system including, but not limited to diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), renal conditions including, but not limited to acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases as well as acute and chronic kidney transplant rejection; liver conditions including, but not limited to liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, primary biliary cholangitis, non-alcoholic steatohepatitis and acute and chronic liver transplant rejection; vascular conditions including, but not limited to atherosclerosis, thrombotic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), endothelial dysfunction; cardiovascular conditions including, but not limited to acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage; cancer and cancer metastasis including, but not limited to breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof; ocular conditions including, but not limited to proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular oedema, central arterial/venous occlusion, traumatic injury, glaucoma; metabolic conditions including, but not limited to obesity, dyslipidaemia and diabetes; conditions of the nervous system including, but not limited to neuropathic pain, Alzheimer's disease, schizophrenia, neuro-inflammation (for example, astrogliosis), peripheral and/or autonomic (diabetic) neuropathies.
  • In a further aspect the present invention relates to a compound of general formula (I) for use in the treatment and/or prevention of above mentioned diseases and conditions.
  • In a further aspect the present invention relates to the use of a compound of general formula (I) for the preparation of a medicament for the treatment and/or prevention of above mentioned diseases and conditions.
  • In a further aspect of the present invention the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula (I) to a human being.
    • Pharmaceutical Compositions
  • Suitable preparations for administering the compounds of formula (I) will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
    • Combination Therapy
  • Compounds according to the present invention can be combined with other treatment options known to be used in the art so that at least two active compounds in effective amounts are used to treat an indication for which the present invention is useful at the same time. Although combination therapy preferably includes the administration of two active compounds to the patient at the same time, it is not necessary that the compounds be administered to the patient at the same time, although effective amounts of the individual compounds will be present in the patient at the same time. Compounds according to the present invention may be administered with one or more combination partners as otherwise described herein.
  • Accordingly, the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to treatment with one or more anti-inflammatory molecules from the list consisting of IL6 modulators, anti-IL6R modulators and IL13/IL-4 JAKi modulators. According to another aspect, the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to treatment with one or more anti-fibrotic molecules from the list consisting of CB2 agonists, TGF modulators, FGFR modulators, VEGFR inhibitors, PDGFR inhibitors, FGF modulators, avP6 integrin modulators, anti-CTGF antibodies, ROCK2 inhibitors, rhPTX-2 (Pentraxin-2), JNK1 inhibitors, LOXL2 inhibitors, Galectin3 inhibitors, MK2 inhibitors, Wnt pathway inhibitors, TGFR inhibitors, PDE4 modulators, TRPA1 inhibitors and microRNA modulators.
  • According to another aspect, the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to nintedanib.
  • According to another aspect, the present invention provides a compound of formula (I) according to any of the preceding embodiments, characterised in that the compound of formula (I) is administered in addition to pirfenidone.
    • Preparation
  • The compounds according to the present invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.
  • The general processes for preparing the compounds according to the invention will become apparent to the one skilled in the art studying the following schemes. Starting materials may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.
  • Figure US20230100516A1-20230330-C00017
  • Compounds of general formula (I) may be prepared by palladium-mediated Buchwald reactions or copper-mediated Ullmann reactions of pyridazinyl halogenides or triflates (II) with amines (III) wherein X is a leaving group which for example denotes Cl, Br, I or OTf (triflate).
  • Figure US20230100516A1-20230330-C00018
  • Compounds of general formula (I) may alternatively be prepared by palladium-mediated Buchwald reactions or copper-mediated Ullmann reactions of pyridazinyl halogenides or triflates (VIII) with alcohols (VII) wherein X is a leaving group which for example denotes Cl, Br, I or OTf (triflate).
    • EXAMPLES Experimental Part
  • The Examples that follow are intended to illustrate the present invention without restricting it. The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C.
  • Abreviations:
    9-BBN 9-Borabicyclo(3.3.1)nonane
    aq. aqueous
    ACN acetonitrile
    AcOH acetic acid
    Boc Tert-butyloxycarbonyl
    Brett 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-
    Phos tri-i-propyl-1,1′-biphenyl
    Brett methanesulfonato(2-dicyclohexylphosphino-3,6-dimeth-
    Phos oxy-2′,4′,6′-tri-i-propyl-1,1′-bi-
    Pd G3 phenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)
    ° C. degree Celsius
    CDI carbonyldiimidazole
    CO carbon monoxide
    conc. concentrated
    CPHOS [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethyl-
    Pd G3 amino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]
    palladium(II) methanesulfonate
    CuI copper (I) iodide
    Cy cyclohexane
    d day
    DCM dichloromethane
    DIPE diisopropyl ether
    DIPEA N,N-diisopropylethylamine
    DMA N,N-dimethylacetamide
    DMF N,N-dimethylformamide
    DMI 1.3-dimethyl-2-imidazolidinone
    DMSO dimethyl sulfoxide
    dppf 1,1′-Bis(diphenylphosphino)ferrocene
    EE ethyl acetate
    ESI-MS electrospray ionisation mass spectrometry
    EtOAc ethyl acetate
    EtOH ethanol
    Ex. example
    Eq equivalent
    g gramm
    h hour
    HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-
    yl)uranium hexafluorophosphate
    HCl hydrogen chloride
    HPLC high performance liquid chromatography
    JOSIPHOS {(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]eth-
    SL-J009- yldi-tert-butylphosphine}[2-(2′-amino-1,1′-bi-
    1 Pd G3 phenyl)]palladium(II) methanesulfonate
    K2CO3 potassium carbonate
    KH2PO4 potassium dihydrogenphosphate
    KHSO4 potassium hydrogensulfate
    LiBH4 lithium borohydride
    L liter
    L- lithium tri-sec-butylborohydride
    selectride
    M molar weight/g/mol
    MeOH methanol
    MgSO4 magnesium sulfate
    mg milligramm
    MgSO4 magnesium sulfate
    min minute
    mL milliliter
    mmol millimol
    N 1 mol/L
    NaB(OAc)3H sodium triacteoxyborohydride
    NaCl sodium chloride
    NaH sodium hydride
    NaHCO3 sodium bicarbonate
    NaOAc sodium acetate
    NaOH sodium hydroxide
    NaOtAm sodium tert-pentoxide
    NaOtBu sodium tert-butoxide
    Na2SO4 sodium sulfate
    Na2S2O3 sodium thiosulfate
    Na2SO4 sodium sulfate
    NEt3 triethylamine
    NH4Cl ammonium chloride
    NH4OH ammonium hydroxide
    NMP N-Methyl-2-pyrrolidone
    No. number
    Pd2(dba)3 Tirs(dibenzylideneacetone)dipalladium(0)
    Pd/C palladium on activated carbon
    psi pounds per square inch
    PTK phase-transfer-cartridge
    RP reversed phase
    RT room temperature (about 20° C.)
    Rt retention time
    RUPHOS chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-
    pallada- 1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-
    cycle methyl-t-butyl ether adduct
    sat. saturated
    SFC supercritical fluid chromatography
    tBME tert-butylmethylether
    TEA triethylamine
    TFA trifluoroacetic acid
    THF tetrahydrofuran
    Vol.-% volume percent
    XANTPHOS 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
    XPHOS (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-
    Pd G3 1,1′-biphenyl) [2-(2′-amino-1,1′-bi-
    phenyl)lpalladium(II) methanesulfonate
    X-Phos (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-
    1,1′-biphenyl)
    • Preparation of Starting Compounds Example I Example I.1
  • 3-{[6-(Difluoromethyl)pyridin-3-yl]methoxy}-6-iodopyridazine
  • Figure US20230100516A1-20230330-C00019
  • 17.70 g (53.33 mmol) 3,6-Diiodopyridazine (CAS-No. 20698-04-8) and 8.50 g (53.41 mmol) [6-(difluoromethyl)pyridin-3-yl]methanol (CAS-No. 946578-33-2) in 25 mL THF are cooled to 0° C. and 2.33 g (53.33 mmol) sodium hydride (55% purity) is added. The reaction mixture is stirred at RT overnight and concentrated under reduced pressure. The residue is diluted with water (400 mL). The precipitate is filtered, washed with water and tBME and dried at 50° C. in vacuo overnight to afford 17.50 g of the product.
      • C11H8F2IN3O (M=363.1 g/mol)
      • ESI-MS: 364 [M+H]+
      • Rt (HPLC): 0.90 min (method A)
  • The following compounds are prepared according to the general procedure (example 1.1) described above:
  • Starting Reaction HPLC retention
    time (method)
    Ex. material Structure conditions ESI-MS [min]
    I.2
    Figure US20230100516A1-20230330-C00020
    Figure US20230100516A1-20230330-C00021
         		1.1 eq NaH; 0° C. to RT 382/383/384 [M + H]+ 0.99 (B)
    I.3 XII
    Figure US20230100516A1-20230330-C00022
         		1.0 eq. NaH; 0° C. to RT 382/383 [M + H]+ 1.00 (B)
    • Example II Example II.1
  • 4-(4-Acetylpiperazin-1-yl)-3-fluorobenzonitrile
  • Figure US20230100516A1-20230330-C00023
  • To a solution of 0.40 g (1.95 mmol) 3-fluoro-4-piperazin-1-yl-benzonitrile (CAS-No. 182181-38-0) and 0.60 ml (4.30 mmol) triethylamine in 7 mL DCM is added 0.14 mL (1.95 mmol) acetyl chloride and the mixture is stirred at RT overnight. The reaction mixture is treated with 0.09 mL (1.25 mmol) triethylamine and is stirred at RT for 2 h. The organic layer is washed with water, dried with PTK and the solvent is evaporated under reduced pressure to afford 0.5 g of the crude product which was used in the next step without further purification.
      • C13H14FN3O (M=247.3 g/mol)
      • ESI-MS: 248 [IM+H]+
      • Rt (HPLC): 0.82 min (method B)
  • The following compounds are prepared according to the general procedure (example II.1) described above:
  • HPLC
    retention
    time
    Starting Reaction (method)
    Ex. material(s) Structure conditions ESI-MS [min]
    II.2 VI.1
    Figure US20230100516A1-20230330-C00024
         		3 eq NEt3; 1 h 270 [M + H]+ 0.87 (B)
    II.3 VII.1
    Figure US20230100516A1-20230330-C00025
         		3 eq NEt3; 1 h; workup with sat. KHSO4 −/ NaHCO3 − solution 242 [M + H]+ 0.81 (B)
    II.4 VI.2
    Figure US20230100516A1-20230330-C00026
         		3 eq NEt3; 1 h; washed with KH2PO4 − solution 242 [M + H]+ 0.78 (B)
    II.5 VI.4
    Figure US20230100516A1-20230330-C00027
         		3 eq NEt3; RT; 5.5 h 242 [M + H]+ 0.84 (E)
    II.6 VI.5
    Figure US20230100516A1-20230330-C00028
         		3 eq DIPEA; 1.5 eq acetyl chloride; 3 h; RT; workup with sat. Na—HCO3 − solutio/1M KHSO4 − solution; 256 [M + H]+ 0.86 (B)
    purification by
    column
    chromatography
    on silica gel (gradient
    DCM/MeO
    H = 100:1 to 90:10)
    • Example III Example III.1
  • 1-{4-[4-(aminomethyl)-2-fluorophenyl]piperazin-1-y}ethan-1-one
  • Figure US20230100516A1-20230330-C00029
  • A mixture of 550 mg (2.22 mmol) 4-(4-acetylpiperazin-1-yl)-3-fluorobenzonitrile (example II.1), 55.0 mg Raney-Nickel and 15 mL 7 N ammonia in MeOH is stirred under a hydrogen atmosphere (50 psi) at 50° C. overnight, filtered and reduced in vacuo to give 0.51 g of the product.
      • C13H18FN3O (M=251.3 g/mol)
      • ESI-MS: 252 [IM+H]+
      • Rt (HPLC): 0.68 min (method A)
  • The following compounds are prepared according to the general procedure (example III.1) described above:
  • HPLC
    retention
    time
    Starting Reaction (method)
    Ex. material Structure conditions ESI-MS [min]
    III.2 IV.1
    Figure US20230100516A1-20230330-C00030
         		252 [M + H]+ 0.69 (A)
    III.3 V.1
    Figure US20230100516A1-20230330-C00031
         		3 h 229 [M + H − NH3]+ 0.65 (A)
    III.4 II.2
    Figure US20230100516A1-20230330-C00032
         		3 h 257 [M + H − NH3]+ 0.72 (A)
    III.5
    Figure US20230100516A1-20230330-C00033
    Figure US20230100516A1-20230330-C00034
         		40° C.; 48 h 217 [M + H − NH3]+ 0.45 (E)
    III.6 II.3
    Figure US20230100516A1-20230330-C00035
         		3.5 h 283 [M + H − NH3]+ 0.56 (B)
    III.7 V.4
    Figure US20230100516A1-20230330-C00036
         		product precipitated with HCl in 1,4-dioxane 262 [M + H]+ 0.69 (A)
    III.8 IX.1
    Figure US20230100516A1-20230330-C00037
         		40° C.; purified by HPLC 218 [M + H − NH3]+ 0.61 (A)
    III.9 IX.2
    Figure US20230100516A1-20230330-C00038
         		40° C.; purified by HPLC 218 [M + H − NH3]+ 0.63 (A)
    III.10 II.4
    Figure US20230100516A1-20230330-C00039
         		RT; 20 h 229 [M − NH3]+ 0.58 (B)
    III.11 X
    Figure US20230100516A1-20230330-C00040
         		262 [M + H] 0.67 (B)
    III.12 IV.2
    Figure US20230100516A1-20230330-C00041
         		1 d 302 [M + H]+ 0.68 (B)
    III.13 V.7
    Figure US20230100516A1-20230330-C00042
         		248 [M + H]+ 0.21 (B)
    III.14 V.8
    Figure US20230100516A1-20230330-C00043
         		247 [M + H − NH3]+ 0.68 (A)
    III.15 II.5
    Figure US20230100516A1-20230330-C00044
         		229 [M + H − NH3]+ 0.58 (E)
    III.16 II.6
    Figure US20230100516A1-20230330-C00045
         		50 mg catalyst; 20 mL 7M NH3/ MeOH; purified by HPLC 260 [M + H − NH3]+ 0.67 (B)
    III.17 X.3
    Figure US20230100516A1-20230330-C00046
         		275 [M + H]+ 0.63 (A)
    III.18 X.4
    Figure US20230100516A1-20230330-C00047
         		275 [M + H]+ 0.66 (A)
    III.19 X.5
    Figure US20230100516A1-20230330-C00048
         		260 [M + H]+ 0.71 (A)
    III.20 X.6
    Figure US20230100516A1-20230330-C00049
         		260 [M + H]+ 0.72 (A)
    III.21 X.8
    Figure US20230100516A1-20230330-C00050
         		264 [M + H]+ 0.70 (A)
    • Example IV Example IV.1
  • 4-(4-Acetylpiperazin-1-yl)-2-fluorobenzonitrile
  • Figure US20230100516A1-20230330-C00051
  • A mixture of 0.50 g (2.50 mmol) 4-bromo-2-fluorobenzonitrile (CAS-No. 105942-08-3), 0.32 g (2.50 mmol) 1-(piperazin-1-yl)ethan-1-one (CAS No. 13889-98-0), 1.63 g (5.00 mmol) cesium carbonate and 0.05 g (0.06 mmol) XPhos Pd G3 (CAS-No. 1445085-55-1) in 2 mL 1,4-dioxane is stirred at 80° C. overnight. It is diluted with water. The remaining solid is filtered, washed with water und dried under air atmosphere to afford 0.57 g of the product.
      • C13H14FN3O (M=247.3 g/mol)
      • ESI-MS: 248 [M+H]+
      • Rt (HPLC): 0.79 min (method A)
  • The following compound is prepared according to the general procedure (example IV.1) described above:
  • HPLC
    retention
    time
    Starting Reaction ESI- (method)
    Ex. material Structure conditions MS [min]
    IV.2
    Figure US20230100516A1-20230330-C00052
    Figure US20230100516A1-20230330-C00053
         		3 h; workup: extraction with DCM; purification via crystallization with DIPE 298 [M + H]+ 0.88 (B)
    • Example V Example V.1
  • 4-{6-Methvl-7-oxo-2,6-diazaspiro[3.4]octan-2-yl}benzonitrile
  • Figure US20230100516A1-20230330-C00054
  • 222 mg (1.81 mmol) 4-Fluorobenzonitrile (CAS No. 1194-02-1) and 320 mg (1.81 mmol) 6-methyl-2,6-diazaspiro1[3.4]octan-7-one hydrochloride (CAS No. 2097951-61-4) diluted with 1.6 mL DMS0 are treated with 790 mg (5.62 mmol) K2CO3 and stirred at 120° C. for 3 h and at RT overnight. The reaction mixture is cooled and is diluted with water. The precipitate is filtered, is washed with water and dried in vacuo at 50° C. to yield 340 mg of the product.
      • C14H15N3O (M=241.3 g/mol)
      • ESI-MS: 242 [M+H]+
      • Rt (HPLC): 0.79 min (method B)
  • The following compounds are prepared according to the general procedure (example V.1) described above:
  •
    Ex. Starting materials Structure
    V.2
    Figure US20230100516A1-20230330-C00055
    Figure US20230100516A1-20230330-C00056
    V.3
    Figure US20230100516A1-20230330-C00057
    Figure US20230100516A1-20230330-C00058
    V.4
    Figure US20230100516A1-20230330-C00059
    Figure US20230100516A1-20230330-C00060
    V.5
    Figure US20230100516A1-20230330-C00061
    Figure US20230100516A1-20230330-C00062
    V.6
    Figure US20230100516A1-20230330-C00063
    Figure US20230100516A1-20230330-C00064
    V.7
    Figure US20230100516A1-20230330-C00065
    Figure US20230100516A1-20230330-C00066
    V.8
    Figure US20230100516A1-20230330-C00067
    Figure US20230100516A1-20230330-C00068
    V.9
    Figure US20230100516A1-20230330-C00069
    Figure US20230100516A1-20230330-C00070
    V.10
    Figure US20230100516A1-20230330-C00071
    Figure US20230100516A1-20230330-C00072
    V.11
    Figure US20230100516A1-20230330-C00073
    Figure US20230100516A1-20230330-C00074
    V.12
    Figure US20230100516A1-20230330-C00075
    Figure US20230100516A1-20230330-C00076
    V.13
    Figure US20230100516A1-20230330-C00077
    Figure US20230100516A1-20230330-C00078
    V.14
    Figure US20230100516A1-20230330-C00079
    Figure US20230100516A1-20230330-C00080
    V.15
    Figure US20230100516A1-20230330-C00081
    Figure US20230100516A1-20230330-C00082
    HPLC retention time
    Ex. Reaction conditions ESI-MS (method) [min]
    V.2 3.1 eq K2CO3, 2 h 328 [M + H]+ 1.11 (B)
    V.3 2.1 eq K2CO3; 2 h 300 [M + H]+ 1.06 (B)
    V.4 1.5 eq K2CO3; 2.5 h; workup: 258 [M + H]+ 0.87 (B)
    extraction with EtOAc
    V.5 1.65 eq fluoride; overnight 300 [M + H]+ 1.04 (B)
    V.6 2.1 eq K2CO3; overnight; workup: 316 [M + H]+ 0.88 (A)
    extraction with EtOAc
    V.7 80° C.; extraction with 244 [M +H ]+ 0.62 min (B)
    water/EtOAc; purified by HPLC
    V.8 ACN; 50° C.; 1.5 h; workup: 260 [M + H]+ 0.87 (B)
    filtration and concentration
    V.9 1.5 eq K2CO3 300 [M + H]+ 1.02 (B)
    V.10 2.1 eq K2CO3 314 [M + H]+ 1.12 (B)
    V.11 DIPEA; 50° C.; 1.5 h 329 [M + H]+ 1.04 (B)
    V.12 DIPEA; 60° C.; 1.5 h 329 [M + H]+ 1.02 (B)
    V.13 3 eq K3PO4; NMP; 110° C.; 314 [M + H]+ 1.08 (B)
    8 h; workup:
    extraction with water/EE;
    purification by HPLC
    V.14 3 eq K3PO4; NMP; 110° C.; 314 [M + H]+ 1.07 (B)
    8 h; workup:
    extraction with water/EE;
    purification by HPLC
    V.15 3 eq K2CO3; workup: 260 [M + H]+ 1.06 (A)
    filtration; concentration;
    extraction with DCM
    • Example VI Example VI.1
  • 4-{2,7-Diazaspiro[3.5]nonan-2-yl}benzonitrile; trifluoroacetic acid
  • Figure US20230100516A1-20230330-C00083
  • 255 mg (0.78 mmol) tert-Butyl 2-(4-cyanophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (example V.2) is diluted with 5 mL DCM and 300 μL (3.89 mmol) TFA is added. The reaction mixture is stirred at RT for 2 h and concentrated under reduced pressure to afford 0.26 g of the product.
      • C14H17N3*C2HF3O2 (M=341.3 g/mol)
      • ESI-MS: 228 [M+H]+
      • Rt (HPLC): 0.69 min (method B)
  • The following compounds are prepared according to the general procedure (example VI.1) described above:
  • HPLC
    retention
    time
    Starting Reaction (method)
    Ex. material Structure conditions ESI-MS [min]
    VI.2 V.5
    Figure US20230100516A1-20230330-C00084
         		4 eq TFA 200 [M + H]+ 0.62 (B)
    VI.3 V.6
    Figure US20230100516A1-20230330-C00085
         		8 eq TFA; overnight 216 [M + H]+ 0.84 (A)
    VI.4 V.9
    Figure US20230100516A1-20230330-C00086
         		overnight 200 [M + H]+ 0.78 (A)
    VI.5 V.10
    Figure US20230100516A1-20230330-C00087
         		stirred 1.5 h 214 [M + H]+ 0.70 (B)
    VI.6 V.11
    Figure US20230100516A1-20230330-C00088
         		4 h 229 [M + H]+ 0.75 (A)
    VI.7 V.12
    Figure US20230100516A1-20230330-C00089
         		workup: added 4M NaOH; extracted with DCM; dried with MgSO4; 229 [M + H]+ 0.71 (A)
    filtered; evaportion
    VI.8 V.13
    Figure US20230100516A1-20230330-C00090
         		overnight 214 [M + H]+ 0.81 (A)
    VI.9 V.14
    Figure US20230100516A1-20230330-C00091
         		overnight 214 [M + H]+ 0.80 (A)
    • Example VII Example VII.1
  • 4-{2,6-Diazaspiro[3.3]heptan-2-yl}benzonitrile
  • Figure US20230100516A1-20230330-C00092
  • A solution of 0.90 g (3.01 mmol) tert-butyl 6-(4-cyanophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (example V.3) in 8 mL ACN is treated with 1.14 g (6.01 mmol) p-toluenesulfonic acid monohydrate and stirred at RT for 24 h. The reaction mixture is diluted with DCM and extracted with sat. NaHCO3— solution. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure to provide 0.6 g of the product.
      • C12H13N3 (M=199.3 g/mol)
      • ESI-MS: 200 [M+H]+
      • Rt (HPLC): 0.62 min (method B)
  • The following compounds are prepared according to the general procedure (example VII.1) described above:
  • HPLC
    Starting Reaction retention time
    Ex. material Structure conditions ESI-MS (method) [min]
    VII.2 V.15
    Figure US20230100516A1-20230330-C00093
         		218 [M + H]+ 0.83 (A)
    • Example VIII N-[(4-bromophenyl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-amine
  • Figure US20230100516A1-20230330-C00094
  • 1000 mg (2.62 mmol) 3-Iodo-6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazine (example 1.2), 586 mg (3.15 mmol) 4-Bromobenzylamine, 50 mg (0.26 mmol) copper iodide, 88 mg (0.52 mmol) 2-(2-methyl-1-oxopropyl)cyclohexanone and 2.56 g (7.87 mmol) cesium carbonate in 10 mL DMF are stirred at 60° C. overnight. The reaction mixture is purified by HPLC to afford 850 mg of the product.
      • C18H14BrF3N40 (M=439.2 g/mol)
      • ESI-MS: 439/441 [M+H]+
      • Rt (HPLC): 1.08 min (method A)
    Example IX Example IX.1
  • 5-(4-Acetylpiperazin-1-yl)pyridine-2-carbonitrile
  • Figure US20230100516A1-20230330-C00095
  • A mixture of 250 mg (2.05 mmol) 5-fluoropyridine-2-carbonitrile (CAS No. 327056-62-2), 310 mg (2.46 mmol) 1-acetylpiperazine (CAS No. 13889-98-0) and 700 μL (4.10 mmol) DIPEA in 3 mL DMSO is stirred at 80° C. for 45 min and quenched with semi conc. NaCl/solution. The water phase is extracted with EtOAc. The combined organic phases are dried via PTK and concentrated in vacuo to give 0.57 g of the product.
      • C12H14N40 (M=230.3 g/mol)
      • ESI-MS: 231 [M+H]+
      • Rt (HPLC): 0.67 min (method A)
  • The following compounds are prepared according to the general procedure (example IX.1) described above:
  • HPLC
    Starting retention time
    Ex. materials/s Structure ESI-MS (method) [min]
    IX.2
    Figure US20230100516A1-20230330-C00096
    Figure US20230100516A1-20230330-C00097
         		231 [M + H]+ 0.72 (A)
    • Example X Example X.1
  • 4-(4-Acetyl-3,3-dimethylpiperazin-1-yl)benzonitrile
  • Figure US20230100516A1-20230330-C00098
  • 800 mg (1.21 mmol) 4-(3,3-Dimethylpiperazin-1-yl)benzonitrile trifluoroacetic acid (example VI.3) is dissolved in 3 mL pyridine and 2.00 mL (21.2 mmol) acetic anhydride is added. The reaction mixture is refluxed overnight and is evaporated under reduced pressure. The residue is taken up in sat. NaHCO3-solution and extracted with EtOAc. The organic layer is dried, is concentrated in vacuo and purified by column chromatography (silica gel; gradient: DCM/MeOH=98:2 to 9:1) to obtain the product.
      • C15H19N30 (M=257.3 g/mol)
      • ESI-MS: 258 [M+H]+
      • Rt (HPLC): 0.85 min (method A)
  • The following compounds are prepared according to the general procedure (example X.1) described above:
  • HPLC
    retention
    time
    Starting Reaction (method)
    Ex. material/s Structure conditions ESI-MS [min]
    X.2
    Figure US20230100516A1-20230330-C00099
    Figure US20230100516A1-20230330-C00100
         		1.1 eq acetanhydride; DCM 283 [M + H]+ 0.74 (A)
    X.3 VI.6
    Figure US20230100516A1-20230330-C00101
         		2.7 eq acetanhydride; RT; overnight; evaporation 271 [M + H]+ 0.76 (A)
    X.4 VI.7
    Figure US20230100516A1-20230330-C00102
         		1.8 eq acetanhydride; RT; overnight; evaporation 271 [M + H]+ 0.91 (A)
    X.5 VI.8
    Figure US20230100516A1-20230330-C00103
         		1.2 eq acetanhydride; 3 eq TEA; DCM; RT; 256 [M + H]+ 0.81 (A)
    overnight;
    workup:
    extraction
    with water,
    1M citric
    acid and
    diluted
    ammonia;
    evaporation
    X.6 VI.9
    Figure US20230100516A1-20230330-C00104
         		1.1 eq acetanhydride; 3 eq TEA; DCM; RT; 256 [M + H]+ 0.80 (A)
    overnight;
    workup:
    extraction
    with water,
    1M citric
    acid and
    diluted
    ammonia;
    evaporation
    X.8 VII.2
    Figure US20230100516A1-20230330-C00105
         		1.1 eq acetanhydride; DCM; 3.5 h; RT; workup: purification by HPLC 260 [M + H]+ 0.96 (B)
    • Example XI Methyl 6-(difluoromethyl)-5-fluoropyridine-3-carboxylate
  • Figure US20230100516A1-20230330-C00106
  • 800 mg (3.54 mmol) 5-bromo-2-(difluoromethyl)-3-fluoropyridine[prepared from commercially available 5-bromo-3-fluoropyridine-2-carboxaldehyde (1 eq.), CAS-Nr. 669066-93-7, through reaction with deoxofluor (2 eq.) in DCM overnight] in 40 mL MeOH is treated with 154.8 mg (0.28 mmol) 1,1′-Bis-(diphenylphosphino)-ferrocene, 63.5 mg (0.28 mmol) Palladium(II)-acetate and 1.5 mL (10.79 mmol) TEA. The reaction mixture is stirred under carbon monoxide atmosphere (5 bar) at 50° C. for 15 h. The reaction mixture is filtered and the filtrate is evaporated in vacuo to provide the product. The residue is purified by column chromatography (silica gel; gradient: Cy/EE=100:0 to 60:40) to afford 460 mg of the product.
      • C8H6F3NO2 (M=205.1 g/mol)
      • ESI-MS: 206 [M+H]+
      • Rt (HPLC): 0.88 min (method B)
    Example XII [6-(difluoromethyl)-5-fluoropyridin-3-yl]methanol
  • Figure US20230100516A1-20230330-C00107
  • 98 mg (4.49 mmol) lithium borohydride in 10 mL THF is treated with 460 mg (2.42 mmol) Methyl 6-(difluoromethyl)-5-fluoropyridine-3-carboxylate (example XI) dissolved in 10 mL THF under nitrogen atmosphere. 0.2 mL MeOH is added and the reaction mixture is stirred at 50° C. for 2 h. The reaction mixture is diluted with 5 mL 1 M hydrochloric acid and after gas evolution the THF is evaporated. The residue is basified with 4M NaOH and the aqueous solution is extracted with DCM. The organic phase is evaporated in vacuo to provide the product. The residue is purified by column chromatography (silica gel; gradient: Cy/EE=80:20 to 20:80) to afford 290 mg of the product.
      • C7H6F3NO (M=177.1 g/mol)
      • ESI-MS: 178 [M+H]+
      • Rt (HPLC): 0.64 min (method B)
    Example XIII 1-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]ethan-1-one hydrochloride
  • Figure US20230100516A1-20230330-C00108
  • 2.64 g (9.3 mmol) tert-butyl (3aR,8aS)-6-acetyl-decahydropyrrolo[3,4-d]azepine-2-carboxylate (example X.2) is diluted with 30 mL 1,4-dioxane, 9.3 mL (37.4 mmol) 4 M hydrogenchloride in 1,4-dioxane is added and the reaction mixture is stirred at RT for 4 h. To the reaction mixture is added leq 4 M hydrogen chloride in 1,4-dioxane and it is stirred at RT overnight. The mixture is evaporated in vacuo, the residue is treated with diethylether and the precipitate is filtered. The filter cake is diluted with MeOH and is evaporated to give the product.
      • C10H18N2O*HCl (M=182.3 g/mol)
      • ESI-MS: 183 [M+H]+
      • Rt (HPLC): 0.50 min (method A)
    Example XIV N-(4-((3aR,3bS,6aR,6bS)-octahydrocyclobuta[1,2-c:3,4-c′]dipyrrol-2(1H)-yl)benzyl)-6-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3-amine
  • Figure US20230100516A1-20230330-C00109
  • 59.7 mg (0.27 mmol) (3aR,3bR,6aS,6bS)-decahydrocyclobuta[1,2-c:3,4-c′]dipyrrole, 120.0 mg (0.27 mmol)N-[(4-bromophenyl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-amine (example VIII), 3.07 mg (0.01 mmol) Palladium(II)acetate, 6.5 mg (0.01 mmol) X-phos and 89.0 mg (0.27 mmol) cesium carbonate are dissolved in 2.00 mL toluene and 0.50 mL tert-butanol under argon atmosphere. The solution is degassed a few times. The reaction solution is stirred at 80° C. overnight. The reaction mixture is diluted with water and is extract with EE. The organic layer is dried with MgSO4, is filtered over charcoal and is evaporated. The residue is purified by HPLC to afford 15 mg of the product.
      • C28H31F3N6O2 (M=496.5 g/mol)
      • ESI-MS: 497 [M+H]+
      • Rt (HPLC): 0.98 min (method A)
    Preparation of Final Compounds Example 1.1 1-(6-(4-(((6-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one
  • Figure US20230100516A1-20230330-C00110
  • To a solution of 163 mg (0.43 mmol) 3-iodo-6-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazine (example 1.2) and 150 mg (0.43 mmol) 1-(6-(4-(aminomethyl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (example 111.6) in 2 mL dimethylacetamide is added 418 mg (1.28 mmol) cesium carbonate, 8.1 mg (0.04 mmol) copper (I) iodide and 14.4 mg (0.09 mmol) 2-(2-Methyl-1-oxopropyl)cyclohexanone and the mixture was stirred at 50° C. overnight. The mixture was diluted with acetonitrile, filtered and the filtrate was purified by HPLC to afford 43 mg of the desired product.
      • C25H25F3N6O2 (M=498.5 g/mol)
      • ESI-MS: 499 [M+H]+
      • Rt (HPLC): 0.93 min (method A)
  • 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.52 Hz, 1H), 8.13 (dd, J=1.39, 8.11 Hz, 1H), 7.92 (d, J=8.11 Hz, 1H), 7.16 (d, J=8.49 Hz, 2H), 6.89-7.03 (m, 2H), 6.84 (t, J=5.64 Hz, 1H), 6.40 (d, J=8.49 Hz, 2H), 5.48 (s, 2H), 4.33 (d, J=5.58 Hz, 2H), 4.27 (s, 2H), 3.99 (s, 2H), 3.89 (s, 4H), 1.74 (s, 3H)
  • The following compounds are prepared according to the general procedure (example 1.1) described above:
  • Starting
    Ex. materials Structure
    1.2 I.1 III.6
    Figure US20230100516A1-20230330-C00111
    1.3 I.1 III.1
    Figure US20230100516A1-20230330-C00112
    1.4 I.1 III.2
    Figure US20230100516A1-20230330-C00113
    1.5 I.1 III.3
    Figure US20230100516A1-20230330-C00114
    1.6 I.1 III.4
    Figure US20230100516A1-20230330-C00115
    1.7 I.1 III.11
    Figure US20230100516A1-20230330-C00116
  • HPLC retention
    time (method)
    Ex. Reaction conditions ESI-MS [min]
    1.2 directly purified by HPLC 481 [M + H]+ 0.89 (A)
    1.3 directly purified by HPLC 487 [M + H]+ 0.69 (C)
    1.4 directly purified by HPLC 487 [M + H]+ 0.70 (C)
    1.5 1.1 eq benzylic amine; 40° C. 481 [M + H]+ 0.66 (D)
    1.6 1.1 eq benzylic amine; 40° C. 509 [M + H]+ 0.72 (D)
    1.7 directly purified by HPLC 497 [M + H]+ 0.77 (C)
  • Ex. 1H-NMR data
    1.2 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.05 (dd, J = 1.71, 8.05 Hz, 1H),
    7.71 (d, J = 7.98 Hz, 1H), 7.17 (d, J = 8.36 Hz, 2H), 6.95 (q, J = 9.42 Hz, 3H), 6.77-
    6.86 (m, 1H), 6.40 (d, J = 8.36 Hz, 2H), 5.44 (s, 2H), 4.34 (d, J = 5.58 Hz, 2H), 4.27
    (s, 2H), 3.99 (s, 2H), 3.89 (s, 4H), 1.74 (s, 3H)
    1.3 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.39 Hz, 1H), 8.05 (dd, J = 1.90,
    7.98 Hz, 1H), 7.71 (d, J = 7.86 Hz, 1H), 6.94-7.20 (m, 7H), 5.44 (s, 2H), 4.42 (d,
    J = 5.70 Hz, 2H), 3.55-3.63 (m, 4H), 2.88-3.00 (m, 4H), 2.03 (s, 3H)
    1.4 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.05 (dd, J = 1.52, 7.98 Hz, 1H),
    7.71 (d, J = 7.98 Hz, 1H), 7.24 (t, J = 8.74 Hz, 1H), 6.91-7.02 (m, 3H), 6.87 (t,
    J = 5.58 Hz, 1H), 6.71-6.83 (m, 2H), 5.44 (s, 2H), 4.40 (d, J = 5.58 Hz, 2H), 3.55
    (br s, 4H), 3.06-3.20 (m, 4H), 2.03 (s, 3H)
    1.5 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.05 (dd, J = 1.27, 7.98 Hz, 1H),
    7.71 (d, J = 7.98 Hz, 1H), 7.17 (d, J = 8.24 Hz, 2H), 6.95 (q, J = 9.42 Hz, 3H), 6.79-
    6.86 (m, 1H), 6.40 (d, J = 8.24 Hz, 2H), 5.44 (s, 2H), 4.34 (d, J = 5.58 Hz, 2H),
    3.69-3.80 (m, 4H), 3.57 (s, 2H), 2.72 (s, 3H), 2.57 (s, 2H)
    1.6 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.01-8.09 (m, 1H), 7.71 (d,
    J = 8.11 Hz, 1H), 7.16 (d, J = 8.24 Hz, 2H), 6.90-7.10 (m, 3H), 6.79-6.84 (m, 1H),
    6.38 (d, J = 8.36 Hz, 2H), 5.44 (s, 2H), 4.33 (d, J = 5.58 Hz, 2H), 3.50-3.59 (m,
    4H), 3.40 (td, J = 5.53, 14.04 Hz, 4H), 1.99 (s, 3H), 1.58-1.80 (m, 4H)
    1.7 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.52 Hz, 1H), 8.05 (dd, J = 1.96, 8.05
    Hz, 1H), 7.69-7.74 (m, 1H), 7.18 (d, J = 8.62 Hz, 2H), 6.90-7.11 (m, 3H), 6.78-
    6.84 (m, 1H), 6.69 (d, J = 8.74 Hz, 2H), 5.44 (s, 2H), 4.33 (d, J = 5.58 Hz, 2H), 3.72
    (t, J = 5.64 Hz, 2H), 3.33-3.36 (m, 4H), 2.01 (s, 3H), 1.38 (s, 6H)
    • Example 2.1 N-methyl-N-[1-(4-{[(6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-yl)amino]methyl}phenyl)piperidin-4-yl]acetamide
  • Figure US20230100516A1-20230330-C00117
  • A mixture of 50.0 mg (0.13 mmol) 3-iodo-6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}-pyridazine (example 1.2), 45.20 mg (0.14 mmol) 1-{4-[4-(1-aminocyclopropyl)phenyl]-piperazin-1-yl}ethan-1-one (example III.7), 6.2 mg (32.8 μmol) copper iodide, 13.2 mg (0.07 mmol) [(2,6-difluorophenyl)carbamoyl]formic acid (CAS No. 1018295-42-5) and 85.5 mg (0.39 mmol) potassium phosphate in 2 mL DMSO is stirred at 80° C. for 1.5 h, then at 100° C. for 1 h. The reaction mixture is directly purified by HPLC to afford 54 mg of the product.
      • C26H29F3N6O2 (M=514.5 g/mol)
      • ESI-MS: 515 [M+H]+
      • Rt (HPLC): 0.60 min (method C)
  • 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.14 Hz, 1H), 8.14 (dd, J=1.39, 8.11 Hz, 1H), 7.92 (d, J=8.11 Hz, 1H), 7.19 (d, J=8.24 Hz, 2H), 6.84-7.05 (m, 5H), 5.49 (s, 2H), 4.29-4.46 (m, 3H), 3.64-3.82 (m, 3H), 2.59-2.87 (m, 5H), 1.94-2.11 (m, 3H), 1.45-1.92 (m, 4H)
  • The following compounds are prepared according to the general procedure (example 2.1) described above:
  • Starting
    Ex. materials Structure
    2.2 I.2 III.5
    Figure US20230100516A1-20230330-C00118
    2.3 I.1 III.9
    Figure US20230100516A1-20230330-C00119
    2.4 I.1 III.8
    Figure US20230100516A1-20230330-C00120
    2.5 I.2 III.9
    Figure US20230100516A1-20230330-C00121
    2.6 I.1 III.10
    Figure US20230100516A1-20230330-C00122
    2.7 I.1 III.12
    Figure US20230100516A1-20230330-C00123
    2.8 I.2 III.13
    Figure US20230100516A1-20230330-C00124
    2.9 I.2 III.14
    Figure US20230100516A1-20230330-C00125
    2.10 I.1 III.13
    Figure US20230100516A1-20230330-C00126
    2.11 I.2 III.15
    Figure US20230100516A1-20230330-C00127
    2.12 I.3 III.5
    Figure US20230100516A1-20230330-C00128
    2.13 I.2 III.16
    Figure US20230100516A1-20230330-C00129
    2.14 I.1 III.16
    Figure US20230100516A1-20230330-C00130
    2.15 I.2 III.8
    Figure US20230100516A1-20230330-C00131
    2.16 I.1 III.17
    Figure US20230100516A1-20230330-C00132
    2.17 I.2 III.18
    Figure US20230100516A1-20230330-C00133
    2.18 I.1 III.18
    Figure US20230100516A1-20230330-C00134
    2.19 I.2 III.19
    Figure US20230100516A1-20230330-C00135
    2.20 I.2 III.20
    Figure US20230100516A1-20230330-C00136
    2.21 I.2 III.21
    Figure US20230100516A1-20230330-C00137
    2.22 I.2 III.4
    Figure US20230100516A1-20230330-C00138
    2.23 I.2 III.10
    Figure US20230100516A1-20230330-C00139
  • HPLC retention
    time (method)
    Ex. Reaction conditions ESI-MS [min]
    2.2 1.1 eq benzylic amine; 0.25 eq CuI; 487 [M + H]+ 0.79 (B)
    0.5 eq ligand; 120° C.; 3 h
    2.3 1 eq idodie; 1.1 eq amine; 100° C.; 470 [M + H]+ 0.85 (A)
    2.5 h
    2.4 1 eq idodie; 1.1 eq amine; 80° C.; 470 [M + H]+ 0.82 (A)
    1.5 h
    2.5 1 eq idodie; 1.1 eq amine; 80° C.; 488 [M + H]+ 0.90 (A)
    1.5 h; 100° C.; 1 h
    2.6 1 eq iodide; 1.14 eq amine; 80° C.; 481 [M + H]+ 0.66 (D)
    directly purified by HPLC
    2.7 1 eq iodide; 1.5 eq amine; overnight; 537 [M + H]+ 0.84 (B)
    directly purified by HPLC
    2.8 1.0 eq iodide; 1.1 eq benzylic amine; 501 [M + H]+ 0.74 (D)
    0.5 eq CuI; 0.5 eq ligand; 50° C.;
    overnight; directly purified by HPLC
    2.9 1.0 eq iodide; 1.1 eq benzylic amine; 517 [M + H]+ 0.92 (A)
    0.5 eq CuI; 0.5 eq ligand; 50° C.;
    overnight; directly purified by HPLC
    2.10 1 eq iodide; 1.1 eq benzylic amine; 483 [M + H]+ 0.67 (D)
    0.5 eq CuI; 0.5 eq ligand; 50° C.
    overnight; directly purified by HPLC
    2.11 0.25 eq CuI; 0.5 eq ligand; 50° C.; 499 [M + H]+ 0.75 (D)
    overnight; directly purified by HPLC
    2.12 0.2 eq CuI; 3 eq base; 0.4 eq ligand; 487 [M + H]+ 0.69 (D)
    70° C.; 3 h; directly purified by HPLC
    2.13 0.2 eq CuI; 3 eq base; 0.4 eq ligand; 513 [M + H]+ 0.77 (C)
    70° C. overnight; directly purified by
    HPLC
    2.14 0.2 eq CuI; 3 eq base; 0.4 eq ligand; 495 [M + H]+ 0.70 (C)
    70° C. overnight; directly purified by
    HPLC
    2.15 1 eq iodide; 1.1 eq amine; 80° C.; 488 [M + H]+ 0.88 (A)
    30 min
    2.16 3 eq base; 0.4 eq ligand; 80° C.; 45 510 [M + H]+ 0.62 (D)
    min; 110° C.; 10 min; extraction with
    EE; purification by HPLC
    2.17 3 eq base; 0.4 eq ligand; 70° C.; 528 [M + H]+ 0.68 (D)
    overnight; directly purified by HPLC
    2.18 3 eq base; 0.4 eq ligand; 70° C.; 510 [M + H]+ 0.62 (D)
    overnight; RT over weekend; directly
    purified by HPLC
    2.19 3 eq base; 0.4 eq ligand; 80° C.; 513 [M + H]+ 0.96 (A)
    overnight; workup: diluted with sat.
    NH4CI/NH3; precipitate is filtered and
    directly purified by HPLC
    2.20 3 eq base; 0.4 eq ligand; 80° C.; 513 [M + H]+ 0.96 (A)
    overnight; workup: diluted with sat.
    NH4Cl/NH3; precipitate is filtered and
    directly purified by HPLC
    2.21 3 eq base; 0.4 eq ligand; 80° C.; 517 [M + H]+ 0.96 (A)
    overnight; workup: diluted with sat.
    NH4Cl/NH3; extraction with EE;
    purified by HPLC
    2.22 3 eq base; 0.4 eq ligand; 70° C.; 527 [M + H]+ 0.79 (C)
    2 h; RT overnight;
    2.23 3 eq base; 0.4 eq ligand; 80° C.; 499 [M + H]+ 0.93 (A)
    overnight; workup: diluted with sat.
    NH4Cl/NH3; extraction with EE; purified
    by HPLC
  • Ex. 1H-NMR data
    2.2 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.14 Hz, 1H), 8.13 (dd, J = 1.39,
    8.11 Hz, 1H), 7.92 (d, J = 7.98 Hz, 1H), 7.22 (d, J = 8.62 Hz, 2H), 6.85-7.04 (m,
    5H), 5.49 (s, 2H), 4.37 (d, J = 5.70 Hz, 2H), 3.48-3.64 (m, 4H), 2.98-3.16 (m,
    4H), 2.03 (s, 3H)
    2.3 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.39 Hz, 1H), 8.13 (d, J = 2.15 Hz,
    1H), 8.05 (dd, J = 1.90, 8.11 Hz, 1H), 7.71 (d, J = 7.98 Hz, 1H), 7.56 (dd, J = 2.41,
    8.74 Hz, 1H), 6.75-7.02 (m, 5H), 5.45 (s, 2H), 4.34 (d, J = 5.70 Hz, 2H), 3.48-
    3.57 (m, 6H), 3.38-3.47 (m, 2H), 2.03 (s, 3H)
    2.4 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.39 Hz, 1H), 8.24 (br d, J = 1.77
    Hz, 1H), 8.05 (dd, J = 1.96, 8.05 Hz, 1H), 7.71 (d, J = 7.98 Hz, 1H), 7.33 (dd,
    J = 2.85, 8.68 Hz, 1H), 7.21 (d, J = 8.62 Hz, 1H), 6.90-7.12 (m, 4H), 5.43 (s, 2H),
    4.48 (d, J = 5.70 Hz, 2H), 3.57 (br d, J = 3.80 Hz, 4H), 3.05-3.22 (m, 4H), 2.04 (s,
    3H)
    2.5 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 1.27 Hz, 1H), 8.08-8.17 (m, 2H),
    7.92 (d, J = 8.11 Hz, 1H), 7.56 (dd, J = 2.41, 8.74 Hz, 1H), 6.96-7.04 (m, 1H),
    6.85-6.96 (m, 2H), 6.82 (d, J = 8.74 Hz, 1H), 5.49 (s, 2H), 4.34 (d, J = 5.70 Hz,
    2H), 3.35-3.60 (m, 8H), 2.03 (s, 3H)
    2.6 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.05 (d, J = 8.11 Hz, 1H), 7.71
    (d, J = 7.98 Hz, 1H), 7.16 (dd, J = 2.41, 8.62 Hz, 2H), 6.88-7.02 (m, 3H), 6.74-
    6.86 (m, 1H), 6.57 (d, J = 7.86 Hz, 2H), 5.45 (s, 2H), 4.43-4.79 (m, 2H), 4.33 (t,
    J = 5.51 Hz, 2H), 3.44-3.66 (m, 2H), 2.85-3.28 (m, 2H), 1.70-2.06 (m, 5H)
    2.7 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.52 Hz, 1H), 8.05 (dd, J = 1.96,
    8.05 Hz, 1H), 7.71 (d, J = 8.11 Hz, 1H), 7.43 (d, J = 8.24 Hz, 1H), 7.14-7.24 (m,
    2H), 6.91-7.04 (m, 4H), 5.44 (s, 2H), 4.56 (br d, J = 5.32 Hz, 2H), 3.57 (br d,
    J = 3.55 Hz, 4H), 3.11-3.26 (m, 4H), 2.04 (s, 3H)
    2.8 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.01 Hz, 1H), 8.14 (dd, J = 1.46,
    8.05 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.20 (d, J = 8.62 Hz, 2H), 6.92-7.03 (m,
    2H), 6.84-6.92 (m, 3H), 5.49 (s, 2H), 4.51-4.61 (m, 2H), 4.46 (t, J = 6.02 Hz,
    2H), 4.36 (d, J = 5.70 Hz, 2H), 3.44 (quin, J = 6.27 Hz, 1H), 3.07-3.17 (m, 4H),
    2.36-2.44 (m, 4H)
    2.9 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.27 Hz, 1H), 8.13 (dd, J = 1.39,
    8.11 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 6.91-7.05 (m, 5H), 6.50 (dd, J = 8.49,
    9.38 Hz, 1H), 5.48 (s, 2H), 4.35 (d, J = 5.70 Hz, 2H), 4.26 (s, 2H), 3.98 (d,
    J = 1.65 Hz, 6H), 1.74 (s, 3H)
    2.10 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.39 Hz, 1H), 8.05 (dd, J = 1.90,
    7.98 Hz, 1H), 7.71 (d, J = 7.98 Hz, 1H), 7.20 (d, J = 8.62 Hz, 2H), 6.83-7.11 (m,
    6H), 5.44 (s, 2H), 4.52-4.59 (m, 2H), 4.46 (t, J = 6.08 Hz, 2H), 4.36 (d, J = 5.58
    Hz, 2H), 3.38-3.49 (m, 1H), 3.04-3.18 (m, 4H), 2.34-2.44 (m, 4H)
    2.11 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.13 (dd, J = 1.33, 8.05 Hz, 1H),
    7.99 (d, J = 3.93 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.14 (d, J = 8.49 Hz, 2H),
    6.89-7.02 (m, 2H), 6.81 (t, J = 5.58 Hz, 1H), 6.50 (d, J = 8.62 Hz, 2H), 5.49 (s,
    2H), 4.32 (d, J = 5.58 Hz, 2H), 3.52 (d, J = 9.38 Hz, 2H), 3.14 (br d, J = 8.62 Hz,
    2H), 2.42 (td, J = 2.11, 3.77 Hz, 1H), 1.70-1.80 (m, 5H)
    2.12 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.01 (d, J = 11.03 Hz, 1H), 7.10-
    7.29 (m, 3H), 6.95-7.04 (m, 2H), 6.85-6.95 (m, 3H), 5.46 (s, 2H), 4.37 (d,
    J = 5.70 Hz, 2H), 3.51-3.60 (m, 4H), 2.98-3.16 (m, 4H), 2.03 (s, 3H)
    2.13 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.27 Hz, 1H), 8.13 (dd, J = 1.46,
    8.05 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.16 (d, J = 8.62 Hz, 2H), 6.89-7.03 (m,
    2H), 6.81 (t, J = 5.64 Hz, 1H), 6.50 (d, J = 8.62 Hz, 2H), 5.49 (s, 2H), 4.33 (d,
    J = 5.58 Hz, 2H), 3.73 (dd, J = 7.67, 10.58 Hz, 1H), 3.57 (dd, J = 7.73, 12.17 Hz,
    1H), 3.33-3.48 (m, 3H), 3.19-3.26 (m, 1H), 2.90-3.18 (m, 4H), 1.93 (s, 3H)
    2.14 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.39 Hz, 1H), 8.05 (dd, J = 1.90,
    7.98 Hz, 1H), 7.71 (d, J = 7.98 Hz, 1H), 7.16 (d, J = 8.49 Hz, 2H), 6.89-7.11 (m,
    3H), 6.77-6.84 (m, 1H), 6.50 (d, J = 8.62 Hz, 2H), 5.44 (s, 2H), 4.33 (d, J = 5.58
    Hz, 2H), 3.73 (dd, J = 7.60, 10.65 Hz, 1H), 3.57 (dd, J = 7.73, 12.17 Hz, 1H),
    3.32-3.48 (m, 3H), 3.22 (dd, J = 4.69, 12.17 Hz, 1H), 2.90-3.19 (m, 4H), 1.93 (s,
    3H)
    2.15 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.27 Hz, 1H), 8.24 (d, J = 2.66 Hz,
    1H), 8.13 (dd, J = 1.52, 8.11 Hz, 1H), 7.92 (d, J = 7.98 Hz, 1H), 7.32 (dd, J = 2.92,
    8.62 Hz, 1H), 7.21 (d, J = 8.62 Hz, 1H), 6.98-7.08 (m, 3H), 5.48 (s, 2H), 4.48 (d,
    J = 5.70 Hz, 2H), 3.57 (br d, J = 3.55 Hz, 4H), 3.06-3.24 (m, 4H), 2.04 (s, 3H)
    2.16 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J = 1.39 Hz, 1H), 8.05 (dd,
    J = 7.98, 2.03 Hz, 1H), 7.75 (d, J = 2.79 Hz, 1H), 7.71 (d, J = 7.98 Hz, 1H), 7.16
    (d, J = 8.36 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J = 4.31 Hz, 2H), 6.92-6.98 (m, 2H),
    6.71-6.89 (m, 1H), 5.44 (s, 2H), 4.44 (d, J = 5.83 Hz, 2H), 3.62 (d, J = 1.77 Hz,
    4H), 2.67 (t, J = 1.84 Hz, 1 H), 2.33 (t, J = 1.84 Hz, 1 H), 2.00 (s, 3 H), 1.70-1.83
    (m, 2 H), 1.56-1.70 (m, 2H), 1.24 (s, 1H)
    2.17 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (d, J = 1.27 Hz, 1H), 8.14 (dd,
    J = 8.05, 1.46 Hz, 1H), 8.05 (d, J = 1.90 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.52
    (d, J = 2.28 Hz, 1H), 7.50 (d, J = 2.28 Hz, 1H), 6.97-7.02 (m, 1H), 6.91-6.95 (m,
    1 H), 6.34 (d, J = 8.49 Hz, 1H), 5.49 (s, 2H), 4.31 (d, J = 5.58 Hz, 2H), 3.66 (d,
    J = 1.27 Hz, 4H), 3.40 (dt, J = 14.54, 5.66 Hz, 4H), 2.07 (s, 1H), 1.99 (s, 3H),
    1.70-1.77 (m, 2H), 1.26 (s, 1H)
    2.18 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J = 1.52 Hz, 1H), 8.01-8.09 (m,
    1 H), 7.71 (d, J = 8.11 Hz, 1H), 7.51 (dd, J = 8.49, 2.41 Hz, 1H), 7.09 (s, 1H),
    6.90-7.01 (m, 1 H), 6.87 (t, J = 5.64 Hz, 1H), 6.82 (s, 1 H), 6.34 (d, J = 8.36 Hz,
    1H), 5.45 (s, 2H), 4.32 (d, J = 5.70 Hz, 2H), 3.66 (d, J = 1.27 Hz, 4H), 3.40 (dt,
    J = 14.76, 5.54 Hz, 4H), 2.5 (m, 1H), 1.99 (s, 3H), 1.71-1.77 (m, 2 H), 1.61-1.68
    (m, 2H)
    2.19 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (d, J = 1.39 Hz, 1H), 8.14 (dd,
    J = 8.05, 1.46 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.19 (d, J = 8.62 Hz, 2H), 6.98
    (q, J = 9.38 Hz, 2H), 6.85-6.88 (m, 2H), 6.84 (s, 1H), 5.49 (s, 2H), 4.35 (d,
    J = 5.58 Hz, 2H), 4.27 (br d, J = 5.20 Hz, 2H), 3.80-3.97 (m, 1H), 3.39 (br d,
    J = 11.79 Hz, 2H), 2.84 (br d, J = 12.80 Hz, 1H), 1.96 (s, 3H), 1.84-1.91 (m, 2H),
    1.68-1.81 (m, 1H), 1.48-1.64 (m, 1H)
    2.20 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (d, J = 1.27 Hz, 1H), 8.14 (dd,
    J = 8.05, 1.46 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.17 (d, J = 8.74 Hz, 2H), 6.90-
    7.02 (m, 2H), 6.82 (br d, J = 3.55 Hz, 1H), 6.54-6.70 (m, 2H), 5.49 (s, 2H), 4.60
    (br s, 1H), 4.32 (d, J = 5.58 Hz, 2H), 4.05-4.23 (m, 2H), 3.57-3.71 (m, 1H),
    3.52 (br d, J = 10.14 Hz, 1H), 3.42 (br s, 2H), 2.01 (s, 2H), 1.90 (s, 3H), 1.67-
    1.86 (m, 1H)
    2.21 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (d, J = 1.39 Hz, 1H), 8.14 (dd,
    J = 8.11, 1.52 Hz, 1H), 7.92 (d, J = 7.98 Hz, 1H), 7.20 (t, J = 8.43 Hz, 1H), 6.90-
    7.03 (m, 2 H), 6.83 (t, J = 5.58 Hz, 1H), 6.12-6.37 (m, 2H), 5.49 (s, 2H), 4.37 (d,
    J = 5.45 Hz, 2H), 4.27 (s, 2H), 3.99 (s, 2H), 3.92 (s, 4H), 1.74 (s, 3H)
    2.22 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.39 Hz, 1H), 8.14 (dd, J = 1.52,
    8.11 Hz, 1H), 7.92 (d, J = 8.11 Hz, 1H), 7.16 (d, J = 8.49 Hz, 2H), 6.90-7.05 (m,
    2H), 6.83 (t, J = 5.70 Hz, 1H), 6.38 (d, J = 8.49 Hz, 2H), 5.49 (s, 2H), 4.33 (d,
    J = 5.58 Hz, 2H), 3.51-3.59 (m, 4H), 3.37-3.45 (m, 4H), 1.99 (s, 3H), 1.60-1.78
    (m, 4H)
    2.23 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (s, 1H), 8.14 (d, J = 8.11 Hz, 1H),
    7.92 (d, J = 8.11 Hz, 1H), 7.16 (dd, J = 8.62, 2.66 Hz, 1H), 6.97-7.05 (m, 1H),
    6.95 (d, J = 5.45 Hz, 1H), 6.92 (d, J = 5.45 Hz, 1H), 6.77-6.89 (m, 1H), 6.56 (d,
    J = 7.98 Hz, 2H), 5.49 (s, 2H), 4.74 (s, 1H), 4.58 (br d, J = 8.74 Hz, 1H), 4.47 (s,
    1H), 4.32 (t, J = 5.51 Hz, 2H), 3.58 (dd, J = 9.00, 1.77 Hz, 1H), 3.48-3.55 (m,
    1H), 3.34 (d, J = 9.89 Hz, 1H), 2.91 (d, J = 8.87 Hz, 1H), 1.98 (s, 2H), 1.90-1.95
    (m, 1H) 1.80-1.89 (m, 1H)
    • Example 3 1-[4-(4-{[(6-{[6-(Difluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-yl)amino]methyl}-phenyl)piperazin-1-yl]ethan-1-one
  • Figure US20230100516A1-20230330-C00140
  • A mixture of 80.0 mg (0.22 mmol) 3-{[6-(difluoromethyl)pyridin-3-yl]methoxy}-6-iodopyridazine (example 1.1), 61.7 mg (0.26 mmol) 1-{4-[4-(aminomethyl)phenyl]piperazin-1-yl}ethan-1-one (example III.5), 260 μL (0.66 mmol) sodium tert-pentoxide (2.5 mol/L in methyl-THF) and 2.0 mg (2.20 μmol) JOSIPHOS SL-J009-1 Pd G3 (MDL No. MFCD27978424) in 0.4 mL tert-amylalcohol is stirred at 35° C. overnight. The reaction mixture is diluted with ACN and DMF, filtered und purified by prep. HPLC to yield 12 mg of the product.
      • C24H26F2N6O2 (M=468.5 g/mol)
      • ESI-MS: 469 [M+H]+
      • Rt (HPLC): 0.88 min (method A)
  • 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J=1.39 Hz, 1H), 8.05 (dd, J=1.90, 7.98 Hz, 1H), 7.71 (d, J=7.98 Hz, 1H), 7.22 (d, J=8.62 Hz, 2H), 6.97-7.12 (m, 1H), 6.83-6.97 (m, 5H), 5.44 (s, 2H), 4.37 (d, J=5.58 Hz, 2H), 3.50-3.60 (m, 4H), 3.00-3.20 (m, 4H), 2.03 (s, 3H)
    • Example 4 1-[(3aR,8aS)-2-(4-{[(6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-yl)amino]methyl}phenyl)-decahydropyrrolo[3,4-d]azepin-6-yl]ethan-1-one
  • Figure US20230100516A1-20230330-C00141
  • 59.7 mg (0.27 mmol) 1-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]ethan-1-one hydrochloride (example XIII), 100.0 mg (0.23 mmol)N-[(4-bromophenyl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-amine (example VIII), 17.7 mg (0.02 mmol) 2nd generation Ruphos precatalyst and 48.1 mg (0.50 mmol) sodium-tertbutoxide are dissolved in 1.00 mL methyl-THF under argon atmosphere. The solution is degassed a few times. The reaction solution is stirred at 80° C. for 2 h. Then another 481 mg (0.50 mmol) sodium-tert-butoxide are added and the reaction solution is stirred at 100° C. overnight. The reaction solution is filtered and purified by HPLC to afford 14 mg of the product.
      • C28H31F3N6O2 (M=540.6 g/mol)
      • ESI-MS: 541 [M+H]+
      • Rt (HPLC): 0.81 min (method F)
  • 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.27 Hz, 1H), 8.13 (dd, J=1.46, 8.05 Hz, 1H), 7.92 (d, J=7.98 Hz, 1H), 7.14 (d, J=8.49 Hz, 2H), 6.90-7.05 (m, 2H), 6.79 (t, J=5.64 Hz, 1H), 6.47 (d, J=8.62 Hz, 2H), 5.49 (s, 2H), 4.31 (d, J=5.58 Hz, 2H), 3.57-3.80 (m, 2H), 3.33-3.46 (m, 4H), 3.20-3.30 (m, 2H), 2.93 (td, J=6.23, 9.35 Hz, 2H), 2.00 (s, 3H), 1.53-1.89 (m, 4H)
    • Example 5 1-((3aR,3bS,6aR,6bS)-5-(4-(((6-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)phenyl)octahydrocyclobuta[1,2-c:3,4-c′]dipyrrol-2(1H)-yl)ethan-1-one
  • Figure US20230100516A1-20230330-C00142
  • 15 mg (0.03 mmol)N-(4-((3aR,3bS,6aR,6bS)-octahydrocyclobuta[1,2-c:3,4-c′]dipyrrol2(1H)-yl)benzyl)-6-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3-amine (example XIV) is dissolved in 0.5 mL DCM and 2.86 μL mL (0.03 mmol) acetic anhydride is added. The reaction mixture is stirred for 1 h at RT. The reaction solution is diluted with 0.5 mL MeOH and is purified by HPLC to afford 7 mg of the product.
      • C28H29F3N6O2 (M=538.564 g/mol)
      • ESI-MS: 539 [M+H]+
      • Rt (HPLC): 0.99 min (method A)
  • 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.89 (d, J=1.14 Hz, 1H), 8.19 (dd, J=1.52, 8.11 Hz, 1H), 7.94 (d, J=8.24 Hz, 1H), 7.85 (d, J=9.50 Hz, 1H), 7.41 (d, J=9.38 Hz, 1H), 7.08 (d, J=8.49 Hz, 2H), 6.65 (d, J=8.62 Hz, 2H), 5.63 (s, 2H), 5.06 (s, 2H), 3.79 (d, J=12.17 Hz, 1H), 3.66 (d, J=11.15 Hz, 1H), 3.54 (dd, J=1.90, 9.89 Hz, 2H), 3.35 (br dd, J=6.78, 11.22 Hz, 2H), 3.06 (dd, J=6.84, 12.29 Hz, 1H), 2.82 (br dd, J=6.97, 9.51 Hz, 2H), 2.55-2.64 (m, 1H), 2.44-2.49 (m, 2H), 2.02-2.06 (m, 3H)
    • Analytical HPLC Methods Method A
  • time Vol.-% water Flow
    (min) (incl. 0.1% NH4OH) Vol.-% ACN [mL/min]
    0.00 97 3 2.2
    0.20 97 3 2.2
    1.20 0 100 2.2
    1.25 0 100 3
    1.40 0 100 3

    Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60° C.
    • Method B
  • time Vol.-% water Flow
    (min) (incl. 0.1% TFA) Vol.-% ACN [mL/min]
    0.00 97 3 2.2
    0.20 97 3 2.2
    1.20 0 100 2.2
    1.25 0 100 3.0
    1.40 0 100 3.0
  • Analytical column: Stable Bond (Agilent) 1.8 μm; 3.0×30 mm; column temperature: 60° C.
    • Method C
  • time Vol.-% water Flow
    (min) (incl. 0.1% NH4OH) Vol.-% ACN [mL/min]
    0.00 95 5 1.5
    1.30 0 100 1.5
    1.50 0 100 1.5
    1.60 95 5 1.5
  • Analytical column: XBridge (Waters) C18_3.0×30 mm_2.5 μm; column temperature: 60° C.
    • Method D
  • time Vol.-% water Flow
    (min) (incl. 0.1% NH4OH) Vol.-% ACN [mL/min]
    0.00 95 5 1.5
    1.30 0 100 1.5
    1.50 0 100 1.5
    1.60 95 5 1.5

    Analytical column: XBridge C18_3.0×30 mm_2.5 μm (Waters); column temperature: 60° C.
    • Method E
  • time Vol.-% water Flow
    (min) (incl. 0.1% TFA) Vol.-% ACN [mL/min]
    0.00 97 3 2.2
    0.20 97 3 2.2
    1.20 0 100 2.2
    1.25 0 100 3.0
    1.40 0 100 3.0
  • Analytical column: Sunfire (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60° C.
    • Method F
  • time Vol.-% water Flow
    (min) (incl. 0.1% NH4OH) Vol.-% ACN [mL/min]
    0.00 95 5 1.5
    1.30 0 100 1.5
    1.50 0 100 1.5
    1.60 95 5 1.5
  • Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60° C.

Claims (9)

1. A compound according to formula (I)
Figure US20230100516A1-20230330-C00143
wherein
A is pyridyl substituted with one or two members of the group consisting of fluoro and F1-7-fluoro-C1-3-alkyl;
E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of fluoro and F1-7-fluoro-C1-3-alkyl;
K is selected from the group consisting of
Figure US20230100516A1-20230330-C00144
R3 is selected from the group consisting of R4(O)C—, oxetanyl, methyl,
R5(O)C(CH3)N— and R5(O)CHN—;
R4 is methyl;
R5 is methyl.
2. The compound of formula (I) according to claim 1, wherein A is pyridyl substituted with one or two members of the group consisting of F and F1-3-fluoro-C1-alkyl.
3. The compound of formula (I) according to claim 1, wherein A is selected from the group consisting of
Figure US20230100516A1-20230330-C00145
4. The compound of formula (I) according to claim 1, wherein E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of F, F2HC, and F3C.
5. The compound of formula (I) according to claim 1, wherein E is selected from the group consisting of
Figure US20230100516A1-20230330-C00146
6. The compound of formula (I) according to claim 1, selected from the group consisting of
Figure US20230100516A1-20230330-C00147
Figure US20230100516A1-20230330-C00148
Figure US20230100516A1-20230330-C00149
Figure US20230100516A1-20230330-C00150
Figure US20230100516A1-20230330-C00151
7. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
8. A method for the treatment or prevention of inflammatory airway diseases or fibrotic diseases comprising administering to a patient a compound of formula (I) according to claim 1 or pharmaceutically acceptable salt thereof.
9. The method according to claim 8, wherein said method is for the treatment or prevention of idiopathic lung disease (IPF) or systemic sclerosis (SSc).
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