WO2022049253A1 - Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators - Google Patents

Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators Download PDF

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WO2022049253A1
WO2022049253A1 PCT/EP2021/074382 EP2021074382W WO2022049253A1 WO 2022049253 A1 WO2022049253 A1 WO 2022049253A1 EP 2021074382 W EP2021074382 W EP 2021074382W WO 2022049253 A1 WO2022049253 A1 WO 2022049253A1
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pyridin
acetamide
acetamido
chloro
nitropyridin
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PCT/EP2021/074382
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French (fr)
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Stefan BÄURLE
Sven Ring
Jens Nagel
Alexis LAUX-BIEHLMANN
Reinhard Nubbemeyer
Elisabeth Pook
Daryl Simon Walter
John Scott
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Bayer Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • WO2019081573A1 describes as well pharmaceutical compositions and combinations comprising an active ingredient which is an antagonist or a negative allosteric modulator of P2X4 for the treatment or prophylaxis of brain ischemia, ischemic brain injury, Ischemic Stroke (IS), haemorrhagic stroke, traumatic brain injury, spinal cord injury.
  • WO2019177117A1 describes a drug for preventing or treating cough, the drug containing as an active ingredient a compound having a P2X4 receptor antagonizing action, a tautomer, stereoisomer, or pharmacologically acceptable salt of said compound, or a hydrate or solvate thereof.
  • R7, R8, R9, R10 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C 1 -C 3 )-alkyl, cyclopropyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, -SCH 3 , (C 1 -C 3 )-haloalkoxy,
  • R2 is (C 1 -C 3 )-alkyl
  • R12, R13 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, -SCH 3 , (C 1 -C 3 )-haloalkoxy,
  • heteroaryl includes all possible isomeric forms thereof, e.g. tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term pyrimidinyl includes pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl; or the term pyrazolyl includes 7/7-pyrazolyl; or the term imidazolyl includes 7/7-imidazolyl and 4/7- imidazolyl; the term thiophenyl includes 2-thiophenyl and 3-thiophenyl; or the term thiazolyl includes 1 ,3-thiazol-5-yl, 1 ,3-thiazol-4-yl and 1 ,3
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • R3 means a chlorine, fluorine, cyano
  • R4a is a halogen atom, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-haloalkoxy in position 6 of the phenyl group
  • R4b is a halogen atom, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-haloalkyl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-haloalkoxy in position 4 of the phenyl group.
  • R3 is selected from the group consisting of a hydrogen atom, methyl, fluorine, and chlorine
  • R4a is selected from the group consisting of a hydrogen atom, methyl, and chlorine, -CF 3 , and -OCF 3
  • R4b is selected from the group consisting of a hydrogen atom, methyl, fluorine, chlorine, and -CF 3 .
  • the reaction with HATLI or T3P takes place in an inert solvent, such as N,N-dimethylformamide, dichloromethane or dimethyl sulfoxide in the presence of the appropriate aromatic amine of general formula (VIII) and a tertiary amine (such as triethylamine or diisopropylethylamine) at temperatures between -30 °C and +80 °C.
  • an inert solvent such as N,N-dimethylformamide, dichloromethane or dimethyl sulfoxide
  • a tertiary amine such as triethylamine or diisopropylethylamine
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to effectively inhibit P2X4, as antagonists or negative allosteric modulators, and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases.
  • Neurodegenerative disorders such as Alzheimer's disease, Parkinson’s disease, Stroke, brain ischemia, ischemic brain injury, Ischemic Stroke (IS), haemorrhagic stroke, traumatic brain injury, spinal cord injury;
  • the present invention also provides methods of treating the following pain syndromes, diseases or disorders:
  • Pain-associated syndromes disease or disorders, including hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, abdominal pain such as functional bowel disorders, irritable bowel syndrome, inflammatory bowel disease, bladder pain syndrome, inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis-associated pain, pain associated with fibrotic diseases, central pain;
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular of the diseases reported above.
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • surfactants for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),
  • the catalyst was filtered off via cehte and rinsed with ethyl acetate.
  • the filtrate was partitioned between water and ethyl acetate and extracted with ethyl acetate.
  • the combined arganic layers were washed with brine, dried with sodium sulfate and the solvents removed in vacuo.
  • the crude product was purified via chromatography.
  • the nitro compound was dissolved in acetic acid and iron powder (5 eq.) was added. The mixture was vigorously stirred for 18 h. Solids were filtered off via a celite pad and rinsed with ethyl acetate. The organic phase evaporated to dryness. The residue was either codestilled several times with toluene until all acetic acid was removed or it was partitioned between ethyl acetate and water and sat. aqueous sodium bicarbonate solution added until pH > 7. The phases were separated, the aqueous layer extracted with ethyl acetate and the combined organic layers were washed with sat. aqueous sodium bicarbonate solution and brine and dried with sodium sulfate. The solvents were removed in vacuo and the product was taken to the next step without further purification.
  • Step 2 Methyl 5-[(tert-butoxycarbonyl)amino]-2-methylpyrazolo[1,5-a]pyridine-3- carboxylate
  • N-(5-fluoropyridin-3-yl)-N-(4-nitropyridin-2-yl)acetamide (Int. 59) (910 mg, 3.29 mmol) were dissolved in ethanol (55 mL), the palladium catalyst was added (10%Pd on activated charcoal, 350 mg, 0.1 eq.) and the mixture hydrogenated (1 atm hydrogen) for 2 h at rt. The catylyst was filtered off, rinsed with ethanol and DCM and the solvent evaporated to dryness. The residue was purified via chromatography to yield 370 mg (45% of theory) of the title compound as colorless dry foam.
  • N-(3-chloropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide (Int. 79, 820 mg, 2.80 mmol) were dissolved in acetic acid (32 mL) and iron powder (5 eq., 782 mg, 14.0 mmol) was added portionwise. The mixture was vigorously stirred for 18 h at rt. Then the solids were filtered off via a pad of celite, rinsed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and sat. aqueous sodium bicarbonate solution added until pH > 7.
  • N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)acetamide (Int. 110, 100 mg, 0.38 mmol) and 2-chlorophenylacetic acid (130 mg, 2 eq.) were dissolved in DMF (3 mL) and T3P (363 mg, 1.14 mmol, 3 eq.) and triethylamine (230 mg, 2.28 mmol, 6 eq.) were added.

Abstract

Substituted N-heteroaryl-N-pyridinylacetamide of general formula (I), methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases.

Description

SUBSTITUTED N-HETEROARYL-N-PYRIDINYLACETAMIDES AS P2X4 MODULATORS
The present invention covers substituted N-heteroaryl-N-pyridinylacetamide compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for the treatment or prophylaxis of diseases associated with pain, pain syndromes (acute and chronic), inflammatory- induced pain, neuropathic pain, diabetic neuropathic pain, diabetic neuropathy, cancer- associated pain, chemotherapy or intoxication induced pain, pelvic pain, endometriosis- associated pain as well as endometriosis as such, bladder pain syndrome; asthma, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease (COPD), chronic cough, diseases related to goblet cells and lung fibrosis, liver fibrosis, fatty liver disorders, NASH (Non-Alcoholic Steato-Hepatitis); brain ischemia, ischemic brain injury, ischemic stroke, haemorrhagic stroke, traumatic brain injury, spinal cord injury, aneurysm; dry eye, ocular neuropathic pain; chronic itch, pruritus; osteoarthritis, burning mouth syndrome, migraine disorders, irritable bowel disease; urology related syndromes like, overactive urinary bladder, interstitial cystitis, bladder pain syndrome. The present invention, as described and defined herein, covers pharmaceutical compositions and combinations comprising an active ingredient which is an antagonist or a negative allosteric modulator of P2X4.
BACKGROUND
The present invention covers substituted N-heteroaryl-N-pyridinylacetamides of general formula (I) which are antagonists or negative allosteric modulators of P2X4. Adenosine triphosphate ATP is widely recognized as an important neurotransmitter implicated in various physiological and pathophysiological roles by acting through different subtypes of purinergic receptors (Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 2011, Prog Neurobiol 95:229-274). To date, seven members of the P2X family have been cloned, comprising P2X1-7 (Burnstock 2013, Front Cell Neurosci 7:227). The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types largely known to be involved in inflammatory/ immune processes specifically including monocytes, macrophages, mast cells and microglia cells (Wang et al., 2004, BMC Immunol 5:16; Brone et al., 2007 Immunol Lett 113:83-89). Activation of P2X4 by extracellular ATP is known, amongst other things, to lead to release of pro-inflammatory cytokines and prostaglandins (PGE2) (Bo et al., 2003 Cell Tissue Res 313:159-165; lllmann et al., 2010, EMBO Journal 29:2290-2300; de Ribero Vaccari et al., 2012, J Neurosci 32:3058-3066). Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain. Mice lacking the P2X4 receptor do not develop pain hypersensitivity in response to numerous inflammatory challenges such as complete Freunds Adjuvant (CFA), carrageenan or formalin (lllmann et al., 2010, EMBO Journal 29:2290-2300). In addition, mice lacking the P2X4R do not develop mechanical allodynia after peripheral nerve injury, indicating very prominent role of P2X4 in neuropathic pain conditions (Tsuda et al., 2009, Mol Pain 5:28; Ulmann et al., 2008, J Neurocsci 28:11263-11268). Moehring et al. (Elife. 2018 Jan 16;7 ’’Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling”) reported experiments identifying P2X4 signalling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signalling that occurs in cutaneous pain and itch disorders.
Besides the extensively described role of P2X4 in acute and chronic pain-related diseases (Trang and Salter, 2012, Purinergic Signalling 8:621-628; Burnstock , 2013 Eur J Pharmacol 716:24-40), P2X4 is considered as a critically important mediator of inflammatory diseases such as, respiratory diseases (e.g. asthma, COPD), lung diseases including fibrosis, cancer and atherosclerosis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).
EP 2 597 088 A1 describes P2X4 receptor antagonists and in particular a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further disclosed the use of P2X4 receptor antagonist diazepine derivatives represented by the formula (I), (II), (III), or its pharmacologically acceptable salt, which shows P2X4 receptor antagonism, being effective as an agent for prevention or treatment of nociceptive, inflammatory, and neuropathic pain. In more detail, EP 2 597 088 A1 describes P2X4 receptor antagonists being effective as a preventive or therapeutic agent for pain caused by various cancers, diabetic neuritis, viral diseases such as herpes, and osteoarthritis. The preventive or therapeutic agent according to EP 2 597 088 A1 can also be used in combination with other agents such as opioid analgesic (e.g., morphine, fentanyl), sodium channel inhibitor (e.g., novocaine, lidocaine), or NSAIDs (e.g., aspirin, ibuprofen). The P2X4 receptor antagonist used for pain caused by cancers can be also used in combination with a carcinostatic such as a chemotherapic. Further P2X4 receptor antagonists and their use are disclosed in W02013105608, W02015005467 and W02015005468, WO2016198374, W02017191000, WO2018/104305, WO2018/104307.
“Discovery and characterization of novel, potent and selective P2X4 receptor antagonists for the treatment of pain” was presented at the Society for Neuroscience Annual Meeting 2014 (Carrie A Bowen et al.; poster N. 241.1) Said poster describes the methods to identify novel, potent and selective small-molecule antagonists that inhibit P2X4 across species, and how to evaluate selected compounds in experimental models of neuropathic and inflammatory pain. In particular a method for human, rat, mouse P2X4R FLI PR-based screening, a human P2X4R electrophysiology assay, a suitable mouse neuropathy model and a mouse inflammation model were described.
WO2015088564 and WO2015088565 provide P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. Said P2X4 receptor modulating compounds are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
LIS2018/0280409 describes methods for the treatment of a human subject who has had a stroke by administering to the subject a pharmaceutical composition including an antagonist of the P2X4 receptor. The antagonist of the P2X4 receptor can be administered in the acute phase of stroke, optionally in combination with a thrombolytic therapeutic or a procedure on the subject involving a clot-removal device.
WO2019081573A1 describes as well pharmaceutical compositions and combinations comprising an active ingredient which is an antagonist or a negative allosteric modulator of P2X4 for the treatment or prophylaxis of brain ischemia, ischemic brain injury, Ischemic Stroke (IS), haemorrhagic stroke, traumatic brain injury, spinal cord injury. WO2019177117A1 describes a drug for preventing or treating cough, the drug containing as an active ingredient a compound having a P2X4 receptor antagonizing action, a tautomer, stereoisomer, or pharmacologically acceptable salt of said compound, or a hydrate or solvate thereof.
There is no reference in the state of the art about substituted N-heteroaryl-N- pyridinylacetamides of general formula (I) as described and defined herein and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, particularly to the use of substituted N-heteroaryl- N-pyridinylacetamides of general formula (I) for the treatment or prophylaxis of diseases associated with pain, or for the treatment or prophylaxis of pain syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain including diabetic neuropathic pain, pelvic pain, cancer or chemotherapy -associated pain, endometriosis-associated pain as well as endometriosis as such, bladder pain syndrome, cancer as such, and proliferative diseases as such like endometriosis, as a sole agent or in combination with other active ingredients.
Therefore, the inhibitors of P2X4 of the current invention represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.
DESCRIPTION of the INVENTION
In accordance with a first aspect, the present invention covers compounds of general formula (I) in which:
Figure imgf000005_0001
R1 is selected from the group consisting of a 5- or 6-membered heteroaryl being a monovalent, monocyclic heteroaryl having 5 or 6 ring atoms and wherein one, two or three ring atoms of a monovalent 5-membered hydrocarbon ring system being replaced by one, two or three heteroatoms independently selected from S, N, NH and O; and wherein one or two ring atoms of a monovalent 6- membered hydrocarbon ring system being replaced by one or two nitrogen atoms and said 5- or 6-membered heteroaryl being connected through a carbon or a nitrogen atom to the rest of the molecule or a bicyclic 8- to 10-membered heteroaryl being a bicyclic, monovalent, fused or bridged heterobicycloalkyl, having 8, 9 or 10 ring atoms with at least one aromatic ring and wherein one, two or three ring atoms of a monovalent, 8- to 10-membered bicyclic hydrocarbon ring system being replaced by one, two or three heteroatoms independently selected from NH, N, O, S, SO and SO2., said bicyclic 8- to 10-membered heteroaryl being connected through a carbon or a nitrogen atom to the rest of the molecule, and in which the 5- or 6-membered heteroaryl and bicyclic 8- to 10-membered heteroaryl comprise a group_R7, R8, R9, R10, R12, R13, R14, R2 is (C1-C3)-alkyl,
R3 is a halogen atom, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy,
R4a, R4b is selected from the group consisting of a hydrogen, a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy,
R7, R8, R9, R10 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, cyclopropyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, -SCH3, (C1-C3)-haloalkoxy,
R12, R13 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, -SCH3, (C1-C3)-haloalkoxy,
R14 is selected from the group consisting of a hydrogen atom, (C1-C3)-alkyl, (C1-C3)-haloalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a second aspect, the present invention covers compounds of general formula (I):
Figure imgf000006_0001
In which R1 is selected from the group consisting of a 5- or 6-membered heteroaryl
Figure imgf000006_0002
a bicyclic 8- to 10-membered heteroaryl
Figure imgf000007_0001
R2 is (C1-C3)-alkyl,
R3 a halogen atom, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy, R4a, R4b is selected from the group consisting of a hydrogen, a halogen atom,
(C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy,
R5 is selected from the group consisting of -CH2OCH2-, -OCH2CH2-, -OCH2O-, -OCH2OCH2-, and -OCH2CH2O-;
R6 is selected from the group consisting of
Figure imgf000007_0002
R7, R8, R9, R10 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, cyclopropyl, (C1-C3)-haloalkyl, (C1-C3)- alkoxy, -SCH3, (C1-C3)-haloalkoxy
R11 is selected from the group consisting of
Figure imgf000008_0001
R12, R13 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, -SCH3, (C1-C3)-haloalkoxy,
R14 is selected from the group consisting of a hydrogen atom, (C1-C3)-alkyl, (C1-C3)-haloalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
DEFINITIONS:
The term “comprising” when used in the specification includes “consisting of’.
If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.
The terms as mentioned in the present text have the following meanings:
The term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, more particularly fluorine or chlorine atom.
In the context of the present invention, the substituents and residues have the following meanings, unless specified otherwise: in the context of the invention means a straight-chain or branched alkyl
Figure imgf000008_0002
group having 1, 2, or 3 carbon atoms, such as: methyl, ethyl, n-propyl, isopropyl, and isobutyl, for example. C1-C3 )-Alkoxy in the context of the invention means a straight-chain or branched alkoxy group having 1, 2, or 3 carbon atoms, such as: methoxy, ethoxy, n-propoxy, and isopropoxy, for example.
5- or 6-membered heteroaryl is understood as meaning a monovalent, monocyclic heteroaryl having 5 or 6 ring atoms and wherein one, two or three ring atoms of a monovalent 5-membered hydrocarbon ring system is/are replaced by one, two or three heteroatoms independently selected from S, N, NH and O; and wherein one or two ring atoms of a monovalent 6-membered hydrocarbon ring system is/are replaced by one or two nitrogen atoms. The said 5- or 6-membered heteroaryl can be connected through a carbon or a nitrogen atom, if said nitrogen atom is present.
Said 5- or 6-membered heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.
In general, and unless otherwise mentioned, the term “heteroaryl” includes all possible isomeric forms thereof, e.g. tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, to give some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term pyrimidinyl includes pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl; or the term pyrazolyl includes 7/7-pyrazolyl; or the term imidazolyl includes 7/7-imidazolyl and 4/7- imidazolyl; the term thiophenyl includes 2-thiophenyl and 3-thiophenyl; or the term thiazolyl includes 1 ,3-thiazol-5-yl, 1 ,3-thiazol-4-yl and 1 ,3-thiazol-2-yl.
Bicyclic 8- to 10-membered heteroaryl is understood as meaning a bicyclic, monovalent, fused heteroaryl having 8, 9 or 10 ring atoms with at least one aromatic ring and wherein one, two or three ring atoms of a monovalent, 8- to 10-membered bicyclic hydrocarbon ring system is/are replaced by one, two or three heteroatoms independently selected from NH, N, O, S, SO and SO2.
The said bicyclic 8- to 10-membered heteroaryl can be connected through a carbon or a nitrogen atom, if said nitrogen atom is present and includes by definition fused and bridged heterobicycloalkyl groups.
Particularly, bicyclic heteroaryl is selected from for example, benzofuranyl, benzothienyl, benzothiazolyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, benzothiadiazolyl, indazolyl, indolyl, isoindolyl, etc. or for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; indolizinyl, or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention optionally contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to IIIPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co- precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, N- methylpiperidine, /V-methyl-glucamine, /V,/V-dimethyl-glucamine, /V-ethyl-glucamine, 1 ,6- hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1 ,3-propanediol, 3-amino- 1 ,2-propanediol, 4-amino-1 ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-ber\zy\-N,N,N- trimethylammonium, choline or benzalkonium. Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI",
"x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
In a specific embodiment of the invention R1 is selected from the group consisting of a 5- or 6-membered heteroaryl
Figure imgf000013_0001
a bicyclic 8- to 10-membered heteroaryl
Figure imgf000013_0002
R5 is selected from the group consisting of -CH2OCH2-, -OCH2CH2-, -OCH2O-, -OCH2OCH2-, and -OCH2CH2O-,
R6 is selected from the group consisting of
Figure imgf000013_0003
R11 is selected from the group consisting of
Figure imgf000013_0004
R14 is selected from the group consisting of a hydrogen atom, (Ci-C3)-alkyl, (C1-C3)-haloalkyl, preferably from the group consisting of a hydrogen atom or methyl and more preferably R14 is a methyl.
A specific embodiment of the invention is that in which R2 means methyl, ethyl or n- propyl; more particularly R2 means a methyl or ethyl.
According to a further embodiment of the invention, R3 means a chlorine, fluorine, cyano, or a hydrogen atom.
In a further specific embodiment of the invention, R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy; and R4b is a hydrogen atom.
Furthermore, in relation to a further form of the invention, R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)- alkoxy, (C1-C3)-haloalkoxy; and R4b is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy.
The invention further comprises particular embodiments in which R3 means a chlorine, fluorine, cyano, R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy in position 3 or 6 of the phenyl group; and R4b is a hydrogen atom.
In a further specific embodiment of the invention R3 means a chlorine, fluorine, cyano, R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy in position 6 of the phenyl group; and R4b is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy in position 4 of the phenyl group.
In a further specific embodiment of the invention R3 is selected from the group consisting of a hydrogen atom, methyl, fluorine, and chlorine; R4a is selected from the group consisting of a hydrogen atom, methyl, and chlorine, -CF3, and -OCF3; and R4b is selected from the group consisting of a hydrogen atom, methyl, fluorine, chlorine, and -CF3.
According to a particular form of embodiment according to the invention R1 is selected from the group consisting of a 5- or 6-membered heteroaryl
Figure imgf000015_0001
a bicyclic 8- to 10-membered heteroaryl
Figure imgf000015_0002
R2 is selected from the group consisting of methyl, and -CH2CH3,
R3 is selected from the group consisting of a hydrogen atom, methyl, fluorine, and chlorine,
R4a is selected from the group consisting of a hydrogen atom, methyl, chlorine, -CF3, and -OCF3, R4b is selected from the group consisting of a hydrogen atom, methyl, fluorine, chlorine, and -CF3,
R4c is selected from the group consisting of a hydrogen atom, methyl, fluorine, and chlorine,
R5 is selected from the group consisting of -CH2OCH2-, -OCH2CH2-, -OCH2O-, -OCH2OCH2-, and -OCH2CH2O-
R6 is selected from the group consisting of
Figure imgf000015_0003
R11 is selected from the group consisting of
Figure imgf000016_0001
R7 is selected from the group consisting of a hydrogen atom and fluorine,
R8 is selected from the group consisting of a hydrogen atom, methyl, cyano, cyclopropyl, -CF2H, -CF3 and -OCF3,
R9 is selected from the group consisting of a hydrogen atom, methyl, fluorine, chlorine, cyano, and -CF3,
R10 is selected from the group consisting of a hydrogen atom, methyl, fluorine, -OCH3, and -OCH2CH3,
R12 is selected from the group consisting of a hydrogen atom, fluorine, chlorine, -OCH3, and -SCH3,
R13 is selected from the group consisting of a hydrogen atom, fluorine, chlorine, and -OCH3;
R14 is a methyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers combinations of two or more of the above-mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra. The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (VI), (IX), (X):
Figure imgf000017_0001
in which R1 and R2 are defined according to the group R1 and R2 of general formula (I).
The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra, namely:
1 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4-yl)acetamide
2 N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2,5- dimethylpyridin-4-yl)acetamide
3 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,5-dimethylpyridin-4- yl)acetamide
4 N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,5-dimethylpyridin-4- yl)acetamide
5 N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,5-dimethylpyridin-4- yl)acetamide
6 N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,5-dimethylpyridin-4- yl)acetamide
7 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-methylpyridin-4-yl)acetamide
8 N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-methylpyridin-4- yl)acetamide
9 N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-methylpyridin-4- yl)acetamide
10 N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(3-methylpyridin-4- yl)acetamide
11 N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[3-(trifluoromethyl)pyridin-4- yl]acetamide N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyndin-2-yl}-N-(3-cyanopyridin-4- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-3-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-3-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-3-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoropyridin-3-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoropyridin-3- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoropyridin-3- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoropyridin-3- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1,5-naphthyridin-3-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1,5-naphthyridin-3- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1,5-naphthyridin-3- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(1,5-naphthyridin-3- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-methylpyridin-4- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[2-(difluoromethyl)pyridin-4- yl]acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[2-(difluoromethyl)pyridin-4- yl]acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[2-(trifluoromethyl)pyridin-4- yl]acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-cyclopropylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-cyclopropylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-cyclopropylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(2- cyclopropylpyridin-4-yl)acetamide N-(2-cyclopropylpyndin-4-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-cyanopyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-cyanopyridin-4- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,6-dimethylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,6-dimethylpyridin-4- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,6-dimethylpyridin-4- yl)acetamide
N-(pyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(pyrazolo[1,5- a]pyridin-5-yl)acetamide
N-(4-{2-[4-fluoro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(pyrazolo[1,5- a]pyridin-5-yl)acetamide
N-(4-{2-[3-fluoro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(pyrazolo[1,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5- a]pyridin-5-yl)acetamide
N-(pyrazolo[1 ,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6-trimethylphenyl)acetamido]pyridin-2- yljacetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(pyrazolo[1,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin-5- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)acetamide N-{4-[2-(2,6-dichlorophenyl)acetamido]pyndin-2-yl}-N-(pyrazolo[1,5-a]pyndin-5- yl)acetamide
N-{4-[2-(2,6-dichloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-(pyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-fluoro-2-(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(2-methylpyrazolo[1 ,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methylpyrazolo[1,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-methylpyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-7-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-7- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-7- yl)acetamide
N-(1-benzothiophen-5-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1-benzothiophen-5-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1-benzothiophen-5-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-6-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-6- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-6-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4-yl)acetamide N-{4-[2-(2,3-dimethylphenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[2-(trifluoromethyl)phenyl]acetamido}pyridin-2- yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- fluoropyridin-4-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[4-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[3-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,3-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,6-dichloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[2-(trifluoromethoxy)phenyl]acetamido}pyridin-2- yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[4-fluoro-2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methoxypyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-methoxypyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-methoxypyridin-4- yl)acetamide N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-methoxypyridin-4- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[2-(trifluoromethoxy)pyridin-4- yl]acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[2-(trifluoromethoxy)pyridin-
4-yl]acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- ethoxypyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-ethoxypyridin-4-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-ethoxypyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-ethoxypyridin-4- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-ethoxypyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(imidazo[1 ,2-a]pyridin-
7-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(imidazo[1 ,2-a]pyridin-7- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(4-chloropyrazolo[1,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(4-chloropyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(4-chloropyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-(4-chloropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,6- dichlorophenyl)acetamido]pyridin-2-yl}acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[4-chloro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(4-fluoro-2,6- dimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(6-chloropyrazolo[1,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(6-chloropyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-{2-[2-(trifluoromethyl)phenyl]acetamido}pyridin-2- yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-{2-[4-chloro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)acetamide
N-(3-chloropyridin-4-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-(3-chloro-2-methoxypyridin-4-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloro-2- methoxypyridin-4-yl)acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2-methylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2-methylpyridin-4- yl)acetamide N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(6-fluoropyrazolo[1 ,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(6-fluoropyrazolo[1,5- a]pyridin-5-yl)acetamide
N-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(4-fluoropyrazolo[1 ,5-a]pyridin-
5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(4-fluoropyrazolo[1,5- a]pyridin-5-yl)acetamide
N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[2-(trifluoromethyl)phenyl]acetamido}pyridin-2- yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(3- fluoropyridin-4-yl)acetamide N-(3-fluoropyridin-4-yl)-N-(4-{2-[4-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[3-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-(3-fluoropyridin-4-yl)-N-{4-[2-(2,4,6-trimethylphenyl)acetamido]pyridin-2- yljacetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(3- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,6-dichloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[2-(trifluoromethoxy)phenyl]acetamido}pyridin-2- yl)acetamide N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(6-methoxypyrazolo[1 ,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(6- methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(6-methoxypyrazolo[1,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(6- methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide N-(6-methoxypyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(4- methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(4-methoxypyrazolo[1,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(4-methoxypyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[4-(methylsulfanyl)pyrazolo[1,5- a]pyridin-5-yl]acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-(2H,4H-1 ,3-benzodioxin-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(2H,4H-1 , 3- benzodioxi n-6-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol-6- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol-6- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol-6- yl)acetamide
N-(2H-1 ,3-benzodioxol-5-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(2H-1 ,3-benzodioxol-5-yl)-N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(2H-1 ,3-benzodioxol-5-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide N-(2H-1 ,3-benzodioxol-5-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(2H-1 ,3-benzodioxol-5-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1 ,4-benzodioxin-6- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1,4- benzodioxin-6-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1 ,4- benzodioxin-6-yl)acetamide
N-{4-[2-(2-chloro-6-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1,4- benzodioxin-6-yl)acetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzoxazol-6-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chloro-6-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2- yljacetamide N-(1 ,3-benzothiazol-5-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-5-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-5-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chloro-6-fluorophenyl)acetamido]pyridin-2- yljacetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indol-5- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indol-5- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indol-5- yl)acetamide
N-{4-[2-(2-Chlor-4-fluorphenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamid
N-{4-[2-(2-Chlor-6-fluorphenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamid
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1,3-dihydro-2-benzofuran-5- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1 ,3-dihydro-2- benzofuran-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(1,3-dihydro-2-benzofuran-5- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1-benzofuran-5- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamide N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1-benzofuran-5- yl)acetamide
N-{4-[2-(2-Chlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H-indol-6-yl)acetamid
N-{4-[2-(2,6-Dichlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indol-6- yl)acetamid
N-{4-[2-(2-Chlor-6-fluorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H-indol-6- yl)acetamid
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indol-6- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indol-6- yl)acetamide
N-{4-[2-(2-Chlor-4-fluorphenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2-Chlor-6-fluorphenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2,6-Dichlorphenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H-benzotriazol-5- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H-benzotriazol-5- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2,6-Dichlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol-5- yl)acetamide
N-{4-[2-(2-Chlor-3-fluorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol-5- yl)acetamid
N-{4-[2-(2-Chlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol-5- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-pyrazol-5- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H-pyrazol-5- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazin-2-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin-
5-yl)propanamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin- 5-yl)propanamide 236 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin-5- yl)propanamide
237 N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1,5-a]pyridin-5- yl)propanamide
238 N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)propanamide
239 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4-yl)propanamide
240 N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)propanamide
241 N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4-yl)propanamide
242 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)propanamide
243 N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)propanamide
244 N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)propanamide
245 N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)propanamide
246 N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)propanamide
247 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)propanamide
248 N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)propenamide
249 N-(3-chloropyridin-4-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2- yljpropanamide
250 N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)propanamide
251 N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)propenamide
The compounds of general formula (I) according to the invention can be prepared according to the following scheme 1.
Scheme 1
Figure imgf000031_0001
The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, R1 , R2, R3, R4a or R4b can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
Scheme 1 depicts the synthesis starting from either heteroaromatic amines of the formula (II), and 2-bromo-4-nitropyridine (III), or heteroaromatic halides of formula (IV) wherein Hal stands for Cl, Br, I or a triflate, Br being preferred; and 4-nitropyridine-2- amine (V). The two starting materials can be cross-coupled by Pd-mediated reactions (Buchwald-Hartwig-coupling) known to those skilled in the art. A suitable solvent like for example /V,/V-dimethylformamide,1 ,4-dioxane or toluene is used and a base such as potassium carbonate, potassium phosphate, caesium carbonate or potassium tertbutanolate is added. Appropriate palladium catalysts in combination with suitable phosphine ligands are utilized as catalyst catalyst-ligand system, for example bis(dibenzylidenaceton) palladium(O) and 4,5-bis-(diphenylphosphino)-9,9-dimethyl xanthene (Xantphos). The reaction is performed at temperatures between 80 °C and 120 °C, preferred at 100 °C until complete conversion, typically for 18 h.
Heteroaromatic amines of general formula (VI) may react according to standard procedures with carboxylic acid anhydrides (VII) or the corresponding acetyl chlorides (VIII) to yield amides of general formula (IX). In case of the use of anhydrides (VII) like e.g. acetanhyride, it may also serve as solvent. N,N-dimethylaminopyridine may be used as catalyst (0.1 eq). The reaction usually takes place between 100 and 130°C until complete conversion (2 - 18 h). In case of the use of carboxylic acid chloride, e.g. acetyl chloride, dichloromethane may be used as solvent and a base, e.g. triethyl amine, is added.
The nitro group in compounds of the general formula (IX) are reduced to the corresponding amino group of compounds of general formula (X) via procedures known to those skilled in the art, e.g. via hydrogenation in presence of a suitable catalyst like palladium or platinum, e.g. 10% Pd on activated charcoal. Preferably, atmospheric hydrogen pressure is utilized. Suitable solvents like ethanol, methanol or ethyl acetate (which is preferred) are used. Alternatively, other reduction methods are used, most notably the reduction with iron powder (5 eq.) in acetic acid. The mixture is stirred vigorously until complete conversion (2 - 18 h).
Aromatic amines of general formula (X) may react with carboxylic acids of general formula (XI) by methods known to those skilled in the art to give the amide compounds of general formula (I). The reaction is mediated by activating a carboxylic acid of general formula (XI) with reagents such as dicyclohexylcarbodiimide (DCC), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N-hydroxybenzotriazole (HOBT), N- [(dimethylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyliden]-N- methylmethanaminium hexafluorophosphate (HATLI) or propylphosphonic anhydride (T3P). For example, the reaction with HATLI or T3P takes place in an inert solvent, such as N,N-dimethylformamide, dichloromethane or dimethyl sulfoxide in the presence of the appropriate aromatic amine of general formula (VIII) and a tertiary amine (such as triethylamine or diisopropylethylamine) at temperatures between -30 °C and +80 °C. The use of T3P as coupling reagent is generally preferred.
Particularly, the invention covers the intermediate compounds of intermediate compounds of general formula (VI), (IX), (X):
Figure imgf000033_0001
in which R1 , and R2 are as defined for the compound of general formula (I) supra.
Intermediate compounds of general formula (VI) according to the invention are in particular:
N-(3-chloropyridin-4-yl)-4-nitropyridin-2-amine
N-(2-methylpyridin-4-yl)-4-nitropyridin-2-amine
N-(2,5-dimethylpyridin-4-yl)-4-nitropyridin-2-amine
N-(3-methylpyridin-4-yl)-4-nitropyridin-2-amine
4-nitro-N-[3-(trifluoromethyl)pyridin-4-yl]pyridin-2-amine 4-[(4-nitropyridin-2- yl)amino]pyridine-3-carbonitrile
4-nitro-N-(pyridin-3-yl)pyridin-2-amine
N-(5-fluoropyridin-3-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)-1 ,5-naphthyridin-3-amine
N-[2-(difluoromethyl)pyridin-4-yl]-4-nitropyridin-2-amine
4-nitro-N-[2-(trifluoromethyl)pyridin-4-yl]pyridin-2-amine
N-(2-cyclopropylpyridin-4-yl)-4-nitropyridin-2-amine
4-[(4-nitropyridin-2-yl)amino]pyridine-2-carbonitrile
N-(2,6-dimethylpyridin-4-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
N-(4-nitropyridin-2-yl)isoquinolin-7-amine
N-(1-benzothiophen-5-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)isoquinolin-6-amine
4-nitro-N-(pyridin-4-yl)pyridin-2-amine
N-(2-fluoropyridin-4-yl)-4-nitropyridin-2-amine
N-(2-methoxypyridin-4-yl)-4-nitropyridin-2-amine
4-nitro-N-[2-(trifluoromethoxy)pyridin-4-yl]pyridin-2-amine
N-(2-ethoxypyridin-4-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)imidazo[1,2-a]pyridin-7-amine
4-chloro-N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
6-chloro-N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
N-(3-chloro-2-methoxypyridin-4-yl)-4-nitropyridin-2-amine
N-(5-fluoro-2-methylpyridin-4-yl)-4-nitropyridin-2-amine 6-fluoro-N-(4-nitropyndin-2-yl)pyrazolo[1,5-a]pyridin-5-amine 4-fluoro-N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine N-(3-fluoropyridin-4-yl)-4-nitropyridin-2-amine 6-methoxy-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine 4-methoxy-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine
4-(methylsulfanyl)-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine N-(2H,4H-1,3-benzodioxin-6-yl)-4-nitropyridin-2-amine 1-methyl-N-(4-nitropyridin-2-yl)-1 H-indazol-6-amine N-(2H-1 ,3-benzodioxol-5-yl)-4-nitropyridin-2-amine N-(2,3-dihydro-1-benzofuran-5-yl)-4-nitropyridin-2-amine N-(1,3-dihydro-2-benzofuran-
5-yl)-4-nitropyridin-2-amine N-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-4-nitropyridin-2-amine N-(4-nitropyridin-2-yl)-1 ,3-benzoxazol-6-amine N-(4-nitropyridin-2-yl)-1 ,2-benzoxazol-6-amine N-(4-nitropyridin-2-yl)-1 ,2-benzothiazol-6-amine N-(4-nitropyridin-2-yl)-1 ,3-benzothiazol-6-amine N-(4-nitropyridin-2-yl)-1 ,3- benzothiazol-5-amine 1-methyl-N-(4-nitropyridin-2-yl)-1 H-indol-5-amine
1-methyl-N-(4-nitropyridin-2-yl)-1 H-indol-6-amin
2-methyl-N-(4-nitropyridin-2-yl)-2H-benzotriazol-5-amin 1-methyl-N-(4-nitropyridin-2-yl)-1 H-indazol-5-amin N-(1-methyl-1H-pyrazol-5-yl)-4-nitropyridin-2-amine N-(4-nitropyridin-2-yl)pyrazin-2-amine
Intermediate compounds of general formula (IX) according to the invention are in particular:
N-(4-nitropyridin-2-yl)-N-(pyridin-4-yl)acetamide N-(2,5-dimethylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide N-(3-methylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide N-(4-nitropyridin-2-yl)-N-[3-(trifluoromethyl)pyridin-4-yl]acetamide N-(3-cyanopyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide N-(4-nitropyridin-2-yl)-N-(pyridin-3-yl)acetamide N-(5-fluoropyridin-3-yl)-N-(4-nitropyridin-2-yl)acetamide N-(1,5-naphthyridin-3-yl)-N-(4-nitropyridin-2-yl)acetamide N-(2-methylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide N-[2-(difluoromethyl)pyridin-4-yl]-N-(4-nitropyridin-2-yl)acetamide N-(4-nitropyndin-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]acetamide
N-(2-cyclopropylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-cyanopyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2,6-dimethylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(2-methylpyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(isoquinolin-7-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-benzothiophen-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(isoquinolin-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-methoxypyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-[2-(trifluoromethoxy)pyridin-4-yl]acetamide
N-(2-ethoxypyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(imidazo[1 ,2-a]pyridin-7-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-chloropyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(6-chloropyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(3-chloro-2-methoxypyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(5-fluoro-2-methylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(6-methoxypyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-[4-(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]-N-(4-nitropyridin-2-yl)acetamideN-
(2H,4H-1 ,3-benzodioxin-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-methyl-1H-indazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2H-1 ,3-benzodioxol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2,3-dihydro-1-benzofuran-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1,3-dihydro-2-benzofuran-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1,3-benzoxazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1,2-benzoxazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1,3-benzothiazol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1,3-benzothiazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1,2-benzothiazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide N-(1-methyl-1 H-indol-5-yl)-N-(4-nitropyndin-2-yl)acetamide
N-(1-methyl-1 H-indol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-methyl-2H-benzotriazol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-methyl-1H-pyrazol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyrazin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyrazolo[1,5-a]pyridin-5-yl)propenamide
N-(4-nitropyridin-2-yl)-N-(pyridin-4-yl)propenamide
N-(2-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)propenamide
N-(3-chloropyridin-4-yl)-N-(4-nitropyridin-2-yl)propenamide
N-(3-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)propenamide
Intermediate compounds of general formula (X) according to the invention are in particular:
N-(4-aminopyridin-2-yl)-N-(5-fluoropyridin-3-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,5-dimethylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-methylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[3-(trifluoromethyl)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-(3-cyanopyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyridin-3-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,5-naphthyridin-3-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-methylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[2-(difluoromethyl)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-(2-cyclopropylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-cyanopyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,6-dimethylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-methylpyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(isoquinolin-7-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-benzothiophen-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(isoquinolin-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-fluoropyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-methoxypyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[2-(trifluoromethoxy)pyridin-4-yl]acetamide N-(4-aminopyndin-2-yl)-N-(2-ethoxypyndin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(imidazo[1 ,2-a]pyridin-7-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(4-chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-chloro-2-methoxypyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(5-fluoro-2-methylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-fluoropyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(6-methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[4-(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-(4-aminopyridin-2-yl)-N-(2H,4H-1,3-benzodioxin-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-methyl-1 H-indazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2H-1 ,3-benzodioxol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,3-dihydro-1-benzofuran-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-dihydro-2-benzofuran-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-benzoxazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,2-benzoxazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,2-benzothiazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-benzothiazol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-benzothiazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-methyl-1 H-indol-5-yl)acetamide
N-(4-Aminopyridin-2-yl)-N-(1-methyl-1 H-indol-6-yl)acetamide
N-(4-Aminopyridin-2-yl)-N-(2-methyl-2H-benzotriazol-5-yl)acetamide
N-(4-Aminopyridin-2-yl)-N-(1-methyl-1 H-indazol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-methyl-1 H-pyrazol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyrazin-2-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyrazolo[1 ,5-a]pyridin-5-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(pyridin-4-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(2-fluoropyridin-4-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(3-fluoropyridin-4-yl)propanamide In accordance with a further aspect, the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
The compounds of general formula (I) of the present invention can be converted to any salt, more particularly pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
A compound according to the invention is used for the manufacture of a medicament.
Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit P2X4, as antagonists or negative allosteric modulators, and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases.
Compounds of the present invention can be utilized to inhibit, antagonize, negative allosteric modulate, etc., the P2X4 receptor. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
The present invention also provides methods of treating the following syndromes, diseases or disorders:
• Genitourinary, gastrointestinal, respiratory, proliferative and pain-related diseases, conditions and disorders;
• Gynecological diseases including primary and secondary dysmenorrhea, dyspareunia, vulvudynia, endometriosis and adenomyosis; endometriosis- associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular abdominal pain, dysmenorrhea, dyspareunia, dysuria, dyschezia or pelvic hypersensitivity;
• Urinary tract disease states including those associated with bladder outlet obstruction; overactive bladder or cystitis, interstitial cystitis, bladder pain syndrome, urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome;
• Epilepsy, partial and generalized seizures;
• Respiratory disorders including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, interstitial pulmonary fibrosis, bronchospasm, chronic chough, refractory chronic cough, idiopathic chronic cough;
• Gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS; gastroesophageal reflux, gastrointestinal distension, Crohn’s disease and the like;
• Fatty liver disorders, in particular NASH (Non-Alcoholic Steato-Hepatitis); fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction; atherosclerosis; lipid disorders;
• Neurodegenerative disorders such as Alzheimer's disease, Parkinson’s disease, Stroke, brain ischemia, ischemic brain injury, Ischemic Stroke (IS), haemorrhagic stroke, traumatic brain injury, spinal cord injury;
• Chronic itch, pruritus;
• Wound healing, impaired wound healing;
• Heart disorders including ischemia reperfusion injury, cardiac ischemia;
• Arthritis, chronic arthritis, juvenile arthritis, osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis and related neuralgias, and disease of the skeleton like degeneration of the joints, gout and acute gout, hemophilic arthropathy (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).
The present invention also provides methods of treating the following pain syndromes, diseases or disorders:
• Pain-associated syndromes, disease or disorders, including hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, abdominal pain such as functional bowel disorders, irritable bowel syndrome, inflammatory bowel disease, bladder pain syndrome, inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis-associated pain, pain associated with fibrotic diseases, central pain;
• Pain due to burning mouth syndrome, pain due to burns;
• Pain due to migraine (acute and prophylactic treatment), cluster headaches, pain due to nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries);
• Pain due to neuritis, neuralgias;
• Pain due to poisoning;
• Pain due to ischemic injury;
• Pain due to interstitial cystitis;
• Cancer pain, cancer cachexia, pain due to viral, parasitic or bacterial infections;
• Pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic lower back pain, neck pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, fibromyalgia, myofascial disorders, pain associated with gastrointestinal distension, chronic arthritic pain and related neuralgias;
• Pain associated with cancer, morphine-resistant pain, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy.
The pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, particularly acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy — induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy and/ or chemotherapy induced neuropathy), autonomic neuropathy pain states, peripheral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadnplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, autoimmune disease such as multiple sclerosis and spinal-cord injury, ischemia, neurodegeneration, stroke, post stroke pain, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), pelvic hypersensitivity, cystitis, stomach, duodenal ulcer, muscle pain, pain due to colicky and referred pain.
Compounds of the invention are thus expected to be useful in the treatment of inflammation. The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including, inter alia, acute, chronic, ulcerative, fibrotic, allergic and autoimmune diseases, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, necrosis, endometriosis and other forms of inflammation known to those skilled in the art.
The compounds according to the invention are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, toothache, sprains and strains, myositis, synovitis.
The compounds of the present invention may also be useful in the treatment, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and HIV), bacterial infections, fungal infections, surgical or dental procedures, malignancies (e.g. melanoma, breast cancer, colon cancer, lung cancer and prostate cancer), rheumatic fever, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, impaired wound healing, dermatitis, eczema, diabetes mellitus, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
Compounds of the invention are also expected to be useful in the treatment of conditions associated or causing bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, Paget's disease and/or periodontal diseases. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals and can be treated by administering pharmaceutical compositions of the present invention.
The term “treating” or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as those reported above.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of the following syndromes, diseases or disorders: pain, pain syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain including diabetic neuropathic pain and diabetic neuropathy, cancer-associated pain, chemotherapy or intoxication induced pain, pelvic pain, endometriosis-associated pain as well as endometriosis as such, bladder pain syndrome; lung diseases and respiratory disorder in particular asthma, bronchiolitis obliterans syndrome, COPD, chronic cough, diseases related to goblet cells and lung fibrosis, liver diseases, in particular liver fibrosis, fatty liver disorders, NASH (Non-Alcoholic Steato-Hepatitis); brain ischemia, ischemic brain injury, Ischemic Stroke (IS), haemorrhagic stroke, traumatic brain injury, spinal cord injury, aneurysm; ophthalmology indications, dry eye, ocular neuropathic pain;
Chronic itch, pruritus; osteoarthritis, burning mouth syndrome, migraine disorders, irritable bowel disease; urology related syndromes like, overactive urinary bladder, interstitial cystitis, bladder pain syndrome.
In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, particularly of the diseases reported above. The pharmaceutical activity of the compounds according to the invention can be explained by their activity as inhibitors, antagonizing and/or negative allosteric modulating, the P2X4 receptor.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular of the diseases reported above.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular of the diseases reported above.
In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular of the diseases reported above.
In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular of the diseases reported above, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes. It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystal I me cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),
• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),
• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),
• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),
• isotonicity agents (for example glucose, sodium chloride),
• adsorbents (for example highly-disperse silicas),
• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)), • flow regulators, lubricants, ghdants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),
• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),
• capsule materials (for example gelatine, hydroxypropylmethylcellulose),
• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
• penetration enhancers,
• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),
• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),
• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations.
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment and prevention, i.e. prophylaxis, of the syndromes, diseases or disorders reported above, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
EXPERIMENTAL SECTION
NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical shifts are given in ppm; all spectra were calibrated to solvent residual peak. Integrals are given in integers.
Alternatively, the 1H-NMR data of selected compounds are listed in the form of 1H-NMR peaklists. Therein, for each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The 5 value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1, (intensityi), δ 2 (intensity2), ... , δ; (intensity;), ... , δn (intensity,,).
The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1H-NMR peaklist is similar to a classical 1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13C satellite peaks, and/or spinning sidebands. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary perse to the skilled person.
Table 1 : Abbreviations
The following table lists the abbreviations used herein.
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Other abbreviations have their meanings customary per se to the skilled person.
The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or online electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
UPLC-MS Standard Procedures
Analytical UPLC-MS was performed as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ESI-). In most of the cases method 1 is used. If not, it is indicated.
Method 1:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
Method 2:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
Method 3:
Instrument: Waters Acquity Platform ZQ4000; column: Waters BEHC 18, 50 mm x 2.1 mm, 1.7p; eluent A: water/0.05% formic acid, eluent B: acetonitrile/0.05% formic acid; gradient: 0.0 min 98% A - 0.2 min: 98% A -> 1.7 min: 10% A -> 1.9 min: 10% A - 2 min: 98% A
Figure imgf000052_0001
2.5 min: 98% A; flow: 1.3 ml/min; column temperature: 60°C; UV- detection: 200-400 nm.
EXPERIMENTAL SECTION - GENERAL PROCEDURES
General procedure A:
Formation of bisarylamines from aromatic amide and 2-bromo-4-nitropyridine (GP A):
Aromatic amine (1.0 - 1.5 eq.) and 2-bromo-4-nitropyridine (1.0 - 1.5 eq) were dissolved in toluene or 1,4-dioxane or DMF (ca. 70 eq.). Under inert atmosphere (Argon), bis(dibenzylidenaceton) palladium(O) (CAS [32005-36-0], 0.03 eq.), 4,5-bis- (diphenylphosphino)-9,9-dimethyl xanthene (Xantphos, CAS [161265-03-8], 0.07 eq.), and caesium carbonate (1.6 eq.) were added and the mixture stirred at 100°C for ca. 18 h. After cooling to rt, the catalyst was filtered off via cehte and rinsed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate and extracted with ethyl acetate. The combined arganic layers were washed with brine, dried with sodium sulfate and the solvents removed in vacuo. The crude product was purified via chromatography.
General procedure B:
Formation of bisarylamines from arylhalogenide and 2-amino-4-nitro-pyridine (GP B):
Aromatic bromide (1.0 - 1.5 eq., alternatively, the corresponding iodide may be used), 4-nitropyridine-2-amine (1.0 - 1.5 eq.) and caesium carbonate (1.6 eq.) were dissolved in 1 ,4-dioxane or toluene. The mixture was degassed, and under argon atmosphere, bis(dibenzylidenaceton) palladium(O) (CAS [32005-36-0], 0.03 eq.) and 4,5-bis- (diphenylphosphino)-9,9-dimethyl xanthene (Xantphos, CAS [161265-03-8], 0.07 eq.) were added. The mixture was stirred at 100°C for 18 h. After cooling to rt, the solids were filtered off and rinsed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate and extracted with ethyl acetate. The combined arganic layers were washed with brine, dried with sodium sulfate and the solvents removed in vacuo. The crude product was purified via chromatography.
General procedure C:
Acylation of bisarylamines (GP C):
The bisarylamines were dissolved in acetic anhydride (or the respective corresponding homologue) as reagent and solvent (ca. 50 eq.), 4-/V,/V-dimethylaminopyridine (0.1 eq.) was added and the mixture stirred at 110 - 130°C until complete conversion (2 - 18 h). After cooling to rt, the mixture was either concentrated to dryness in vacuo and directely purified via chromatography or an aqueous workup was done. In this case, the mixture was partitioned between ethyl acetate and water, extracted with ethyl acetate, washed with brine, dried with sodium sulfate and the solvents removed in vacuo. The crude product was purified by chromatography.
General procedure D:
Reduction of nitro compounds by catalytic hydrogenation (GP D):
The nitro compound was dissolved in ethanol or ethyl acetate and the palladium catalyst (10% Pd on activated carbon, 0.1 eq. Pd) was added. The mixture was degassed and charged with hydrogen and hydrogenated at 1 atm hydrogen pressure until complete conversion. Then the catalyst was filtered off and the filtrated concentrated to dryness. The product was purified via chromatography or could be obtained without further purification.
General procedure E:
Reduction of nitro compounds with iron (GP E):
The nitro compound was dissolved in acetic acid and iron powder (5 eq.) was added. The mixture was vigorously stirred for 18 h. Solids were filtered off via a celite pad and rinsed with ethyl acetate. The organic phase evaporated to dryness. The residue was either codestilled several times with toluene until all acetic acid was removed or it was partitioned between ethyl acetate and water and sat. aqueous sodium bicarbonate solution added until pH > 7. The phases were separated, the aqueous layer extracted with ethyl acetate and the combined organic layers were washed with sat. aqueous sodium bicarbonate solution and brine and dried with sodium sulfate. The solvents were removed in vacuo and the product was taken to the next step without further purification.
General procedure F:
Amide formation with T3P (GP F):
Amine (Int. 109 - 165) and carboxylic acid (1-2 eq.) were dissolved in DMF and T3P (1- propanephosphinic anhydride, 50% in DMF, CAS [68957-94-8], 3 eq.) and triethylamine (6 eq.) were added and the mixture stirred at rt until complete conversion. Then the mixture was poured into water, extracted with ethyl acetate, the combined organic layers washed with brine, dried with sodium sulfate and the solvents evaporated. The crude product was purified by chromatography.
Intermediate 1 : N-(3-chloropyridin-4-yl)-4-nitropyridin-2-amine
Figure imgf000054_0001
According to GP A, 4-amino-3-chloropyridine (1.4 eq, 1.00 g, 7.78 mmol) and 2-bromo- 4-nitropyridine (1.13 g, 5.56 mmol, 1.0 eq.) in 1 ,4-dioxane (30 mL) were converted to 920 mg of the title compound (47% of theory) as a yellow solid.
1H NMR (400 MHz, DMSO-d6) 5 [ppm] 7.65 (dd, 1 H), 8.20 (d, 1H), 8.36 (d, 1 H), 8.41 (d, 1 H), 8.53 (s, 1 H), 8.59 (d, 1H), 8.49 (d, 1 H), 9.43 (s, br, 1 H). LCMS (Method 1): Rt = 0.96 min, MS (ESIpos) m/z = 251 [M+H]+
Intermediate 2: N-(2-methylpyridin-4-yl)-4-nitropyridin-2-amine
Figure imgf000055_0001
According to GP B, 4-nitropyridine-2-amine (1.4 eq., 1.00 g, 7.19 mmol) and 4-bromo-2- methylpyridine (1.0 eq., 0.88 g, 5.14 mmol) in 1 ,4-dioxane (30 mL) were converted to 660 mg of the title compound (40 % of theory) as a brown solid.
1H NMR (400 MHz, DMSO-d6) 5 [ppm] 2.41 (s, 3H), 7.49 - 7.54 (m, 3H), 7.62 (d, 1 H), 8.25 (d, 1 H), 8.58 (d, 1 H), 10.03 (s, br, 1 H).
LCMS (Method 1): Rt = 0.93 min, MS (ESIpos) m/z = 231 [M+H]+
Table 2: The following intermediates were synthesized accordingly
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0002
Synthesis of non-commercial building blocks
Intermediate 52: 2-Methylpyrazolo[1 ,5-a]pyridin-5-amine
Figure imgf000065_0001
Step 1 : Amino-4-[(tert-butoxycarbonyl)amino]pyridinium terf-Butyl pyridin-4-ylcarbamate (4.88 g, 25.1 mmol) and O-(2,4- dinitrophenyl)hydroxylamine (5.00 g, 25.1 mmol, 1 eq.) are dissolved in acetonitrile (130 mL) and stirred at 40°C for 18 h. Then the solvent is evaporated in vacuo to dryness and the crude product directly used in the next step.
Step 2: Methyl 5-[(tert-butoxycarbonyl)amino]-2-methylpyrazolo[1,5-a]pyridine-3- carboxylate
Amino-4-[(tert-butoxycarbonyl)amino]pyridinium from step 1 (10.0 g, 47.6 mmol) was dissolved in DMF (180 mL) and methyl-2-butynoate (7.00 g, 71.3 mmol, 1.5 eq.) and potassium carbonate (19.7 g, 143 mmol, 3 eq.) were added. The mixture was stirred at rt for 18 h, then it was partitioned between water and ethyl acetate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate and the solvents evaporated in vacuo. The crude product was purified via flash chromatography to yield 3.6 g (23% of theory) of the desired product as a yellow dry foam.
LCMS (Method 1): Rt = 1.12 min, MS (ESIneg) m/z = 304 [M-H]+
Step 3: 2-Methylpyrazolo[1,5-a]pyridin-5-amin
Methyl 5-[(tert-butoxycarbonyl)amino]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate from step 2 (3.60 mg, 11.8 mmol) was dissolved in 125 mL sulfuric acid (50% in water) and the mixture stirred at 80°C for 18 h. The mixture was cooled to 0°C, and aqueous sodiumhydroxide solution (32%) was cautiously added until pH > 7 was reached. The mixture was further diluted with sat. aqueous sodium bicarbonate solution, the formed solids were filtered off and rinsed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic layers were washed with brine, dried with sodium sulfate and the solvents evaporated in vacuo, to obtain 1.70 g96%) of the title compound as dark yellow solid, which was used without further purification.
1H NMR (400 MHz, DMSO-d6) 5 [ppm] 2.22 (s, 3H). 5.50 (s, br, 2H), 5.76 (s, 1 H), 6.21 (dd, 1 H), 6.28 (dd, 1 H), 8.12 (d, 1 H).
LCMS (Method 2): Rt = 0.51 min, MS (ESIpos) m/z = 148 [M+H]+
Intermediate 53: N-(4-nitropyridin-2-yl)-N-(pyridin-4-yl)acetamide
Figure imgf000066_0001
According to GP C, 4-nitro-N-(pyridin-4-yl)pyridin-2-amine (Int. 20, 615 mg, 1.71 mmol) were dissolved in acetic anhydride (10 mL), DMAP (0.1 eq., 21 mg, 0.17 mmol) was added and the mixture stirred at 130°C for 18 h. The misture was evaporated to dry ness and the residue purified via chromatography to yield 304 mg (68 % of theory) of the title compound.
1H NMR (400 MHz, DMSO-d6) 5 [ppm] 2.06 (s, 3H), 7.39 (d, 2H), 8.05 (dd, 1 H), 8.50 (d, 1 H), 8.63 (d, 2H), 8.74 (d, 1 H).
LCMS (Method 1): Rt = 0.74 min, MS (ESIpos) m/z = 254 [M+H]+
Table 3: The following intermediates were synthesized accordingly
Figure imgf000066_0002
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Table 4: The following intermediates were synthesized according GP C, using propanoic anhydride or butanoic anhydride, respectively
Figure imgf000078_0001
Figure imgf000079_0003
Intermediate 109: N-(4-aminopyridin-2-yl)-N-(5-fluoropyridin-3-yl)acetamide
Figure imgf000079_0001
According to GP D, N-(5-fluoropyridin-3-yl)-N-(4-nitropyridin-2-yl)acetamide (Int. 59) (910 mg, 3.29 mmol) were dissolved in ethanol (55 mL), the palladium catalyst was added (10%Pd on activated charcoal, 350 mg, 0.1 eq.) and the mixture hydrogenated (1 atm hydrogen) for 2 h at rt. The catylyst was filtered off, rinsed with ethanol and DCM and the solvent evaporated to dryness. The residue was purified via chromatography to yield 370 mg (45% of theory) of the title compound as colorless dry foam.
1H NMR (400 MHz, DMSO-d6) 5 [ppm] 2.02 (s, 3H), 6.33 (s, br, 2H), 6.47 (dd, 1 H), 6.51 (s, br, 1 H), 7.73 (dt, 1 H), 7.91 (d, 1 H), 8.29 (m, 1 H), 8.48 (d, 1 H).
LCMS (Method 1): Rt = 0.58 min, MS (ESIpos) m/z = 247 [M+H]+
Intermediate 110: N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)acetamide
Figure imgf000079_0002
According to GP E, N-(3-chloropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide (Int. 79, 820 mg, 2.80 mmol) were dissolved in acetic acid (32 mL) and iron powder (5 eq., 782 mg, 14.0 mmol) was added portionwise. The mixture was vigorously stirred for 18 h at rt. Then the solids were filtered off via a pad of celite, rinsed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and sat. aqueous sodium bicarbonate solution added until pH > 7. The phases were separated, the aqueous layer extracted with ethyl acetate and the combined organic layers were washed with sat. aqueous sodium bicarbonate solution and brine and dried with sodium sulfate. The solvents were removed in vacuo and the product was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 6 [ppm] 2.06 (s, 3H), 6.28 (s, br, 2H), 6.39 (dd, 1H), 6.50 (s, br, 1H), 7.41 (d, 1 H), 7.82 (d, 1H), 8.55 (d, 1 H), 8.75 (s, 1 H).
LCMS (Method 1): Rt = 0.59 min, MS (ESIpos) m/z = 263 [M+H]+
Table 5: The following aromatic amines were generated by reduction of the corresponding nitro compounds (Intermediate 53 - 108), using an appropriate genereal procedure (GP D, GP E):
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
EXPERIMENTAL SECTION - EXAMPLES
Example 1 : N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)acetamide
Figure imgf000092_0001
According to GP F, N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)acetamide (Int. 110, 100 mg, 0.38 mmol) and 2-chlorophenylacetic acid (130 mg, 2 eq.) were dissolved in DMF (3 mL) and T3P (363 mg, 1.14 mmol, 3 eq.) and triethylamine (230 mg, 2.28 mmol, 6 eq.) were added. The mixture was stirred at rt for 3 h, then it was poured into water, extracted with ethyl acetate, the combined organic layers washed with brine, dried with sodium sulfate and the solvents evaporated. The crude product was purified by preparative HPLC to yield 91 mg (57% of theory) of the title compound as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) 5 [ppm] 2.07 (s, 3H), 3.88 (s, 2H), 7.29 - 7.34 (m, 2H), 7.39 - 7.49 (m, 3H), 7.56 (d, 1 H), 7.82 (s, br, 1 H), 8.21 (d, 1 H), 8.61 (d, 1 H), 8.80 (s, 1H), 10.8 (s, 1H).
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 415 [M+H]+
Table 6: The following examples were generated by amide coupling of amines (Int. 111 - 165) with the corresponding carboxylic acids, using genereal procedure (GP F):
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
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Figure imgf000101_0001
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Figure imgf000105_0001
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Figure imgf000107_0001
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Figure imgf000109_0001
Figure imgf000110_0001
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Figure imgf000114_0001
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Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
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Figure imgf000132_0001
Figure imgf000133_0001
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Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
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Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
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Figure imgf000200_0001
Figure imgf000201_0001
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Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
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Figure imgf000214_0001
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Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS
Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein
• the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and
• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
IN VITRO STUDIES
The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:
Human P2X4 HEK Cell FLIPR Assay
Compounds were tested on a HEK293 cell line stably expressing human P2X4. Cells were cultured on poly-D-lysine-coated 384-well plates at a density of 15,000 cells/well and incubated overnight at 37°C, 5% CO2. P2X4 function was assessed by measuring intracellular calcium fluxes caused by Benzoylbenzoyl-ATP (Bz-ATP) using the calcium- chelating dye Fluo8-AM (Molecular Devices) with the Fluorescent Imaging Plate Reader Tetra (FLIPRTetra; Molecular Devices CA). On the day of the assay, the medium was removed and the cells were incubated for 30 min at 37°C and 5% CO2 in 30 pl of dye buffer (Hank's balanced salt solution, 10 mM HEPES, 1.8 mM CaCl2, 1 mM MgCh , 2 mM probenecid, 5 mM D-glucose monohydrate, 5 pM Fluo8-AM, pH=7.4). Compounds diluted in probenecid buffer (Hank's balanced salt solution, 10 mM HEPES, 1.8 mM CaCl2, 1 mM MgCl2, 2 mM probenecid, 5 mM D-glucose monohydrate, pH=7.4) at ten concentrations ranging from 25 pM to 1 nM (final concentration) were dispensed and incubated for 30 min at room temperature. The agonist, Bz-ATP (Tocris Bio-Techne GmbH, DE), was added at a final concentration of 3pM, representing the EC80 routinely determined. The final assay volume was 50pl and final DMSO concentration was 0.5%.
The fluorescence intensity reflecting intarcellular calcium changes was recorded before and after Bz-ATP addition, at an excitation and emission wavelengths of 470-495 nm and 515-575 nm respectively.
The compounds were tested in triplicates and fluorescence intensity raw data normalized to the agonist control and fitted to the four-parameter logistic equation:
Y=Bottom + (Top-Bottom)/(1+10A((LoglC50-X)*HillSlope))
The efficacy of saturating concentrations of the agonist BzATP (3pM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.5% DMSO.
Assay plate acceptance was based on the signal window (S/B) >1.8, Z’>0.5 and the reference compound plC50 within ±3o the mean of historic plC50 of the compound. Failure to meet two of the three criteria determined exclusion of the plate’s results.
FLIPR method for rat P2X4 1321N1 astrocytoma cells
Compounds were tested on a 1321 N1 cell line stably expressing rat P2X4. Cells were cultured on collagen-l-coated 384-well plates at a density of 10,000 cells/well and incubated overnight at 37°C, 5% CO2. P2X4 function was assessed by measuring intracellular calcium fluxes caused by Magnesium-ATP (MgATP) using the calcium- chelating dye Fluo8-AM (Molecular Devices) with the Fluorescent Imaging Plate Reader Tetra (FLIPRTetra; Molecular Devices CA). On the day of the assay, the medium was removed and the cells were incubated for 30 minutes at 37°C and 5% CO2 in 30 pl of dye buffer (Hank's balanced salt solution, 10 mM HEPES, 1.8 mM CaCl2, 1 mM MgCh , 2 mM probenecid, 5 mM D-glucose monohydrate, 5 pM Fluo8-AM, pH=7.4).
Compounds diluted in probenecid buffer (Hank's balanced salt solution, 10 mM HEPES, 1.8 mM CaCh, 1 mM MgCh, 2 mM probenecid, 5 mM D-glucose monohydrate, pH=7.4) at ten concentrations ranging from 25 pM to 1 nM (final concentration) were dispensed and incubated for 30 minutes at room temperature. The agonist, MgATP (Sigma-Aldrich Chemie GmbH, DE), was added at a final concentration of 5pM, representing the ECso routinely determined. The final assay volume was 50pl and final DMSO concentration was 0.5%.
The fluorescence intensity reflecting intracellular calcium changes was recorded before and after MgATP addition, at an excitation and emission wavelengths of 470-495 nm and 515-575 nm respectively. The compounds were tested in triplicates and fluorescence intensity raw data normalized to the agonist control and fitted to the four-parameter logistic equation: Y=Bottom + (Top-Bottom)/(1+10A((LoglC50-X)*HillSlope))
The efficacy of saturating concentrations of the agonist MgATP (5pM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.5% DMSO.
Assay plate acceptance was based on the signal window (S/B) >1.5, Z’>0.5 and the reference compound plC50 within ±3o the mean of historic plC50 of the compound. Failure to meet two of the three criteria determined exclusion of the plate’s results. In Table 7 below the results for the assays are reported
Table 7:
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
IN VIVO STUDIES
CFA Inflammation Model in Rats with Pain Behaviour Read Out
Methods Compound was tested in the model of intraplantar Complete Freund’s Adjuvant (CFA)- induced acute (48-hours setting) inflammatory pain in male Sprague Dawley rats. Briefly, 25 pl of CFA at 1 mg/ml was injected into the plantar surface of one hind paw. Mechanical hyperalgesia was measured using the Pressure Application Measurement apparatus (Ugo Basile, Gemonio, Italy). A linearly increasing pressure was applied to an area of approximately 50 mm2 of the plantar side of the hind paw until a behavioural response (paw withdrawal) was observed or until the pressure reached 1000 grams of force (gf). The pressure at which the behavioural response occurred was recorded as the “Paw Withdrawal Threshold” (PWT). Both CFA-injected and contralateral PWTs were determined for each rat, in each treatment group and at each time point of the studies. The measurements were performed blinded. Mechanical hyperalgesia testing was performed before injecting CFA, 46 hours after CFA injection (pre-drug baseline) and 2 hours after last treatment. Compound or vehicle (10% DMSO, 40% Solutol, 50% water for injection, vol/vol) were dosed via oral route (p.o.) once daily (QD) or twice daily (BID) during 3 days, starting before CFA injection. Data were expressed as the mean PWT for each treatment group and at each time point. PWT data were analysed by performing a two way ANOVA with repeated measures (time x treatment). Planned comparison of means (each versus vehicle) was performed by using a Dunnett’s post hoc test, provided that a main effect was detected. For p values less than 0.05, the results were deemed to be statistically significant.

Claims

CLAIMS A compound of general formula (I):
Figure imgf000239_0001
characterized in that
R1 is selected from the group consisting of a 5- or 6-membered heteroaryl being a monovalent, monocyclic heteroaryl having 5 or 6 ring atoms and wherein one, two or three ring atoms of a monovalent 5-membered hydrocarbon ring system being replaced by one, two or three heteroatoms independently selected from S, N, NH and O; and wherein one or two ring atoms of a monovalent 6- membered hydrocarbon ring system being replaced by one or two nitrogen atoms and said 5- or 6-membered heteroaryl being connected through a carbon or a nitrogen atom to the rest of the molecule or a bicyclic 8- to 10-membered heteroaryl being a bicyclic, monovalent, fused or bridged heterobicycloalkyl, having 8, 9 or 10 ring atoms with at least one aromatic ring and wherein one, two or three ring atoms of a monovalent, 8- to 10-membered bicyclic hydrocarbon ring system being replaced by one, two or three heteroatoms independently selected from NH, N, O, S, SO and SO2., said bicyclic 8- to 10-membered heteroaryl being connected through a carbon or a nitrogen atom to the rest of the molecule, and in which the 5- or 6-membered heteroaryl and bicyclic 8- to 10-membered heteroaryl comprise a group R7, R8, R9, R10, R12, R13,
R2 is (C1-C3)-alkyl,
R3 is a halogen atom, (C1-C3)-alkyl, (Ci-C3)-haloalkyl, (C1-C3)-alkoxy, (Ci-C3)-haloalkoxy,
R4a, R4b is selected from the group consisting of a hydrogen, a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy, R7, R8, R9, R10 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, cyclopropyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, -SCH3, (C1-C3)-haloalkoxy,
R12, R13 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, -SCH3, (C1-C3)-haloalkoxy,
R14 is selected from the group consisting of a hydrogen atom, (C1-C3)-alkyl, (C1-C3)-haloalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. The compound according to claim 1, wherein:
R1 is selected from the group consisting of a 5- or 6-membered heteroaryl
Figure imgf000240_0001
a bicyclic 8- to 10-membered heteroaryl
Figure imgf000240_0002
R5 is selected from the group consisting of -CH2OCH2-, -OCH2CH2-, -OCH2O-, -OCH2OCH2-, and -OCH2CH2O-;
R6 is selected from the group consisting of
Figure imgf000240_0003
R11 is selected from the group consisting of
Figure imgf000241_0001
R12, R13 is selected from the group consisting of a hydrogen atom, a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, -SCH3, (C1-C3)-haloalkoxy,
R14 is selected from the group consisting of a hydrogen atom, (C1-C3)-alkyl, (C1-C3)-haloalkyl. The compound according to any one of the previous claims wherein: R2 means a methyl or ethyl. The compound according to any one of the previous claims wherein: R3 means a chlorine, fluorine, cyano, or a hydrogen atom. The compound according to any one of the previous claims wherein:
R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy and R4b is a hydrogen atom; or
R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy; and R4b is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy. The compound according to any one of the previous claims wherein: R3 means a chlorine, fluorine, cyano, R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy in position 3 or 6 of the phenyl group; and R4b is a hydrogen atom; or
R3 means a chlorine, fluorine, cyano, R4a is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy in position 6 of the phenyl group; and R4b is a halogen atom, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C1-C3)-alkoxy, (C1-C3)-haloalkoxy in position 4 of the phenyl group. The compound according to any one of the previous claims wherein: R14 is a hydrogen atom or methyl The compound according to claim 1 of formula:
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N- (2,5-dimethylpyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,5-dimethylpyridin- 4-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,5- dimethylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,5- dimethylpyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,5- dimethylpyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-methylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- methylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- methylpyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(3-methylpyridin- 4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[3-
(trifluoromethyl)pyridin-4-yl]acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- cyanopyridin-4-yl)acetamide N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-3- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-3- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-3- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoropyridin-3- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(5- fluoropyridin-3-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(5- fluoropyridin-3-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoropyridin-3- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1,5-naphthyridin-3- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1 ,5- naphthyridin-3-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1 ,5- naphthyridin-3-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(1,5-naphthyridin-
3-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methylpyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- methylpyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[2-
(difluoromethyl)pyridin-4-yl]acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[2-
(difluoromethyl)pyridin-4-yl]acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[2-
(trifluoromethyl)pyridin-4-yl]acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-cyclopropylpyridin-
4-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- cyclopropylpyridin-4-yl)acetamide N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- cyclopropylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(2- cyclopropylpyridin-4-yl)acetamide
N-(2-cyclopropylpyridin-4-yl)-N-{4-[2-(2,6- dichlorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-cyanopyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- cyanopyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,6-dimethylpyridin-
4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,6- dimethylpyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,6- dimethylpyridin-4-yl)acetamide
N-(pyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-{2-[4-fluoro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-{2-[3-fluoro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(pyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2,6-dichloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(pyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-fluoro-2-(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)-N- (pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-7- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin- 7-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin- 7-yl)acetamide
N-(1-benzothiophen-5-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1-benzothiophen-5-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1-benzothiophen-5-yl)-N-{4-[2-(2,6- dichlorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-6- yl)acetamide N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin- 6-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(isoquinolin-6- yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)acetamide
N-{4-[2-(2,3-dimethylphenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-
4-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- fluoropyridin-4-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[4-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[3-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- fluoropyridin-4-yl)acetamide
N-{4-[2-(2,3-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(2- fluoropyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,6-dichloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- fluoropyridin-4-yl)acetamide N-(2-fluoropyridin-4-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-{2-[4-fluoro-2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methoxypyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- methoxypyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- methoxypyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2- methoxypyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[2-
(trifluoromethoxy)pyridin-4-yl]acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[2-
(trifluoromethoxy)pyridin-4-yl]acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(2- ethoxypyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-ethoxypyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- ethoxypyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- ethoxypyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-ethoxypyridin- 4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(imidazo[1,2- a]pyridin-7-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(imidazo[1 ,2- a]pyridin-7-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(4- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide N-(4-chloropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,6- dichlorophenyl)acetamido]pyridin-2-yl}acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[4-chloro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(4-fluoro-2,6- dimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(6- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(6- chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-{2-[2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-{2-[4-chloro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- chloropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- chloropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(3- chloropyridin-4-yl)acetamide
N-(3-chloropyridin-4-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-
2-yl}acetamide
N-(3-chloro-2-methoxypyridin-4-yl)-N-{4-[2-(2- chlorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3-chloro-2- methoxypyridin-4-yl)acetamide N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(5- fluoro-2-methylpyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(5-fluoro-2- methylpyridin-4-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(6-fluoropyrazolo[1 ,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(6-fluoropyrazolo[1,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(6- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(6-fluoropyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-fluoropyrazolo[1 ,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(4-fluoropyrazolo[1,5- a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- fluoropyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-fluoropyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[4-chloro-2-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(3- fluoropyridin-4-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[4-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[3-fluoro-2-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-{4-[2-(2-chloro-4,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)acetamide
N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(3- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)acetamide
N-{4-[2-(2-chloro-3,4-difluorophenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)acetamide
N-{4-[2-(2,6-dichloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide N-{4-[2-(4-fluoro-2,6-dimethylphenyl)acetamido]pyridin-2-yl}-N-(6- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(6-methoxypyrazolo[1 ,5-a]pyridin-5-yl)-N-{4-[2-(2,4,6- trimethylphenyl)acetamido]pyridin-2-yl}acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(6- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(6- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(6- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(6-methoxypyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-{2-[2-
(trifluoromethoxy)phenyl]acetamido}pyridin-2-yl)acetamide
N-(4-{2-[2-chloro-3-(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)-N-(4- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(4- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(4- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(4- methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-[4-
(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]acetamide
N-(2H,4H-1 ,3-benzodioxin-6-yl)-N-{4-[2-(2- chlorophenyl)acetamido]pyridin-2-yl}acetamide
N-(2H,4H-1 ,3-benzodioxin-6-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H-indazol- 6-yl)acetamide N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-indazol-6-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-indazol-6-yl)acetamide
N-(2H-1,3-benzodioxol-5-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(2H-1,3-benzodioxol-5-yl)-N-{4-[2-(2-chloro-4- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(2H-1,3-benzodioxol-5-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(2H-1,3-benzodioxol-5-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-
2-yl}acetamide
N-(2H-1,3-benzodioxol-5-yl)-N-{4-[2-(2,6- dichlorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1 ,4- benzodioxin-6-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1 ,4- benzodioxin-6-yl)acetamide
N-{4-[2-(2-chloro-6-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)acetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin- 2-yl}acetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzoxazol-6-yl)-N-{4-[2-(2-chloro-4- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzoxazol-6-yl)-N-(4-{2-[2-chloro-3-
(trifluoromethyl)phenyl]acetamido}pyridin-2-yl)acetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chloro-4- fluorophenyl)acetamido]pyridin-2-yl}acetamide N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,2-benzoxazol-6-yl)-N-{4-[2-(2-chloro-6- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-
2-yl}acetamide
N-(1 ,2-benzothiazol-6-yl)-N-{4-[2-(2-chloro-4- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzothiazol-5-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-5-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzothiazol-5-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-
2-yl}acetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2- yljacetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chloro-4- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chloro-3- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-
2-yl}acetamide
N-(1 ,3-benzothiazol-6-yl)-N-{4-[2-(2-chloro-6- fluorophenyl)acetamido]pyridin-2-yl}acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H-indol-5- yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-indol-5-yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-indol-5-yl)acetamide
N-{4-[2-(2-Chlor-4-fluorphenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamid N-{4-[2-(2-Chlor-6-fluorphenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamid
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(1,3-dihydro-2- benzofuran-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1 ,3-dihydro- 2-benzofuran-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(1,3-dihydro-2- benzofuran-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-
1-benzofuran-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2,3-dihydro-1- benzofuran-5-yl)acetamide
N-{4-[2-(2-Chlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H-indol-6- yl)acetamid
N-{4-[2-(2,6-Dichlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H- indol-6-yl)acetamid
N-{4-[2-(2-Chlor-6-fluorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H- indol-6-yl)acetamid
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-indol-6-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-indol-6-yl)acetamide
N-{4-[2-(2-Chlor-4-fluorphenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2-Chlor-6-fluorphenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2,6-Dichlorphenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-methyl-2H- benzotriazol-5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2-methyl-
2H-benzotriazol-5-yl)acetamide
N-{4-[2-(2,6-Dichlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H- indazol-5-yl)acetamide N-{4-[2-(2-Chlor-3-fluorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H- indazol-5-yl)acetamid
N-{4-[2-(2-Chlorphenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1 H-indazol- 5-yl)acetamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-
1 H-pyrazol-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(1-methyl-1H- pyrazol-5-yl)acetamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazin-2- yl)acetamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-
(pyrazolo[1 ,5-a]pyridin-5-yl)propenamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N- (pyrazolo[1 ,5-a]pyridin-5-yl)propenamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)propenamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyrazolo[1 ,5- a]pyridin-5-yl)propenamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)propanamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)propanamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)propanamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(pyridin-4- yl)propanamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)propanamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- fluoropyridin-4-yl)propenamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(2- fluoropyridin-4-yl)propenamide
N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin-2-yl}-N-(2-fluoropyridin-4- yl)propanamide
N-{4-[2-(2-chloro-4-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- chloropyridin-4-yl)propenamide N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-chloropyridin-4- yl)propanamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- chloropyridin-4-yl)propenamide
N-(3-chloropyridin-4-yl)-N-{4-[2-(2,6-dichlorophenyl)acetamido]pyridin- 2-yl}propenamide
N-{4-[2-(2-chlorophenyl)acetamido]pyridin-2-yl}-N-(3-fluoropyridin-4- yl)propanamide
N-{4-[2-(2-chloro-3-fluorophenyl)acetamido]pyridin-2-yl}-N-(3- fluoropyridin-4-yl)propenamide A compound of general formula (I) according to any one of claims 1 to 8 for use in the treatment or prophylaxis of a disease. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients. Use of a compound of general formula (I) according to any one of claims 1 to 8 for the treatment or prophylaxis of a disease. Use of a compound of general formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prophylaxis of a disease. Use according to claim 9, 11 or 12, wherein the disease is pain, pain syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, diabetic neuropathic pain, diabetic neuropathy, cancer-associated pain, chemotherapy or intoxication induced pain, pelvic pain, endometriosis-associated pain as well as endometriosis as such, bladder pain syndrome; asthma, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease (COPD), chronic cough, diseases related to goblet cells and lung fibrosis, liver fibrosis, fatty liver disorders, NASH (Non-Alcoholic Steato-Hepatitis); brain ischemia, ischemic brain injury, ischemic stroke, haemorrhagic stroke, traumatic brain injury, spinal cord injury, aneurysm; dry eye, ocular neuropathic pain; chronic itch, pruritus; osteoarthritis, burning mouth syndrome, migraine disorders, irritable bowel disease; urology related syndromes like, overactive urinary bladder, interstitial cystitis, bladder pain syndrome. A compound of formula of general formula (VI), (IX). (X):
Figure imgf000257_0001
in which R1, and R2 are defined according to a compound of general formula (I) in claim 1. A compound according to claim 14 of formula:
N-(3-chloropyridin-4-yl)-4-nitropyridin-2-amine
N-(2-methylpyridin-4-yl)-4-nitropyridin-2-amine
N-(2,5-dimethylpyridin-4-yl)-4-nitropyridin-2-amine
N-(3-methylpyridin-4-yl)-4-nitropyridin-2-amine
4-nitro-N-[3-(trifluoromethyl)pyridin-4-yl]pyridin-2-amine 4-[(4-nitropyridin-2- yl)amino]pyridine-3-carbonitrile
4-nitro-N-(pyridin-3-yl)pyridin-2-amine
N-(5-fluoropyridin-3-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)-1 ,5-naphthyridin-3-amine
N-[2-(difluoromethyl)pyridin-4-yl]-4-nitropyridin-2-amine
4-nitro-N-[2-(trifluoromethyl)pyridin-4-yl]pyridin-2-amine
N-(2-cyclopropylpyridin-4-yl)-4-nitropyridin-2-amine
4-[(4-nitropyridin-2-yl)amino]pyridine-2-carbonitrile
N-(2,6-dimethylpyridin-4-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
N-(4-nitropyridin-2-yl)isoquinolin-7-amine
N-(1-benzothiophen-5-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)isoquinolin-6-amine
4-nitro-N-(pyridin-4-yl)pyridin-2-amine
N-(2-fluoropyridin-4-yl)-4-nitropyridin-2-amine
N-(2-methoxypyridin-4-yl)-4-nitropyridin-2-amine
4-nitro-N-[2-(trifluoromethoxy)pyridin-4-yl]pyridin-2-amine
N-(2-ethoxypyridin-4-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)imidazo[1 ,2-a]pyridin-7-amine
4-chloro-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine
6-chloro-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine
N-(3-chloro-2-methoxypyridin-4-yl)-4-nitropyridin-2-amine
N-(5-fluoro-2-methylpyridin-4-yl)-4-nitropyridin-2-amine 6-fluoro-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine
4-fluoro-N-(4-nitropyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine
N-(3-fluoropyridin-4-yl)-4-nitropyridin-2-amine
6-methoxy-N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
4-methoxy-N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
4-(methylsulfanyl)-N-(4-nitropyridin-2-yl)pyrazolo[1,5-a]pyridin-5-amine
N-(2H,4H-1 , 3- benzodioxi n-6-yl)-4-nitropyridin-2-amine
1-methyl-N-(4-nitropyridin-2-yl)-1H-indazol-6-amine
N-(2H-1 ,3-benzodioxol-5-yl)-4-nitropyridin-2-amine
N-(2,3-dihydro-1-benzofuran-5-yl)-4-nitropyridin-2-amine N-(1,3-dihydro-2- benzofuran-5-yl)-4-nitropyridin-2-amine
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)-1 ,3-benzoxazol-6-amine
N-(4-nitropyridin-2-yl)-1 ,2-benzoxazol-6-amine
N-(4-nitropyridin-2-yl)-1 ,2-benzothiazol-6-amine
N-(4-nitropyridin-2-yl)-1 ,3-benzothiazol-6-amine
N-(4-nitropyridin-2-yl)-1 ,3-benzothiazol-5-amine
1-methyl-N-(4-nitropyridin-2-yl)-1H-indol-5-amine
1-methyl-N-(4-nitropyridin-2-yl)-1H-indol-6-amin
2-methyl-N-(4-nitropyridin-2-yl)-2H-benzotriazol-5-amin
1-methyl-N-(4-nitropyridin-2-yl)-1H-indazol-5-amin
N-(1-methyl-1 H-pyrazol-5-yl)-4-nitropyridin-2-amine
N-(4-nitropyridin-2-yl)pyrazin-2-amine
N-(4-nitropyridin-2-yl)-N-(pyridin-4-yl)acetamide N-(2,5-dimethylpyridin-4-yl)-
N-(4-nitropyridin-2-yl)acetamide
N-(3-methylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-[3-(trifluoromethyl)pyridin-4-yl]acetamide
N-(3-cyanopyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyridin-3-yl)acetamide
N-(5-fluoropyridin-3-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,5-naphthyridin-3-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-methylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-[2-(difluoromethyl)pyridin-4-yl]-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]acetamide
N-(2-cyclopropylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-cyanopyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide N-(2,6-dimethylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(isoquinolin-7-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-benzothiophen-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(isoquinolin-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-methoxypyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-[2-(trifluoromethoxy)pyridin-4-yl]acetamide
N-(2-ethoxypyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(imidazo[1 ,2-a]pyridin-7-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(3-chloropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(3-chloro-2-methoxypyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(5-fluoro-2-methylpyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(3-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(6-methoxypyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-methoxypyrazolo[1 ,5-a]pyridin-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-[4-(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5-yl]-N-(4-nitropyridin-2-yl)acetamide
N-(2H,4H-1 , 3- benzodioxi n-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-methyl-1 H-indazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2H-1 ,3-benzodioxol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2,3-dihydro-1-benzofuran-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,3-dihydro-2-benzofuran-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,3-benzoxazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,2-benzoxazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,3-benzothiazol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,3-benzothiazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1 ,2-benzothiazol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-methyl-1 H-indol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(1-methyl-1 H-indol-6-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(2-methyl-2H-benzotriazol-5-yl)-N-(4-nitropyridin-2-yl)acetamide N-(1-methyl-1 H-pyrazol-5-yl)-N-(4-nitropyridin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyrazin-2-yl)acetamide
N-(4-nitropyridin-2-yl)-N-(pyrazolo[1 ,5-a]pyridin-5-yl)propenamide
N-(4-nitropyridin-2-yl)-N-(pyridin-4-yl)propenamide
N-(2-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)propenamide
N-(3-chloropyridin-4-yl)-N-(4-nitropyridin-2-yl)propenamide
N-(3-fluoropyridin-4-yl)-N-(4-nitropyridin-2-yl)propenamide
N-(4-aminopyridin-2-yl)-N-(5-fluoropyridin-3-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,5-dimethylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-methylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[3-(trifluoromethyl)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-(3-cyanopyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyridin-3-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,5-naphthyridin-3-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-methylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[2-(difluoromethyl)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-[2-(trifluoromethyl)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-(2-cyclopropylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-cyanopyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,6-dimethylpyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(isoquinolin-7-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-benzothiophen-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(isoquinolin-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-fluoropyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2-methoxypyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[2-(trifluoromethoxy)pyridin-4-yl]acetamide
N-(4-aminopyridin-2-yl)-N-(2-ethoxypyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(imidazo[1,2-a]pyridin-7-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(4-chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(6-chloropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-chloro-2-methoxypyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(5-fluoro-2-methylpyridin-4-yl)acetamide N-(4-aminopyridin-2-yl)-N-(6-fluoropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(3-fluoropyridin-4-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(6-methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(4-methoxypyrazolo[1 ,5-a]pyridin-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-[4-(methylsulfanyl)pyrazolo[1 ,5-a]pyridin-5- yl]acetamide
N-(4-aminopyridin-2-yl)-N-(2H,4H-1 , 3- benzodioxi n-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-methyl-1 H-indazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2H-1,3-benzodioxol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2,3-dihydro-1-benzofuran-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-dihydro-2-benzofuran-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(2, 3-dihydro-1, 4- benzodioxi n-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-benzoxazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,2-benzoxazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,2-benzothiazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-benzothiazol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1 ,3-benzothiazol-6-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-methyl-1H-indol-5-yl)acetamide
N-(4-Aminopyridin-2-yl)-N-(1-methyl-1 H-indol-6-yl)acetamide
N-(4-Aminopyridin-2-yl)-N-(2-methyl-2H-benzotriazol-5-yl)acetamide
N-(4-Aminopyridin-2-yl)-N-(1-methyl-1 H-indazol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(1-methyl-1 H-pyrazol-5-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyrazin-2-yl)acetamide
N-(4-aminopyridin-2-yl)-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(pyridin-4-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(2-fluoropyridin-4-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(3-chloropyridin-4-yl)propanamide
N-(4-aminopyridin-2-yl)-N-(3-fluoropyridin-4-yl)propanamide
PCT/EP2021/074382 2020-09-07 2021-09-03 Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators WO2022049253A1 (en)

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