WO2023097386A1 - Composés n-acylhydrazoniques inhibiteurs sélectifs de hdac6, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses - Google Patents

Composés n-acylhydrazoniques inhibiteurs sélectifs de hdac6, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses Download PDF

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WO2023097386A1
WO2023097386A1 PCT/BR2022/050475 BR2022050475W WO2023097386A1 WO 2023097386 A1 WO2023097386 A1 WO 2023097386A1 BR 2022050475 W BR2022050475 W BR 2022050475W WO 2023097386 A1 WO2023097386 A1 WO 2023097386A1
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methyl
compound
alkyl
hydroxybenzamide
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Portuguese (pt)
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Gabriela BARREIRO
Danilo Pereira De SANT’ANA
Júlia Lammoglia MONTEIRO
Luis Eduardo Reina GAMBA
Carlos Alberto Manssour Fraga
Eliezer Jesus de Lacerda BARREIRO
Lídia Moreira LIMA
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Eurofarma Laboratórios S.A
Universidade Federal Do Rio De Janeiro – Ufrj
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/88—Nicotinoylhydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/08—Six-membered rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to N-acyhydrazonic compounds selective HDAC6 inhibitors, their processes for obtaining, compositions, uses, kits and treatment methods to treat or prevent depressive disorders, anxiety disorders, rheumatoid arthritis and/or pain neuropathic.
  • Histone deacetylases are enzymes responsible for the removal of acetyl groups from lysine residues of histones and non-histone proteins, such as a-tubulin, HSP90, tau protein, among others (Lawlor. Int. J. Oral Sci. 2019, 11, 2).
  • HDACs, together with histone acetyltransferases (HAT) are part of a mechanism that regulates several cellular functions that include epigenetic modifications, cell signaling, metabolism, among others (Yang. RSC Adv. 2019, 9 , 19571; Sangwan. Eur. J. Med, Chem. 2018, 158, 620 and 706).
  • HDACs histone deacetylases
  • HDACs are phylogenetically classified (based on primary homology to yeast proteins) into 4 classes: class I (HDACs 1, 2, 3, and 8), class Ha (HDACs 4, 5, 7, and 9), class llb ( HDACs 6 and 10), class III (called sirtuins 1-7), and class IV (HDAC11 ).
  • Class I, II, and IV HDACs are zinc dependent, while class III HDACs are nicotinamide adenine dinucleotide (NAD + ) dependent.
  • HADC6 and HDAC10, belonging to class IIb, are expressed in specific tissues and act in the cell cytoplasm (Roche.
  • HDAC6 is within the class of those with catalytic activity deacetylating lysine residues from proteins located in the cell cytoplasm, such as a-tubulin, HSP90, tau protein, among others (Osko. Biochemistry 2019, 58, 4912).
  • HDAC6 are expressed in brain, heart, kidney and liver tissues, as well as in the pancreas and testes (Sim ⁇ es-Pires. Mol Neurodegeneration. 2013, 8, 7). HDAC6 is structurally different from other isoforms because it is the only one that has two catalytic domains called CD1 and CD2, the latter being the domain that has catalytic activity on substrates found in the cytosol (a-tubulin, Cortactin, HSP90, HSF-1 , between others). Additionally, HDAC6 possesses the C-terminal ubiquitin-binding domain (ZnF-BP, zinc-finger ubiquitin binding domain), which is implicated in the regulation of protein degradation processes in the proteasome (Brindisi. J. Med. Chem. 2020, 63, 23).
  • ZnF-BP zinc-finger ubiquitin binding domain
  • the deregulation in the activity of these enzymes is related to neurodegenerative diseases, cancer, depressive disorders, anxiety disorders, rheumatoid arthritis, neuropathic pain, among others.
  • HDACs The inhibition of HDACs is already established as a way of intervention of oncological pathologies, specifically hematological lymphomas (Yang. RSC Adv. 2019, 9, 19571 ).
  • FDA Food and Drug Administration
  • SAHA vorinostat
  • FK-228 cyclic depsipeptide romidepsin
  • PXD-101 belinostat
  • LH-589 panobinostat
  • HDACs particularly 1 , 2, 3 and HDAC6 have shown neuroprotective effects and improvement of synaptic plasticity, learning and memory functions (Rodrigues. Med. Res. Rev. 2020 , 1, 35; Laconelli. Int. J. Mol. Sci. 2019, 20, 1605).
  • Mood disorders and anxiety disorders characterized by clinically recognized symptoms and/or behaviors that interfere with the individual's daily life, include depressive and bipolar disorders, anxiety, panic disorder, among others.
  • depressive and bipolar disorders include depressive and bipolar disorders, anxiety, panic disorder, among others.
  • a portion of patients with major depressive disorder for example, are refractory to treatments based on fluoxetine, citalopram, trazodone.
  • fluoxetine citalopram
  • trazodone Given the cases of inefficiency and remission pointed out for these treatments, it is necessary to search for innovative therapies, mainly through innovative mechanisms of action.
  • HDAC6 HDAC6 receptor kinase
  • p-CREB cAMP response element-binding protein
  • BDNF brain-derived neurotrophic factor
  • SSRIS antidepressant serotonin reuptake inhibitors
  • rheumatoid arthritis is a chronic disease that affects the joints, connections, muscles, tendons and fibrous tissues that usually affects adults in the most productive phase of their lives between 20 and 40 years.
  • Drug treatments consist of the use of non-steroidal anti-inflammatory drugs (NSAIDs), steroids, in addition to synthetic or biological disease-modifying drugs (DMARDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • DMARDs synthetic or biological disease-modifying drugs
  • NSAIDs are commonly used for the symptomatic treatment of rheumatoid arthritis, although their indiscriminate and/or chronic use is related to adverse gastrointestinal, renal and cardiovascular effects, resulting from the mode of action of these drugs.
  • DMARDs interfere with the disease course and are widely used as a first-line treatment for rheumatoid arthritis.
  • a significant number of patients do not respond or do not adhere to DMARD treatment due to the progression of adverse effects resulting from the need to escalate doses during treatment.
  • the glucocorticoids used relieve inflammatory symptoms and pain quickly, but are usually used for a short period due to the adverse effects resulting from their chronic use.
  • Biological DMARDs on the other hand, have the inconvenience of parenteral administration and the high cost of treatment, being used as an alternative to conventional DMARDs (Smolen. Nat. Rev. Dis. Primers. 2018, 4 18.001 ).
  • neuropathic pain there is still no specific treatment to control related pathologies.
  • a first-line treatment alternative consists of the use of opioid analgesics, and - as adjuvants - local anesthetics, anticonvulsants and antidepressants.
  • opioid analgesics and - as adjuvants - local anesthetics, anticonvulsants and antidepressants.
  • adverse effects and low efficacy drastically limit the use of these agents to control different pathologies related to pain (Kushnarev. Expert Opin. Investig. Drugs, 2020, 29(3), 259; Emery. Expert Opin. Ther Targets, 2016, 20(8), 975).
  • WO2017018804 discloses 1,3,4-oxadiazole amide derivative compounds effective for the prevention or treatment of HDAC6-mediated diseases, including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases among others.
  • WO2015100363 discloses hydroxamic acid derivatives as HDAC6 inhibitors with indication for the treatment of neurodegenerative diseases.
  • Document WO2016154694 (corresponding to BR 10 2015 007034-9) discloses N-acylhydrazonic derivative compounds with antitumor activity. However, unlike the present invention, these compounds are not selective for HDAC6, they do not target or suggest the treatment of depressive disorders, anxiety disorders, rheumatoid arthritis and neuropathic pain.
  • HDAC inhibitors to treat various pathologies mentioned above, there is still a need for new treatments for the disorders and pathologies mentioned.
  • HDAC inhibitor compounds particularly HDAC6, which have adequate pharmacological action and, preferably, provide mitigated adverse effects.
  • the present invention reveals new N-acylhydrazonic derivatives, potent and selective HDAC6 inhibitors, as an alternative and/or complement to treatments useful for treating diseases or disorders mediated by HDAC6, including without limitation depressive disorders, anxiety disorders, rheumatoid arthritis and neuropathic pain.
  • the present invention describes new HDAC6 inhibitor compounds, in addition to compositions, uses, kits, treatment methods and preparation processes related thereto.
  • the present invention relates to compounds of Formula I: Formula I or a pharmaceutically acceptable salt, hydrate, solvate, isomer or ester thereof, wherein,
  • Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • - Ri is selected from the group consisting of hydrogen, linear or branched C 1-6 alkyl, benzyl, 4-methoxybenzyl, C3-C6 cycloalkyl or aryl;
  • R 2 and Re are independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, straight or branched C 1-6 alkoxy, C3-C7 O-cycloalkyl, C3-C7 heterocycloalkyl, C 1-6 alkyl straight or branched, C3-6 cycloalkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, aryl, amine, N-(alkyl)amines, N ,N -(dialkyl)amines, azetidinyloxy, 1-methylazetidinyloxy, morpholine, pyridinyl, substituted pyridinyl, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6
  • R 3 and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, aryl, pyridinyl, linear or branched C 1 -C alkyl, trifluoromethyl, difluoromethyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethoxy or trifluoromethoxy, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkyl,
  • R4 is selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethyl, trifluoromethyl, C3-6 cycloalkyl, C1-C alkoxy 8 straight or branched, difluoromethoxy, trifluoromethoxy, phenyl, substituted phenyl, aryl or morpholine, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkyl 6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulfon
  • R7, R 8 , R9 and R10 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy or C 1-6 alkyl.
  • the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts, hydrates, solvates, isomers, esters thereof; one or more pharmaceutically acceptable excipients; and compounds containing one or more isotopically enriched atoms such as, for example, but not limited to the 2H hydrogen isotope.
  • kits for administering one or more compounds of Formula I may comprise compositions containing said compounds associated with delivery devices, which may include ampoules , syringes and others.
  • kits according to the present invention comprise more than one compound of Formula I arranged in one or more pharmaceutical forms, accompanied by instructions for administration.
  • the present invention further relates to methods of treatment, prevention, relief, suppression and/or control of depressive disorders, anxiety disorders, rheumatoid arthritis and/or neuropathic pain. Also taught are uses of compound(s) of Formula I to prepare a medicament for the treatment of depressive disorders, anxiety disorders, rheumatoid arthritis, and/or neuropathic pain.
  • the present invention also relates to processes for preparing one or more compounds of Formula I.
  • C 1-6 alkyl refers to saturated straight or branched chain hydrocarbons such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl, but is not limited to these.
  • halogen may be selected from chlorine, bromine, fluorine or iodine.
  • C 1-6 alkoxy refers to alkyl groups attached to a radical oxygen, including methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isoproxy, isobutoxy, tert-butoxy, but not limited to these .
  • C3-7 cycloalkyl refers to saturated or unsaturated alkyl chain cycles. Non-limiting examples are: cyclohexyl, cycloheptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cycloheptenyl, cyclobutenyl, cyclopropenyl and cyclohexenyl.
  • aryl means unsubstituted or substituted mono, di, th or polycyclic aromatic radicals, including, but not limited to, phenyl, substituted phenyl, naphthyl, benzyl, substituted benzyl, anthracenyl.
  • benzyl and substituted benzyl correspond to the benzyl radical without substitution or substituted in any of its positions.
  • Non-limiting examples are: 4-methoxybenzyl, 4-ethoxybenzyl, 4-tertbutoxydobenzyl, 3-methoxybenzyl, 3-ethoxybenzyl, 3-tertbutoxydobenzyl, 2-methoxybenzyl, 4-bromobenzyl, 4-fluorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4 - methylbenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl and 4-trifluoromethylbenzyl.
  • N ,N -(dialkyl)amines refers to groups comprising a tertiary amine linked to an alkyl chain in its structure, such as: dimethylamino, diethylamino, dipropylamino, dibutylamino, not limited to these.
  • N-(alkyl)amines refers to groups comprising a secondary amine linked to an alkyl chain in its structure, such as: methylamino, ethylamino, propylamino, butylamino, not limited to these.
  • -S-C 1-6 alkyl refers to alkyl groups attached to a sulfur radical, including groups such as -S-methyl, -S-ethyl, -S-propyl, -S-butyl, -S-pentyl, -S-isopropyl, -S-isobutyl, -S-tert-butyl, -S-sec-butyl, and not limited to these.
  • C 1-6 alkylsulfonylamide corresponds to the substituted sulfonamide radical.
  • Non-limiting examples are: methylsulfonamide, ethylsulfonamide, butylsulfonamide, tert-butylsulfonamide
  • aryloxy or "substituted aryloxy” refer to aromatic groups substituted with a radical oxygen, such as phenoxy, benzoxy, 4-ethoxyphenoxy; 4-methoxyphenoxy; 3-methoxyphenoxy, 3-ethoxyphenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 4-bromophenoxy, 3-bromophenoxy, and not limited to these.
  • pyridinyl refers to a pyridine ring and its isomers that may be used as substituents. Non-limiting examples are: pyridin-2-yl, pyridin-4-yl and pyridin-3-yl. Additionally, the term “substituted pyridinyl” refers to substituted pyridine rings such as 6-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, 5-methoxypyridin-2-yl, 4-methoxypyridin-2-yl, 2-methoxypyridin-4-yl, 6-methoxypyridin-2-yl, and not limited to these.
  • C 1-6 haloalkyloxy refers to alkoxy groups bonded to a halogen, including groups such as trifluoromethoxy, difluoromethoxy, fluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 2,2- difluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-dichloroethoxy, 2,2,2-trichloroethoxy, 3,3,3-trifluoropropoxy, 3,3-difluoropropoxy, 3-fluoroproxy, 3-chloropropoxy, 3,3- but not limited to dichloropropoxy, 3,3,3-trichloropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentoxy.
  • haloC 1-6 alkyl refers to alkyl groups attached to a halogen, including groups such as trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, tribromomethyl, tribromobutyl, bromomethyl, but not limited to these.
  • (C 1-6 alkylamino)C 1-6 alkoxy refers to groups such as 2-(dimethylamino)methoxy; 2-(dimethylamino)ethoxy; 2-(dimethylamino)propoxy; 2-(dimethylamino)butoxy, not limited to these.
  • (-S-C 1-6 alkyl)C 1-6 alkyloxy refers to groups such as (-S-methyl)methoxy, (-S-ethyl)methoxy, (-S-methyl)ethoxy , (-S-methyl)propoxy, (-S-methyl)butoxy, (-S-ethyl)methoxy, but not limited to these.
  • O-C3-C7 cycloalkyl refers to groups such as cyclopropoxy; cyclopentyloxy; cyclohexyloxy; cyclobutyloxy, not limited to these.
  • C3-C7 O-heterocycloalkyl refers to groups such as azetidinyloxy, 1-methylazetidinyloxy, piperidinyloxy, pyrrolidinyloxy, but is not limited to them.
  • C 1-6 alkylsulfonyl refers to groups such as methylsulfonyl, propylsulfonyl, tert-butylsulfonyl, isopropylsulfonyl, but is not limited to them.
  • C 1-6 alkylsulfinyl refers to groups such as methylsulfinyl, propylsulfinyl, tert-butylsulfinyl, isopropylsulfinyl, but is not limited to these.
  • N-C 1-6 alkylcarbamoyl and “N ,N -C 1-6 alkylcarbamoyl” refer to groups such as mono- and di-alkylated N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-propylcarbamoyl not limited to these.
  • the present invention discloses in a first embodiment a compound of Formula I:
  • Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • - Ri is selected from the group consisting of hydrogen, linear or branched C 1-6 alkyl, benzyl, 4-methoxybenzyl, C3-C6 cycloalkyl or aryl;
  • R 2 and Re are independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, straight or branched C 1-6 alkoxy, C3-C7 O-cycloalkyl, C3-C7 heterocycloalkyl, C 1-6 alkyl straight or branched, C3-6 cycloalkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, aryl, amine, N-(alkyl)amines, N ,N -(dialkyl)amines, azetidinyloxy, 1-methylazetidinyloxy, morpholine, pyridinyl, substituted pyridinyl, aryloxy, substituted aryloxy, oxetanyloxy, - S-C 1-6 alkyl, C 1-6 haloalkyloxy, C 1-6 haloalkyl, (C 1-6 alkylamino)C 1-6
  • - Rs and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, aryl, pyridinyl, linear or branched C 1-6 alkyl, trifluoromethyl, difluoromethyl , N-(alkyl)amines, N,N-(alkyl)amines, difluoromethoxy or trifluoromethoxy, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, ( C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulf
  • R4 is selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethyl, trifluoromethyl, C3-6 cycloalkyl, C1 -C6 alkoxy straight or branched, difluoromethoxy, trifluoromethoxy, phenyl, substituted phenyl, aryl or morpholine, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulfonyl,
  • R7, RS, R9 and R10 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy or C 1-6 alkyl
  • Ri is selected from the group consisting of hydrogen, methyl, ethyl, butyl, propyl, isopropyl, cyclopropyl, tert-butyl, benzyl or substituted benzyl.
  • Ri is selected from the group consisting of hydrogen, methyl, ethyl, butyl, isopropyl, cyclopropyl, benzyl or 4-methoxybenzyl.
  • R2 is selected from the group consisting of hydrogen, bromine, fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, butyl, tert-butyl, propyl, isopropyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, phenyl, morpholine or pyridine.
  • R2 is selected from hydrogen or phenyl.
  • R2 is hydrogen.
  • R2 is phenyl.
  • R2 is selected from the group consisting of hydrogen, fluorine, bromine, chlorine, methyl, trifluoromethoxy, methoxy, trifluoromethyl, difluoromethyl, cyclopropyl, tert-butyl, azetidinyloxy, 1-methylazetidinyloxy, amine, N,N-dimethylamine, methylsulfinyl, phenyl.
  • R3 is selected from the group consisting of hydrogen, fluorine, bromine, chlorine, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, N,N-(dialkyl)amine or phenyl.
  • R3 is hydrogen.
  • R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, N ,N -dimethylamine, methoxy, trifluoromethoxy, phenyl.
  • FU is selected from the group consisting of hydrogen, bromine, fluorine, chlorine, methyl, ethyl, butyl, propyl, isopropyl, tert-butyl, dimethylamine, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , phenyl N ,N -(dialkyl)amine or morpholine.
  • FU is selected from the group consisting of hydrogen, fluorine, bromine, chlorine, methyl, tert-butyl, methoxy, dimethylamine, trifluoromethyl, cyclopropyl, phenyl or morpholine.
  • R 5 is selected from the group consisting of hydrogen, fluorine, bromine, chlorine, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy or phenyl.
  • R 5 is selected from the group consisting of hydrogen, fluorine, bromine, chlorine, methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, phenyl, N ,N -dimethylamine or morpholine.
  • Re is selected from the group consisting of hydrogen, bromine, fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, butyl, tert-butyl, propyl, isopropyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, phenyl, morpholine or pyridine.
  • Re is selected from the group consisting of hydrogen, bromine, fluorine, chlorine, methoxy, methyl, tert-butyl, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, phenyl, azetidinyloxy, 1-methylazetidinyloxy, N,N-dimethylamine, methylsulfinyl, morpholine or pyridine.
  • R 7 , Rs, Rg and Rw are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, butyl, propyl, isopropyl or tert-butyl.
  • R7 , Rs, R9 and Rw are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methoxy, ethoxy or methyl.
  • the compound of Formula I is selected from the group consisting of:
  • the compound(s) of Formula I may have more than one isomer, including without limitation, spatial isomerism, such as geometric (E, Z) and optical (R, S) isomerism .
  • spatial isomerism such as geometric (E, Z) and optical (R, S) isomerism .
  • the compound(s) of Formula I are geometric E isomers.
  • the compound(s) of Formula I may be basic in nature and, accordingly, pharmaceutically acceptable salts may be obtained by adding organic or inorganic acids.
  • organic acids that can be used are fumaric, maleic, benzoic, lactic acid, among others.
  • inorganic acids hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, nitric acid, among others, can be mentioned.
  • the compound(s) of Formula I can be obtained in the form of crystals, which can optionally be presented as pharmaceutically acceptable solvates, in which the solvent is incorporated in stoichiometric proportions or not to the crystalline network.
  • the crystallization solvent is water, resulting in pharmaceutically acceptable hydrates.
  • the compounds of Formula I of the present invention are selective inhibitors of the enzyme histone deacetylase 6 (HDAC6).
  • HDAC6 histone deacetylase 6
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts, hydrates, solvates, isomers and esters thereof; one or more pharmaceutically acceptable excipients and compounds containing one or more isotopically enriched atoms such as, for example, but not limited to the 2H hydrogen isotope.
  • compositions are considered to be any substance, other than the active pharmaceutical ingredient, which has been assessed for its safety and which is intentionally added to the dosage form. Such excipients are selected according to the pharmaceutical dosage form of interest, its route of administration, physical-chemical compatibility with the active ingredient and the effect on efficacy.
  • excipients may be widely known in the prior art and are classified according to their function as diluents, binders, disintegrants or disintegrators, lubricants, suspending agents, thickeners, solvents, surfactants, glidants, anti-caking or flow agents, coating agents, plasticizers, sweeteners, sweeteners, isotonic agents, dyes and pigments, preservatives, antioxidants, modifying or pH control agents, complexing agents, chelating agents, flavorings, flavors, viscosity modifying agents, opacifiers, permeation promoters, among others.
  • the pharmaceutical compositions of the present invention can be administered by various routes, including oral, sublingual, nasal, parenteral, injectable, submuscular, topical, transdermal, ocular, rectal, but not limitations to these.
  • the present invention features a kit comprising a pharmaceutical composition and an application device.
  • the present invention features the use of one or more compounds of Formula I in the preparation of a medicament to treat depressive disorders, anxiety disorders, rheumatoid arthritis and/or neuropathic pain.
  • the present invention features a method of treating, preventing, alleviating, suppressing and/or controlling depressive disorders, anxiety disorders, rheumatoid arthritis and/or neuropathic pain comprising administering a therapeutically effective amount of at least at least one of the compounds of Formula I or pharmaceutically acceptable salts, solvates, isomers, hydrates, esters and compounds containing one or more isotopically enriched atoms such as, for example, but not limited to the 2H hydrogen isotope.
  • the present invention presents a process for obtaining a compound of Formula I comprising the steps of:
  • Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • -Ri is selected from the group consisting of hydrogen, straight or branched C 1-6 alkyl or Cs-Ce cycloalkyl;
  • R 2 and Re are independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, straight or branched C 1-6 alkoxy, C3-C7 O-cycloalkyl, C3-C7 heterocycloalkyl, C 1-6 alkyl straight or branched, C3-6 cycloalkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, aryl, amine, N-(alkyl)amines, N ,N -(dialkyl)amines, azetidinyloxy, 1-methylazetidinyloxy, morpholine, pyridinyl, substituted pyridinyl, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6
  • R 3 and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, aryl, pyridinyl, linear or branched C 1 -C alkyl, trifluoromethyl, difluoromethyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethoxy or trifluoromethoxy, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkyl,
  • R4 is selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethyl, trifluoromethyl, C3-6 cycloalkyl, C1 -C6 alkoxy straight or branched, difluoromethoxy, trifluoromethoxy, phenyl, substituted phenyl, aryl or morpholine, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulfonyl,
  • R 7 , R 8 , R 8 and R 10 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy or C 1-6 alkyl
  • Steps (a) and (b) were carried out based on the document: Rodrigues. chem. Med. chem. 2010, 20, 6439, hereby fully incorporated by reference. Adequacy of reaction conditions for certain compounds of Formula IV and Formula I were performed. [0080] In an embodiment of the sixth embodiment, the reaction of step (a) is performed at a temperature between 25-80 ° C, preferably at 25 ° C. In another embodiment, the reaction time of step (a) varies between 4-48h.
  • the intermediates of Formula VII used in step (a) are methyl or ethyl benzoates or benzoic acids.
  • the hydrazine derivative used in step (a) for forming the benzohydrazide of Formula VI is preferably selected from hydrazine hydroxide, monomethyl hydrazine, cyclopropyl hydrazine and isopropyl hydrazine.
  • the intermediates of Formula II used in step (b) are selected from among 4-formyl-N-hydroxybenzamide, 3-fluoro-4-formyl-N-hydroxybenzamide, 2-fluoro-4 -formyl-N-hydroxybenzamide, 6-formyl-N-hydroxynicotinamide, 5-formyl-N-hydroxynicotinamide, 4-formyl-N-hydroxy-3-methylbenzamide, 4-formyl-N-hydroxy-2-methylbenzamide, 2-chloro -4-formyl-N-hydroxybenzamide, 3-chloro-4-formyl-N-hydroxybenzamide, 4-formyl-N-hydroxy-2-methoxybenzamide or 4-formyl-N-hydroxy-3-methoxybenzamide; the solvent is selected from ethanol or methanol.
  • step (b) is performed in reaction times that vary between 1 -16h.
  • the obtaining process may comprise an additional step prior to step (a) for obtaining methyl benzoates. This step was performed based on previous documents (Martin. Acc. Chem. Res. 2008, 41 , 1461 ; Barder. J. Am. Chem. Soc. 2005, 127, 4685) referring to C-C bond formation mediated by catalysis of palladium.
  • the obtaining process may comprise an additional step prior to step (a) for obtaining methyl benzoates.
  • This step is the oxidation of the corresponding benzaldehydes in a basic medium in the presence of iodine (1 2 ) and was carried out based on a predecessor document (Yamada. Tetrahedron Lett. 33, 1992, 4329).
  • step (a) of the obtaining process is replaced by the reaction between benzoic acids and tert-butyl methylhydrazine-1-carboxylate to formation of N-protected Formula V intermediates.
  • the selected solvent is pyridine or N,N-dimethylformamide
  • the coupling agent is preferably selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and/or 1-hydroxybenzotriazole hydrate
  • the selected base is an organic base, preferably N ,N -diisopropylethylamine
  • the reaction time is selected from 4-24h and the reaction temperature is selected from 25-60 ° C.
  • the present invention presents a process for preparing a compound of Formula I comprising the steps of:
  • Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • - Ri is selected from the group consisting of hydrogen, linear or branched C 1-6 alkyl, benzyl, 4-methoxybenzyl, C3-C6 cycloalkyl or aryl;
  • R 2 and Re are independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, straight or branched C 1-6 alkoxy, C3-C7 O-cycloalkyl, C3-C7 heterocycloalkyl, C 1-6 alkyl straight or branched, C3-6 cycloalkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, aryl, amine, N-(alkyl)amines, N ,N -(dialkyl)amines, azetidinyloxy, 1-methylazetidinyloxy, morpholine, pyridinyl, substituted pyridinyl, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6
  • R 3 and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, aryl, pyridinyl, linear or branched C 1 -C alkyl, trifluoromethyl, difluoromethyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethoxy or trifluoromethoxy, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkyl,
  • R4 is selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethyl, trifluoromethyl, C3-6 cycloalkyl, C1 -C6 alkoxy straight or branched, difluoromethoxy, trifluoromethoxy, phenyl, substituted phenyl, aryl or morpholine, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulfonyl,
  • R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy or C 1-6 alkyl.
  • Steps (a), (b), (c), (d) and (e) were carried out based on document WO 2016/154694 A1, fully incorporated herein by reference. Adequacy of reaction conditions to obtain certain intermediates and compounds of Formula I were performed.
  • said inorganic base of step (c) is selected from potassium carbonate, cesium carbonate, sodium carbonate or sodium hydride; in that said aprotic polar solvent of step (c) is selected from acetone or acetonitrile; in that said alkyl halide of step (c) is selected from methyl iodide or ethyl iodide.
  • step (a) is performed at temperatures between 25-80 o C.
  • the reaction time of step (a) varies between 4-48h.
  • the solvent used in step (b) is toluene or the reaction proceeds without solvent.
  • step (a) of the obtaining process is replaced by the reaction between the corresponding carboxylic acid and 2-aminoisoindoline-1,3-dione to form the intermediate of Formula V.
  • the selected solvent is pyridine
  • the selected coupling agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and the reaction proceeds for 8-24h at a temperature of 25-80 oC .
  • step (c) is performed at a temperature between 40-70 oC .
  • the reaction time of step (c) varies between 2-18h.
  • step (d) is performed at temperatures ranging from 60-80 o C. In another embodiment, the reaction time of step (d) varies between 2-16h.
  • the intermediates of Formula II used in step (e) are selected from among 4-formyl-N-hydroxybenzamide, 3-fluoro-4-formyl-N-hydroxybenzamide, 6-formyl-N- hydroxynicotinamide, 4-formyl-N-hydroxy-3-methylbenzamide, 3-chloro-4-formyl-N-hydroxybenzamide, 5-fluoro-6-formyl-N-hydroxynicotinamide.
  • step (e) reaction time of step (e) varies between 2-24h.
  • the obtaining process may comprise an additional step prior to step (a) for obtaining methyl benzoates.
  • This step is the oxidation of the corresponding benzaldehydes in a basic medium in the presence of iodine (1 2 ) and was carried out based on a previous document (Yamada. Tetrahedron Lett. 33, 1992, 4329).
  • the obtaining process may comprise an additional step prior to step (a) for obtaining the corresponding methyl benzoate.
  • This step was carried out based on the existing literature (Wang. Org. Biomol. Chem. 16, 2018, 6191 ) through the reaction between halogenated alkyl benzoates, preferably fluorinated alkyl benzoate, and saturated heterocycles in a basic medium to obtain intermediates of Formula VII.
  • the present invention presents a process for obtaining a compound of Formula I comprising the steps of:
  • Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • R 1 is selected from the group consisting of hydrogen, straight or branched C 1-6 alkyl, benzyl, 4-methoxybenzyl, C 3 -C 6 cycloalkyl or aryl;
  • R 2 and Re are independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, straight or branched C 1-6 alkoxy, O-C 3 -C 7 cycloalkyl, O-C 3 -C 7 heterocycloalkyl, C 3 -C 7 alkyl C 1-6 straight or branched, C 3-6 cycloalkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, aryl, amine, N-(alkyl)amines, N ,N -(dialkyl)amines, azetidinyloxy, 1-methylazetidinyloxy, morpholine, pyridinyl, substituted pyridinyl, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, C 1-6 haloalkyloxy, C 1-6 haloalkyl, (
  • R 3 and R 5 are independently selected from the group consisting of hydrogen, halogen, straight or branched C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, aryl, pyridinyl, straight or branched C 1 -C 6 alkyl , trifluoromethyl, difluoromethyl, N-(alkyl)amines, N,N-(alkyl)amines, difluoromethoxy or trifluoromethoxy, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, C 1-6 haloalkyloxy, C 1 haloalkyl -6 , (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alky
  • R4 is selected from the group consisting of hydrogen, halogen, straight or branched C 1-6 alkyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethyl, trifluoromethyl, C 3-6 cycloalkyl, C 1 alkoxy -C 6 linear or branched, difluoromethoxy, trifluoromethoxy, phenyl, substituted phenyl, aryl or morpholine, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl )C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulfony
  • R 7 , RS, Rg and R io are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy or C 1-6 alkyl.
  • Step (a) was performed based on the document: Rodrigues. chem. Med. chem. 2010, 20, 6439, hereby fully incorporated by reference.
  • the alcoholic solvent of steps (b) and (d) is a polar protic solvent and/or said acid catalyst of step (b) is a strong inorganic acid.
  • the alcoholic solvent of steps (b) and (d) is a polar protic solvent, preferably a C 1-6 alcohol, preferably selected from ethanol, methanol or a combination thereof with water; in that said acid catalyst of step (b) is a strong inorganic acid, preferably hydrochloric acid or sulfuric acid; in that said polar aprotic solvent of step (c) is selected from acetone or acetonitrile; and/or the alkyl halide of step (c) is selected from 4-methoxybenzyl chloride, benzyl chloride, butyl chloride, ethyl iodide or methyl iodide.
  • a polar protic solvent preferably a C 1-6 alcohol, preferably selected from ethanol, methanol or a combination thereof with water
  • said acid catalyst of step (b) is a strong inorganic acid, preferably hydrochloric acid or sulfuric acid
  • said polar aprotic solvent of step (c) is selected from ace
  • reaction time of step (a) varies between 5-16h.
  • the intermediates of Formula XII used in step (b) are selected from methyl 4-formylbenzoate, methyl 3-fluoro-4-formylbenzoate or 3,5-difluoro-4-formylbenzoate methyl.
  • the solvent used in step (b) is ethanol.
  • step (b) is performed at a temperature between 25-70 o C. In another embodiment, the reaction time of step (b) varies between 2-16h.
  • the inorganic catalyst used in step (e) is a strong inorganic acid, preferably hydrochloric acid.
  • the alkyl halide used in step (c) is selected from 4-methoxybenzyl chloride, benzyl chloride, butyl chloride, ethyl iodide or methyl iodide.
  • the solvent used in step (c) is selected from acetonitrile or acetone.
  • the base used in step (c) is selected from potassium carbonate or cesium carbonate.
  • step (c) is performed at a temperature between 40-70 o C.
  • the reaction time of step (c) varies between 2-18h.
  • the solvent used in step (d) is methanol.
  • the base used in step (d) is selected from sodium hydroxide and DBU.
  • step (d) is performed at a temperature selected between 40-80 o C. In another embodiment, the reaction time of step (d) varies between 18-24h.
  • the present invention presents a process for obtaining a compound of Formula I comprising the steps of:
  • Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • R 2 and Re are independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, straight or branched C 1-6 alkoxy, C3-C7 O-cycloalkyl, C3-C7 heterocycloalkyl, C 1-6 alkyl straight or branched, C3-6 cycloalkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, aryl, amine, N-(alkyl)amines, N ,N -(dialkyl)amines, azetidinyloxy, 1-methylazetidinyloxy, morpholine, pyridinyl, substituted pyridinyl, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6
  • R 3 and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, aryl, pyridinyl, linear or branched C 1 -C alkyl, trifluoromethyl, difluoromethyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethoxy or trifluoromethoxy, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-alkyl C 1-6 alkyloxy, C 1-6 alkyl, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6
  • - FU is selected from the group consisting of hydrogen, halogen, straight or branched C 1-6 alkyl, N-(alkyl)amines, N ,N -(alkyl)amines, difluoromethyl, trifluoromethyl, C3-6 cycloalkyl, C1 -C6 alkoxy straight or branched, difluoromethoxy, trifluoromethoxy, phenyl, substituted phenyl, aryl or morpholine, aryloxy, substituted aryloxy, oxetanyloxy, -S-C 1-6 alkyl, haloC 1-6 alkyloxy, haloC 1-6 alkyl, (C 1-6 alkylamino)C 1-6 alkoxy, (-S-C 1-6 alkyl)C 1-6 alkyloxy, sulfonamide, C 1-6 alkylsulfonylamide, sulfonyl, C 1-6 alkylsulfony
  • R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy or C 1-6 alkyl
  • Step (a) was performed based on the document: Rodrigues. chem. Med. chem. 2010, 20, 6439, hereby fully incorporated by reference.
  • said alcoholic solvent of step (b) is a polar protic solvent and/or said acid catalyst of step (b) is a strong inorganic acid.
  • said alcoholic solvent of step ( (b) is a polar protic solvent, preferably a C1 -6 alcohol, preferably selected from methanol or ethanol; said acid catalyst of step (b) is a strong inorganic acid, preferably hydrochloric acid, and/or the base used in step (c) is inorganic, preferably lithium hydroxide.
  • the solvent used in step (a) is methanol.
  • step (a) is performed at room temperature.
  • the reaction time of step (a) is 8-24h.
  • the intermediate of Formula VII used in step (a) is methyl benzoate.
  • the hydrazine derivative used in step (a) for forming the benzohydrazide is hydrazine hydroxide.
  • the solvent used in step (b) is ethanol.
  • step (b) is performed at room temperature or at 40 oC .
  • the reaction time of step (b) is 2-8h.
  • the base used in step (c) is selected as being lithium hydroxide.
  • the solvent used in step (c) is a mixture of methanol and water.
  • the temperature used in step (c) is 25 o C. In another embodiment, the reaction time of step (c) is 18h.
  • the acid used in step (d) is selected as being para-toluenesulfonic acid.
  • the solvents used in step (d) are dimethylformamide or dichloromethane.
  • the coupling agent used in step (d) is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
  • step (d) is performed at a temperature of 25-40 o C.
  • the reaction time of step (d) is 8-16h.
  • the compound of Formula I of step (d) is obtained after completion of the reaction with dilute acid solution; said preferred acid being hydrochloric acid.
  • the acid used in step (e) is para-toluenesulfonic acid.
  • the solvent used in step (e) is methanol.
  • step (e) is performed at room temperature.
  • the reaction time of step (e) is 12-16h.
  • step (b) of the obtaining process is replaced by the reaction between carbonyl chlorides and (E)-4-((2-methylhydrazinaylidene)methyl) tert-butyl benzoate to obtain of intermediates of Formula X, N-alkylated.
  • the reaction is performed in an aprotic solvent, preferably selected as being dichloromethane, in a basic medium.
  • the base is organic, preferably selected as triethylamine; the selected temperature is 0-40oC and the selected reaction time is 6-10h.
  • the intermediate of Formula X reacts with oxalyl chloride to form the corresponding benzoyl chloride.
  • the reaction is performed in an aprotic solvent, preferably selected to be dichloromethane; the preferred selected temperature is 25oC and the preferred selected reaction time is 4h.
  • step (e) of the obtaining process is replaced by the reaction between benzoyl chloride and hydroxyamine hydrochloride to form the compound of Formula I.
  • the reaction is performed in an aprotic solvent, preferably selected as being dichloromethane ; the preferably selected base is triethylamine; the preferred selected temperature is 0 ° C and the preferred selected reaction time is 6h.
  • the present invention presents a process for obtaining a compound of Formula II comprising the steps of:
  • step (b) the intermediate of Formula XIII obtained in step (a) reacts with hydroxylamine, in a basic medium, leading to the formation of the intermediate hydroxamic acid of Formula XIV:
  • X 6 , X 7 , X 8 and X 9 are independently selected from carbon or nitrogen;
  • R 7 , R 8 , Rg and Rw are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy, or C 1-8 alkyl.
  • step (a) is performed at room temperature or at 0 ° C.
  • the reaction time of step (a) is 2-8h.
  • step (b) is performed at room temperature or at 0 oC .
  • the reaction time of step (b) varies between 4h- 4pm.
  • step (c) is performed at room temperature. In another embodiment, the reaction time of step (c) varies between 2-12h.
  • step (a) of the obtaining process is replaced by the reaction between 4-formylbenzoic acid and Di-tertbutyl-dicarbonate in basic medium to form tert-butyl 4-formylbenzoate.
  • the reaction is performed in a protic solvent, preferably selected as tert-butanol; the preferably selected base is 4-dimethylaminopyridine; the preferred selected temperature is 25 oC and the preferred selected reaction time is 16h.
  • step (a) of the obtaining process is replaced by the reaction between 4-formylbenzoic acid and Di-tertbutyl-dicarbonate in basic medium to form tert-butyl 4-formylbenzoate.
  • the reaction is performed in a protic solvent, preferably selected as tert-butanol; the preferably selected base is 4-dimethylaminopyridine; the preferred selected temperature is 25 oC and the preferred selected reaction time is 16h.
  • the process for obtaining contains a reaction step between tert-butyl 4-formylbenzoate and monomethyl hydrazine to form (E)-4-((2-methylhydrazineylidene)methyl) benzoate tert-butyl.
  • the reaction is performed in a protic solvent, preferably selected as ethanol; the preferred selected temperature is 25 oC and the preferred selected reaction time is 16h.
  • the compounds of Formula I object of the present invention can be prepared from four synthetic routes (methods (i), (ii), (iii) or (iv)) described in Scheme 1 below, but not limiting these.
  • Method (i) comprises the steps of (a) hydrazinolysis of the compound of Formula VII in alcoholic solvent, generating an intermediate benzohydrazide of Formula VI, (b) condensation reaction of the benzohydrazide produced in (a) with reagent of Formula II, in the presence of acid catalyst and alcoholic solvent, generating compounds of Formula I in which Ri is hydrogen, methyl, cyclopropyl or isopopropyl.
  • Steps (a) and (b) were performed based on the Rodrigues document. chem. Med. chem. 2010, 20, 6439, hereby fully incorporated by reference. Adequacy of reaction conditions for certain compounds of Formula IV and Formula I were performed.
  • step (a) of Method (i) the temperature is selected between 25-80 oC , preferably at 25 oC and the reaction time varies between 4-48h.
  • the intermediates of Formula VII are methyl or ethyl benzoates or benzoic acids, and the hydrazine derivative used to form the benzohydrazide of Formula VI is preferably selected from hydrazine hydroxide, monomethyl hydrazine, cyclopropyl hydrazine and isopropyl hydrazine.
  • step (b) of Method (i) the reaction between the benzohydrazides of Formula VI produced in step (a) with the intermediates of Formula II selected from among 4-formyl-N-hydroxybenzamide, 3-fluoro-4- formyl-N-hydroxybenzamide, 2-fluoro-4-formyl-N-hydroxybenzamide, 6-formyl-N-hydroxynicotinamide, 5-formyl-N-hydroxynicotinamide, 4-formyl-N-hydroxy-3-methylbenzamide, 4-formyl- N-hydroxy-2-methylbenzamide, 2-chloro-4-formyl-N-hydroxybenzamide, 3-chloro-4-formyl-N-hydroxybenzamide, 4-formyl-N-hydroxy-2-methoxybenzamide or 4-formyl-N- hydroxy- 3-methoxybenzamide; the solvent is selected from ethanol or methanol; reactions are performed at room temperature; the reaction time varies between 1 -16h and the inorganic catalyst is selected from sulfuric acid or hydrochloric acid.
  • the solvent
  • Method (i) may comprise an additional step prior to step (a) to obtain methyl benzoates.
  • This step is performed through a reaction between heteroaromatic halides and phenylboronic acid as described in the literature ((Martin. Acc. Chem. Res. 2008, 41 , 1461 ; Barder. J. Am. Chem. Soc. 2005, 127, 4685)
  • the selected catalyst is (1 ,1 '-Bis(diphenylphosphine)ferrocene) palladium (II) dichloride;
  • the selected base is potassium carbonate and the solvent is a mixture of 1,4-dioxane in water.
  • the reactions are performed 12-24 hours at a temperature of 80-100oC .
  • Method (i) may comprise an additional step prior to step (a) to obtain methyl benzoates.
  • Such step is carried out through the reaction between oxidation of the corresponding benzaldehydes in basic medium in the presence of iodine (l 2 ) and was carried out based on the existing literature (Yamada. Tetrahedron Lett. 33, 1992, 4329).
  • step (a) of Method (i) is replaced by the reaction between benzoic acids and tert-butyl methylhydrazine-1-carboxylate to form N-protected intermediates of Formula V.
  • the selected solvent is pyridine or, the preferably selected coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and/or 1-hydroxybenzotriazole hydrate;
  • the selected base is an organic base, preferably N,N-diisopropylethylamine;
  • the reaction time is selected from 4-24h and the reaction temperature is selected from 25-60 ° C.
  • Method (ii) comprises the steps: (a) as described in method (i); (b) protecting the benzohydrazide functional group with phthalic anhydride of the compound of Formula VI forming a protected benzamide intermediate of Formula V; (c) N-alkylation of the protected benzamide intermediate of Formula V from reaction with an alkyl halide (Ri-Y, where Y is a halogen) with inorganic base and polar aprotic solvent - forming an intermediate of Formula VI; (d) deprotecting the functional group of the intermediate of Formula IV with hydrazine hydrate, forming the alkylated benzohydrazide intermediate represented by Formula III; and, (e) condensation reaction of the intermediate of Formula III with reagent of Formula II, generating compounds of Formula I in which Ri is a C 1-6 alkyl group.
  • Steps (a), (b), (c), (d) and (e) were carried out based on document WO 2016/154694 A1, fully incorporated herein by reference. Adequacy of reaction conditions to obtain certain intermediates and compounds of Formula I were performed.
  • step (a) of Method (ii) the reactions are performed at temperatures between 25-80 o C and the reaction time varies between 4-48h.
  • the intermediates of Formula VII are methyl benzoates and the hydrazine derivative used to form the benzohydrazide of Formula VI is hydrazine hydroxide.
  • step (b) of Method (ii) the reaction between the benzohydrazides of Formula VI produced in step (a) with phytalic anhydride occurs; the selected solvent is toluene or the reaction proceeds without solvent; temperatures vary from 1 10-150 oC and reaction time varies between 2-5h.
  • step (a) of Method (ii) is replaced by the reaction between the corresponding carboxylic acid and and 2-aminoisoindoline-1,3-dione to form the intermediate of Formula V.
  • the selected solvent is pyridine
  • the selected coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the reaction takes 8-24 hours at 25-80 ° C.
  • step (c) of Method (ii) the reaction occurs between the protected benzohydrazides of Formula V produced in step (b) with an alkyl halide selected from methyl iodide or ethyl iodide; the solvent is selected from acetonitrile or acetone; the base is selected from potassium carbonate or cesium carbonate; temperatures vary between 40-70oC and reaction time varies between 2-18h.
  • an alkyl halide selected from methyl iodide or ethyl iodide
  • the solvent is selected from acetonitrile or acetone
  • the base is selected from potassium carbonate or cesium carbonate
  • temperatures vary between 40-70oC and reaction time varies between 2-18h.
  • step (d) of Method (ii) the reaction between the protected N-alkylbenzohydrazides of Formula IV produced in step (c) with hydrazine hydrate occurs; the selected solvent is ethanol; temperatures vary between 60-80oC and reaction time varies between 2-16h.
  • step (e) of Method (ii) the reaction between the N-alkylbenzohydrazides of Formula III produced in step (d) with the intermediates of Formula II selected from among 4-formyl-N-hydroxybenzamide, 3-fluoro- 4-formyl-N-hydroxybenzamide, 6-formyl-N-hydroxynicotinamide, 4-formyl-N-hydroxy-3-methylbenzamide, 3-chloro-4-formyl-N-hydroxybenzamide, 5-fluoro-6-formyl-N- hydroxynicotinamide; the solvent is selected from ethanol or methanol; reactions are performed at room temperature; the reaction time varies between 2-24h and the selected inorganic catalyst is hydrochloric acid.
  • the intermediates of Formula II selected from among 4-formyl-N-hydroxybenzamide, 3-fluoro- 4-formyl-N-hydroxybenzamide, 6-formyl-N-hydroxynicotinamide, 4-formyl-N-hydroxy-3-methylbenzamide, 3-chloro-4-formyl-N
  • Method (ii) may comprise an additional step prior to step (a) to obtain methyl benzoates.
  • Such step is carried out through the reaction between oxidation of the corresponding benzaldehydes in basic medium in the presence of iodine (l 2 ) and was carried out based on the existing literature (Yamada. Tetrahedron Lett. 33, 1992, 4329).
  • Method (ii) may comprise an additional step prior to step (a) to obtain methyl benzoate.
  • This step was carried out based on the existing literature (Wang. Org. Biomol. Chem. 16, 2018, 6191 ) through the reaction between halogenated alkyl benzoates, preferably fluorinated alkyl benzoate, and saturated heterocycles in a basic medium to obtain intermediates of Formula VII.
  • Method (iii) comprises the steps: (a) as described in method (i); (b) reaction of intermediate benzohydrazide of Formula VI with intermediate of Formula II in acid catalyst and alcoholic solvent forming intermediate of Formula VIII; (c) reaction of intermediate of Formula VIII with reagent Ri-Y (wherein Y is a halogen) in polar aprotic solvent, forming intermediate of Formula IX; (d) reaction of intermediate of Formula IX with hydroxylamine in the presence of base and alcoholic solvent, forming compound of Formula I in which Ri is selected from C 1-6 alkyl or aryl, preferably benzyl or substituted benzyl.
  • step (a) of Method (iii) the solvent is selected from ethanol, methanol or a combination thereof with water; the reactions are performed at temperatures between 60-70 oC and the reaction time varies between 5-16h.
  • the Formula VII intermediates are methyl benzoates and the hydrazine derivative used to form the Formula VI benzohydrazide is hydrazine hydroxide.
  • step (b) of Method (iii) the reaction between the benzohydrazides of Formula VI produced in step (a) with the intermediates of Formula XII selected from among methyl 4-formylbenzoate, 3-fluoro-4-formylbenzoate of methyl or methyl 3,5-difluoro-4-formylbenzoate; the selected solvent is ethanol; the reactions are performed between 25 to 70 and the reaction time varies between 2-16h.
  • step (c) of Method (iii) the reaction takes place between the intermediates of Formula VIII produced in step (b) with an alkyl halide selected from among 4-methoxybenzyl chloride, benzyl chloride, butyl chloride, sodium iodide ethyl or methyl iodide; the solvent is selected from acetonitrile or acetone; the base is selected from potassium carbonate or cesium carbonate; temperatures vary between 40-70oC and reaction time varies between 2-18h.
  • an alkyl halide selected from among 4-methoxybenzyl chloride, benzyl chloride, butyl chloride, sodium iodide ethyl or methyl iodide
  • the solvent is selected from acetonitrile or acetone
  • the base is selected from potassium carbonate or cesium carbonate
  • temperatures vary between 40-70oC and reaction time varies between 2-18h.
  • step (d) of Method (iii) the reaction between the intermediates of Formula IX with hydroxylamine occurs; the selected solvent is methanol; the base used is selected from sodium hydroxide and DBU; the selected temperature between 40-80 oC and the reaction time varies between 18-24h.
  • Method (iv) comprises steps: (a) and (b) according to method (iii); (c) hydrolysis reaction of intermediate VIII in basic medium in C 1-6 alcohol, preferably methanol, forming compound of Formula X; (d) forming the intermediate of Formula XI by reacting the intermediate of Formula X with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine; (e) reacting the intermediate of Formula XI with an organic acid forming a compound of Formula I wherein Ri is hydrogen.
  • step (a) of Method (iv) the selected solvent is methanol; the reaction is performed at room temperature and the selected reaction time is 8-24h.
  • VII is alkyl benzoate and the hydrazine derivative used to form the benzohydrazide is hydrazine hydroxide.
  • step (b) of Method (iv) occurs the reaction between the benzohydrazide produced in step (a) with methyl 4-formylbenzoate, the selected solvent is ethanol; the reaction is performed at room temperature or at 40 ° C and the selected reaction time is 2-8h.
  • step (c) of Method (iv) the hydrolysis reaction of the intermediate of Formula
  • step (b) in basic medium; said base is selected to be hydroxide of lithium; the selected solvent is mixture of methanol and water; the selected temperature is 25oC and the reaction time is 18h.
  • step (d) of Method (iv) the coupling reaction occurs between the intermediate Formula X produced in step (c) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine in an acid medium; said acid is selected as para-toluenesulfonic acid; the selected solvents are dimethylformamide and dichloromethane; the selected coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; the selected temperature between 25-40 oC and the reaction time is 8-16h.
  • the compound of Formula I is obtained after completion of the reaction with dilute acid solution; said preferred acid is hydrochloric acid.
  • step (e) of Method (iv) the deprotection of the intermediate of Formula XI occurs in an acid medium to form the compound of Formula I.
  • Said selected acid is para-toluenesulfonic acid; the selected solvent is methanol; the reaction is performed at room temperature and the selected reaction time is 12-16h.
  • step (b) of Method (v) is replaced by the reaction between carobonyl chlorides and (E)-4-((2-methylhydrazinaylidene)methyl) tert-butyl benzoate to obtain intermediates of Formula X, N-alkylated.
  • the reaction is performed in an aprotic solvent, preferably selected as being dichloromethane, in a basic medium.
  • the base is organic, preferably selected as triethylamine; the selected temperature is 0-40oC and the selected reaction time is 6-10h.
  • the intermediate of Formula X reacts with oxalyl chloride to form the corresponding benzoyl chloride.
  • the reaction is performed in an aprotic solvent, preferably selected to be dichloromethane; the preferred selected temperature is 25oC and the preferred selected reaction time is 4h.
  • step (e) of Method (iv) is replaced by the reaction between benzoyl chloride and hydroxyamine hydrochloride to form the compound of Formula I.
  • the reaction is performed in an aprotic solvent, preferably selected to be dichloromethane; the preferably selected base is triethylamine; the preferred selected temperature is 0 ° C and the preferred selected reaction time is 6h.
  • Scheme 2 describes a process for obtaining the reagent of Formula II (Method (v)), used in the formation step of the processes for preparing compounds of Formula I by Methods (i)-(iv), of Scheme 1 , but not limited to these.
  • This process comprises 3 steps, with step (a) corresponding to the reaction of different aromatic aldehydes of Formula XII with 2,2-dimethoxy-propane in the presence of organic acid, preferably p-toluenesulfonic acid, forming the corresponding ketal.
  • step (b) the compound obtained in step (a) reacts with hydroxylamine leading to the formation of the intermediate hydroxamic acid.
  • step (c) the intermediate obtained in (b) undergoes a ketal hydrolysis reaction leading to the formation of formyl-N-hydroxybenzamides and derivatives of interest (Formula II).
  • Steps (a) - (c) were carried out based on the Rodrigues document. J. Med. chem. 2016, 59,655, hereby fully incorporated by reference. Adaptations of reaction conditions to obtain certain intermediates and compounds of Formula II were performed.
  • step (a) of Method (v) the reaction is performed at room temperature or at 0 ° C and the selected reaction time is 2-8h.
  • step (b) of Method (v) the reaction is performed at room temperature or at 0 ° C and the reaction time varies between 4h-16h.
  • step (c) of Method (v) the reaction is performed at room temperature or at 40 C and the reaction time varies between 2-12h.
  • step (a) of Method (v) is replaced by the reaction between 4-formylbenzoic acid and Di-tertbutyl-dicarbonate in basic medium to form tert-butyl 4-formylbenzoate.
  • the reaction is performed in a protic solvent, preferably selected as tert-butanol; the preferably selected base is 4-dimethylaminopyridine; the preferred selected temperature is 25 oC and the preferred selected reaction time is 16h.
  • step (a) of Method (v) is replaced by the reaction between 4-formylbenzoic acid and Di- tert-butyl-dicarbonate in basic medium to form tert-butyl 4-formylbenzoate.
  • the reaction is performed in a protic solvent, preferably selected as tert-butanol; the preferably selected base is 4-dimethylaminopyridine; the preferred selected temperature is 25 oC and the preferred selected reaction time is 16h.
  • Method (v) contains a reaction step between tert-butyl 4-formylbenzoate and monomethyl hydrazine to form (E)-4-((2-methylhydrazineylidene)methyl) tert- butyl.
  • the reaction is performed in a protic solvent, preferably selected as ethanol; the preferred selected temperature is 25 oC and the preferred selected reaction time is 16h.
  • Step (b) Formation of methyl (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazinaylidene)methyl)benzoate.
  • E 4-(dimethylamino)benzohydrazide (5.7 mmol, 1.0 equivalent) and ethanol (60 mL)
  • catalytic amounts of concentrated HCl (1 drop in 0.5 ml ethanol) and methyl 4-formyl benzoate (1.1 equivalents).
  • the reaction medium remained under magnetic stirring for 2 h.
  • concentration to half the volume of the reaction medium under reduced pressure ice-cold distilled water (10 mL) was added to the reaction flask and the resulting solid was filtered under vacuum.
  • the desired product was obtained in 89% yield.
  • Step (c) Synthesis of methyl (E)-4-((2-(4-(dimethylamino)benzoyl)-2-(4-methoxybenzyl)hydrazinaylidene)methyl)benzoate.
  • Step (b) Synthesis of 4-(tert-butyl)-N-(1,3-dioxoisoindolin-2-yl)benzamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-[1,1'-biphenylyl-4-carboxamide.
  • reaction was cooled to room temperature, filtered through Celite and the solvent concentrated under reduced pressure.
  • the resulting reaction crude was extracted with ethyl acetate (3 x 25 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the product was obtained in 47% yield after purification by column chromatography using a mixture of hexane and ethyl acetate as solvent.
  • reaction was cooled to room temperature, filtered through Celite and the solvent concentrated under reduced pressure.
  • the resulting reaction crude was extracted with ethyl acetate (3 x 25 mL), the organic phase dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the product was obtained in 97% yield after purification by column chromatography using a mixture of hexane and ethyl acetate as solvent.
  • the resulting reaction crude was extracted with ethyl acetate (3 x 25 mL), the organic phase dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the product was obtained in 83% yield after purification by column chromatography using mixture of hexane and ethyl acetate as solvent.
  • the resulting reaction crude was extracted with ethyl acetate (3 x 25 mL), the organic phase dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the product was obtained in 47% yield after purification by column chromatography using a mixture of hexane and ethyl acetate as solvent.
  • the resulting reaction crude was extracted with ethyl acetate (3 x 25 mL), the organic phase dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the product was obtained in 89% yield after purification by column chromatography using a mixture of hexane and ethyl acetate as solvent.
  • Step (a) Synthesis of methyl 4-(dimethoxymethyl)-3-fluoro-benzoate.
  • N-methyll-2-(trifluoromethyl)benzohydrazide (1.0 mmol, 1.0 equivalent), obtained as described in Example 11, was added to a 50 ml round-bottom flask; step e, ethanol (10 ml_), catalytic amounts of 37% HCI (3 drops) and 3-fluoro-4-formyl-N-hydroxybenzamide (1.2 equivalents), obtained as described in Example 32.
  • the reaction was kept under magnetic stirring at room temperature for 24 hours. After this period, the solvent was concentrated.
  • the reaction crude was purified by reverse phase column chromatography using water and methanol mixture. Compound 33 was obtained in 19% yield.
  • Step (b) Synthesis of 2-bromo-N-(1,3-dioxoisoindolin-2-yl)-N-methylbenzamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-3-(trifluoromethoxy)benzamide.
  • Step (a) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-2-(trifluoromethoxy)benzamide.
  • 2-(trifluoromethoxy)benzohydrazide 2.3 mmol, 1.0 equiv.
  • step b the system was heated to a temperature of 120 oC .
  • phthalic anhydride 2.0 equivalents was added and the reaction mixture was kept under magnetic stirring at 150 oC for 2 hours. Subsequently, the system was cooled, the solid obtained was washed with a saturated NaCOs solution and filtered under vacuum. The product was obtained in 68% yield.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-2-(trifluoromethoxy)benzamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-4-phenylpicolinamide.
  • Step (a) Synthesis of methyl fE)-6-((2-benzoyl)hydrazinaylidene)methyl)nicotinate.
  • Step (c) Synthesis of fE)-6-((2-benzoylhydrazinaylidene)methyl)-/ ⁇ /-((tetrahydro-2H-pyran-2-yl)oxy)nicotinamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-3-(trifluoromethyl)picolinamide.
  • Step (c) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-3-(trifluoromethyl)picolinamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-2-(trifluoromethyl)nicotinamide.
  • Step (c) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-2-(trifluoromethyl)nicotinamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-4-(trifluoromethyl)nicotinamide.
  • Step (c) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-4-(trifluoromethyl)nicotinamide.
  • Step (a) Synthesis of tert-butyl 3-(2-(hydrazinecarbonyl)phenoxy)azetidine-1-carboxylate.
  • Step (c) Synthesis of tert-butyl 3-(2-((1,3-dioxoisoindolin-2-yl)(methyl)carbamoyl)phenoxy)azetidine-1-carboxylate.
  • Step (d) Synthesis of tert-butyl 3-(2-(1-methylhydrazine-1-carbonyl)phenoxy)azetidine-1-carboxylate.
  • Step (a) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-2-((1-methylazetidin-3-yl)oxy)benzamide.
  • Step (b) Synthesis of 2-(dimethylamino)-/ ⁇ /-(1,3-dioxoisoindolin-2-yl)benzamide.
  • Step (c) Synthesis of 2-(dimethylamino)-N-(1,3-dioxoisoindolin-2-yl)-N-methylbenzamide.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-2-(methylsulfinyl)benzamide.
  • Step (c) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-/ ⁇ /-methyl-2-(methylsulfinyl)benzamide.
  • Step (b) Synthesis of methyl (E)-4-((2-(2-fluorobenzoyl)-2-methylhydrazinaylidene)methyl)benzoate.
  • Step (b) Synthesis of N-(1,3-dioxoisoindolin-2-yl)-2-methoxy-/ ⁇ /-methylbenzamide.
  • Step (b) Synthesis of methyl (E)-4-((2-ethyl-2-(2-(trifluoromethyl)benzoyl)hydrazinaylidene)methyl)benzoate.
  • Step (b) Synthesis of methyl (E)-4-((2-(2-(difluoromethyl)benzoyl)-2-methylhydrazinaylidene)methyl)-3-fluorobenzoate.

Abstract

La présente invention concerne des composés N-acylhydrazoniques inhibiteurs sélectifs de HDAC6. Plus particulièrement, la présente invention concerne des composés N-acylhydrazoniques représentés par la formule (I), ainsi que leurs procédés d'obtention, des compositions, des trousses, des utilisations et des méthodes de traitement pour traiter ou prévenir des troubles dépressives, des troubles anxieux, la polyarthrite rhumatoïde et/ou la douleur neuropathique.
PCT/BR2022/050475 2021-12-01 2022-12-01 Composés n-acylhydrazoniques inhibiteurs sélectifs de hdac6, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses WO2023097386A1 (fr)

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