WO2010034740A1 - Dérivés (r)-3-(n,n-diméthylamino)pyrrolidine - Google Patents

Dérivés (r)-3-(n,n-diméthylamino)pyrrolidine Download PDF

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WO2010034740A1
WO2010034740A1 PCT/EP2009/062322 EP2009062322W WO2010034740A1 WO 2010034740 A1 WO2010034740 A1 WO 2010034740A1 EP 2009062322 W EP2009062322 W EP 2009062322W WO 2010034740 A1 WO2010034740 A1 WO 2010034740A1
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ring
optionally substituted
amino
formula
cor
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PCT/EP2009/062322
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Jorge Salas Solana
Carmen Almansa Rosales
Robert Soliva Soliva
Montserrat Fontes Ustrell
Josep Comelles Espuga
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Palau Pharma, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a new series of (R)S-(N 1 N- dimethylamino)pyrrolidine derivatives, as well as to processes for their preparation, to pharmaceutical compositions comprising them and to their use in therapy.
  • JAKs The Janus kinases
  • STAT transcription
  • JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as transplant rejection and autoimmune diseases, as well as in solid and hematologic malignancies such as leukemias and lymphomas and in myeloproliferative disorders, and has thus emerged as an interesting target for drug intervention.
  • JAK1 JAK2, JAK3 and Tyk2.
  • JAK3 is mainly found in hematopoietic ceils.
  • JAK3 is associated in a non-covalent manner with the ⁇ c subunit of the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL- 15.
  • IL-2 IL-2
  • IL-4 IL-4
  • IL-7 IL-9
  • IL-13 IL-13
  • IL- 15 cytokines
  • These cytokines play an important role in the proliferation and differentiation of T lymphocytes.
  • JAK3 ⁇ deficient mouse T cells do not respond to ⁇ L-2. This cytokine is fundamental in the regulation of T lymphocytes.
  • JAK3 has also been shown to piay an important role in mast cells, because antigen-induced degranulation and mediator release have been found to be substantialiy reduced in mast ceils from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation nor IgE receptor expression levels. On the other hand, JAK3-/- and JAK3+/ ⁇ mast cells contain the same intracellular mediators. Therefore, JAK3 appears to be essential in the fgE-induced release of mediators in mast cells and its inhibition would be, thus, an effective treatment for aliergic reactions.
  • JAK3 kinase inhibitors have been recognised as a new class of effective immunosuppresive agents useful for transplant rejection prevention and in the treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, muitipie scierosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia (see e.g. O'Shea JJ. et a!, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrije
  • novel compounds that are capable of inhibiting JAK/STAT signaling pathways, and in particular which are capable of inhibiting JAK3 activity, and which are good drug candidates.
  • Compounds should exhibit good activity in in vivo pharmacological assays, good oral absorption when administered by the oral route, as well as be metabolicaliy stable and exhibit a favourable pharmacokinetic profile. Moreover, compounds should not be toxic and exhibit few side effects.
  • One aspect of the invention relates to a compound of formula f
  • Cyi represents phenyl or a 5- or 6-memberecJ aromatic heterocycle bonded to the NH group through a C atom, each of which can be optionally fused to a 5- or
  • Cyi 6-membered saturated, partially unsaturated or aromatic carbocycSic or heterocyclic ring, wherein Cyi can contain from 1 to 4 heteroatoms selected from
  • each Ri independently represents C h alky!, C 2-4 alkenyt, C ⁇ alkynyi, halogen, -CN, -NO 2 , -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -COCONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 3 , -OCO 2 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 2 R 2 , -SO 2 NR 4 COR 3 , -NR 2 R 2 , -NR 4 COR 3 , -NR 2 R 2 , -NR 4 COR 2 , -NR 4 CONR 2 R 2 , -NR 4 CO 2 R 3 , -NR 4 CONR 2 R 2 , -NR 4 CO 2 R 3 , -NR 4 CONR 2 R 2 , -NR 4 CO 2 R 3 , -NR 4 CONR
  • each R 4 independently represents hydrogen or C h alky!; each R 5 independently represents halogen, -CN, -NO 2 , -COR 8 , -CO 2 R 8 , -CONR 8 R 8 , -OR 8 , -OCOR 9 , -OCONR 9 R 9 , -OCO 2 R 9 , -SR 8 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 8 R 8 , -SO 2 NR 4 COR 9 , -NR 8 R 8 , -NR 4 COR 8 , -NR 4 CONR 8 R 8 , -NR 4 CO 2 R 9 , -NR 4 SO 2
  • each R 7 independently represents Ci -4 aikyl, haloCi -4 alkyl, Ci -4 alkoxyCi. 4 aikyl, hydroxyCi -4 alkyl, or any of the meanings described for Ri 1 ; each Rs independently represents hydrogen or R 9 ; each Rg independently represents C h alky!, haioC- ⁇ alkyl, Ci -4 alkoxyC-
  • each R-io independently represents halogen, -CN, -NO 2 , -COR 8 , -CO 2 Rs 1 -CONR 8 R 8 , -OR 8 , -OCOR 9 , -OCONR 9 R 9 , -OCO 2 R 9 , -SR 8 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 8 R 8 , -SO 2 NR 4 COR 9 , -NR 8 R 8 , -NR 4 COR 8 , -NR 4 CONR 8 R 8 , -NR 4 CO 2 R 9 , -NR 4 SO 2 R 9 , or -C( ⁇ N-OH)R 9 ; each R-n independently represents halogen, -CN, -NO 2 , -CORi 2 , -CO 2 R 12 , -CONR 12 R 12 , -ORi 2
  • each R14 independently represents hydrogen or Ci -4 alkyl; with the proviso that the foiiowing compounds are excluded: (R)-2"(3-acetylaminopheny!)amino-4-[3-(W,N-dimethyiamino)pyrroiidin-1-yi]- 7H-pyrrolo[2,3-c/Jpyrimidine f
  • the present invention also relates to the saits and solvates of the compounds of formula f.
  • Some compounds of formula f can have chiral centers that can give rise to various stereoisomers.
  • the present invention relates to each of these stereoisomers and also mixtures thereof.
  • the compounds of formula I are JAK, particularly JAK3, kinase inhibitors and therefore can be useful for the treatment of any disease mediated by this kinase.
  • another aspect of the invention relates to a compound of formuia
  • Cyi represents phenyl or a 5 ⁇ or 6-membered aromatic heterocyde bonded to the NH group through a C atom, each of which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyciic or heterocyclic ring, wherein Cy 1 can contain from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms of the optional 5- or 6-membered fused ring can be optionally oxidized forming CO, SO or SO 2 groups, and wherein Cyi can be optionally substituted with one or more Ri; each Ri independently represents Ci -4 alkyl, C 2-4 alkenyl ) C ⁇ alkynyl, halogen, -CN, -NO 2 , -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -COCONR 2 R 2 , -OR 2 , -OCOR 3 , -O
  • each Cy 2 and Cy 3 independently represent a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring which can be carbocyclic or heterocyclic, in which case it can contain from 1 to 4 heteroatoms selected from N, S and O 5 wherein each Cy 2 and Cy 3 can be saturated, partially unsaturated or aromatic, and can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups; each Cy 4 independently represents a ring selected from (a)-(c):
  • each Ru independently represents hydrogen or Ci -4 alkyl; with the proviso that the foliowing compounds are excluded:
  • Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula ! or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to the use of a compound of formula ! or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAKs, particulariy JAK3.
  • Another aspect of the present invention relates to the use of a compound of formula S or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • Another aspect of the present invention relates to a compound of formula ! or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3.
  • Another aspect of the present invention relates to a compound of formuia I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a compound of formula S or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast DCS-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast DCS-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • Another aspect of the present invention relates to the use of a compound of formula f or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by JAKs, particularly JAK3.
  • Another aspect of the present invention relates to the use of a compound of formula i or a pharmaceutically acceptable salt thereof for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAKs, particularly JAK3, in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention relates to a method of treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a method of treating or preventing a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type S diabetes, complications from diabetes, muitipie sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with ieukemias and lymphomas in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula ! or a pharmaceutical acceptable salt thereof.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type S diabetes, complications from diabetes, muitipie sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thro
  • Another aspect of the present invention relates to a process for the preparation of a compound of formula S as defined above, which comprises: (a) reacting a compound of formula !V (or a protected form thereof) with a compound of formula V (or a protected form thereof)
  • a C 2 - 4 alkenyi group means a straight or branched alkyl chain which contains from 2 to 4 C atoms, and also contains one or two double bonds.
  • Examples include the groups ethenyl, 1 -propenyl, 2-propenyl, isopropenyi, 1- butenyl, 2-butenyi, 3-butenyl and 1 ,3-butadienyl.
  • a C 2-4 alkynyl group means straight or branched alkyi chain which contains from 2 to 4 C atoms, and also contains one or two triple bonds. Examples include the groups ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyS, 3-butynyl and 1 ,3- butadiynyf.
  • Ci- 4 alkoxy group as a group or part of a group, means a group of formula -OCi- 4 alkyi, wherein the C ⁇ aikyi moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butox ⁇ . Haiogen or its abbreviation halo means fluoro, chloro, bromo or iodo.
  • Ci- 4 alkoxyCi. 4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkyl group with one or more C 1-4 alkoxy groups as defined above, which can be the same or different. Examples include, among others, the groups methoxymethy!, ethoxymethyi, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethy!, sec-butoxymethyl, t ⁇ rt- butoxymethyl, dimethoxymethyl, 1-methoxyethy!, 2-methoxyethyl, 2-ethoxyethyl,
  • a group means a group resulting from the replacement of one or more hydrogen atoms from a C- ⁇ alkyl group with one or more haiogen atoms
  • a hydroxyC 1-4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a group with one or more hydroxy groups. Examples include, among others, the groups hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyi, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxy butyl, 3- hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl.
  • a cyanoC ⁇ 4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkyl group with one or more cyano groups. Examples include, among others, the groups cyanomethyl, dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyi, 2,3-dicyanopropyl and 4-cyanobutyf.
  • a Cy 4 -Ci, 4 aikyl group means a group resulting from the replacement of one hydrogen atom from a group with one Cy 4 group. Examples include, among others, the groups (morpho!in-4-y!methy[, 2-(morphofin-4-yi)ethyl, 3- (morphoiin-4-y[)propy!, 4- ⁇ morphoiin-4-y!buty!, (piperazin-i-yOmethyl, (4- methylpiperazin-1 -y!methyl, 2 ⁇ (4-methylpiperazin-1 -yi)ethyi, 3-(4-methylpiperazin- 1-yi)propyl, 4-(4-methySpiperazin-1-yi)butyi, (4-ethylpiperazsn-1 ⁇ yi)methyl, (4- propy!piperazin-1-yl)methyi, (4-butyipiperazin-1 -yl)methyl, (1 ,1-dioxothiomorpholin- 4-
  • Cy 1 refers to a phenyl group or a 5- or 6-membered aromatic heterocycle that must be bonded to the NH group through a C atom, wherein both the phenyl group and the 5- or 6-membered aromatic heterocycie can be optionally fused to a 5- or 6-membered carbocycie or heterocycie which can be saturated, partially unsaturated or aromatic.
  • the Cyi group as a whole, can contain from 1 to 4 heteroatoms in total selected from N, O and S.
  • the optional 5- or 6-membered carbocyciic or heterocyclic fused ring is saturated or partially unsaturated, one or more C or S atoms of said ring can be optionally oxidized forming CO, SO or SO 2 groups.
  • the Cyi group can be optionaily substituted as disclosed above in the definition of a compound of formuia !; said substituents can be the same or different and can be placed on any available position of any of the rings.
  • Cy-i groups include, among others, phenyl, naphthyi, thienyl, furyl, pyrrolyS, thiazolyl, isothiazoiyl, oxazoiyl, isoxazotyl, imidazoiyi, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazoiyl, tetrazolyi, 1 ,3,4- oxadiazolyi, 1 ,3,4-thiadiazolyi, 1 ,2,4-oxadiazolyl, 1 ,2,4-thiadiazoiyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazoiyi, benzooxazolyl, benzofuranyl, isobenzofuranyl, indanyi, indolyi, isoindoSyl, benzothiophenyl, benzo
  • Cy 2 or Cy3 refers to a 3- to 7-membered monocyclic or 6- to 11- membered bicycfic carbocyciic or heterocyclic ring.
  • heterocyclic it can contain from 1 to 4 heteroatoms selected from N, S and O.
  • Bicyclic rings may be formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or eise they can be formed by two rings bonded through a single common C atom forming a spiro ring.
  • a Cy 2 or Cy 3 group can be saturated, partially unsaturated or aromatic.
  • Cy 2 and Cy 3 can be bonded to the rest of the molecule through any available C or N atom, in Cy 2 or Cy 3 one or more C or S atoms of a saturated or partially unsaturated ring can be optionally oxidized forming CO, SO or SO 2 groups. Cy 2 and Cy 3 can be optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system.
  • Cy 2 or Cy 3 groups include, among others, cycSopropyl, cyclobutyl, cyciopentyl, cyclohexyl, cyclohepty ⁇ , azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazoiidtnyl, pyrroiidinyl, thiazoiidinyl, dioxanyl, morphoiinyl, thiomorpholinyl, 1 ,1-dioxothiomorpholinyi, piperazinyl, homopiperazinyl, piperidinyi, pyranyi, tetrahydropyranyl, homopiperidinyi, oxazinyl, oxazolinyi, pyrroiinyi,
  • the term pyrazolopyridinyl can include groups such as 1 H- pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[1 ,5-a]pyridinyl, 1 H-pyrazoio[3,4-c]pyridinyl, 1 H-pyrazolo[4,3-c]pyridinyl and 1 H-pyrazolo[4,3-b]pyridinyi
  • the term imidazopyrazinyi can include groups such as 1 H-imidazo[4,5- ⁇ >]pyrazinyl, imidazo[1 ,2-a]pyrazinyi and imtdazo[1 ,5 ⁇ a]pyrazinyt
  • the term pyrazolopyrimidinyl can include groups such as 1 H-pyrazo!o[3,
  • pyridyi includes 2- pyridyl, 3-pyridyl and 4-pyridyl
  • thienyl includes 2-thienyl and 3-thienyl
  • indoly ⁇ includes 1-indoSyS, 2-indofyl, 3-indo!yi, 4-indotyl, 5-indoiyi, 6-indoiyl and 7-indoiyl.
  • a non-aromatic ring When a non-aromatic ring is present as a substituent of a non-aromatic ring, it can replace one hydrogen atom, or it can replace two hydrogen atoms on the same C atom thus forming a spiro ring.
  • a non-aromatic ring when a non-aromatic ring is present as a substituent of an afkyl, alkenyl or alkynyi group, it can either replace one hydrogen atom, or it can replace two hydrogen atoms and share one C atom with said aikyl, alkenyl or alkynyi group forming groups such as the ones shown below:
  • Cy 1 represents a phenyl group substituted at one or two of positions 3, 4 and 5 with a Ri group. This means that the phenyl group is either substituted with one Ri group at position 3, 4 or 5 of the phenyl ring, or with two R-i groups (which can be the same or different) at positions
  • Cy 1 represents a ring of formula Cy 1 e which can be optionally substituted with one R- t group at the NH group. This means that Cyi ⁇ is either unsubstituted, or substituted with one Ri group placed at the N atom of the Cyi e ring replacing the hydrogen atom of the NH group.
  • treatment is meant eliminating, reducing or ameliorating the cause or the effects of a disease.
  • treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).
  • prevention refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease.
  • the Invention thus relates to the compounds of formula I as defined above.
  • the invention relates to the compounds of formula I wherein Cy 1 represents: a) phenyl; b) a 5-membered aromatic heterocycie bonded to the NH group through a
  • ring A represents a saturated 5- or 6-membered carbocydic or heterocyclic ring, in which case it contains 1 or 2 heteroatoms selected from N, S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 1 can be optionally substituted with one or more R 1 .
  • the invention relates to the compounds of formula ⁇ wherein Cyi represents: a) phenyl substituted at one or two of positions 3, 4 and 5 with an Rv, b) a ring of formula Cy-id
  • Cy 1e wherein Cyi e can be optionally substituted with one Ri at the NH group.
  • the invention relates to the compounds of formula wherein Cy-i represents phenyl, pyridyl or a ring of formula Cyi a
  • Cy 1 a wherein Y represents C or N; ring A represents a 5- or ⁇ -membered saturated, partially unsaturated or aromatic ring which can be carbocycSic or heterocyclic, in which case it contains 1 or 2 heteroatoms selected from N, S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein the phenyl, pyridyl and Cyi a groups can be optionally substituted with one or more R-).
  • the invention relates to the compounds of formula I wherein Cyi represents phenyl or a ring of formula Cy 1b
  • Cy 1 b wherein ring A represents a 5- or 6-membered saturated, partially unsaturated or aromatic ring which can be carbocyclic or heterocyclic, in which case it contains 1 or 2 heteroatoms selected from H 1 S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein the phenyl and Cyi b groups can be optionally substituted with one or more R-j.
  • the invention relates to the compounds of formula S wherein Cy 1 represents phenyl or a ring of formula Cy 1b
  • Cyib wherein ring A represents a saturated 5- or 6-membered carbocyciic or heterocyclic ring, in which case it contains 1 or 2 heteroatoms selected from N, S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO2 groups, and wherein the phenyl and Cyi b groups can be optionally substituted with one or more R-i.
  • the invention relates to the compounds of formula ⁇ wherein Cy-i represents phenyl or a ring of formula Cy ⁇
  • Cyi b wherein ring A represents a saturated 5-membered heterocyclic ring, which contains 1 or 2 heteroatoms selected from N, S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein the phenyl and Cyib groups can be optionally substituted with one or more R 1 ,
  • the invention relates to the compounds of formula ! wherein Cyi represents phenyl or a ring of formula Cy-i b
  • ring A represents a saturated 5-membered heterocyclic ring which contains 1 N atom, wherein one or two C atoms of ring A can be optionally oxidized forming CO groups, and wherein the phenyl and Cy- ⁇ b groups can be optionally substituted with one or more Ri.
  • the invention relates to the compounds of formula I wherein Cyi represents: a) phenyl optionally substituted with one or more R 1 ; or b) a ring of formula Cy- ⁇ e
  • Cy 1e can be optionally substituted with one Ri at the NH group.
  • the invention relates to the compounds of formula f wherein Cy i represents phenyl optionally substituted with one or more R-i.
  • the invention relates to the compounds of formula I wherein Cyi represents phenyl substituted with one or more Ri.
  • the invention relates to the compounds of formula S wherein Cyi represents phenyl substituted with one, two or three R-i. in another embodiment, the invention relates to the compounds of formula i wherein Cy i represents phenyl substituted with one or two Ri.
  • the invention relates to the compounds of formula I wherein Cy i represents phenyl substituted at one or two of positions 3, 4 and 5 with an Ri.
  • the invention relates to the compounds of formula ! wherein Cy i represents phenyl substituted with one R-i, which is placed at position 3 or 4 of the phenyl ring.
  • the invention relates to the compounds of formula I wherein Cy 1 represents phenyl substituted with one Ri which is placed at position
  • the invention in another embodiment, relates to the compounds of formula I wherein Cyi represents phenyl substituted with one Ri which is placed at position
  • the invention relates to the compounds of formula I wherein Cyi represents a ring of formula Cy ⁇
  • Cyib wherein ring A represents a 5- or 6-rnembered saturated, partially unsaturated or aromatic ring which can be carbocyc ⁇ c or heterocyclic, in which case it contains 1 or 2 heteroatoms selected from N, S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein the Cyib group can be optionally substituted with one or more R 1 .
  • the invention relates to the compounds of formula I wherein Cyi represents a ring of formuia Cyi b
  • Cyib wherein ring A represents a saturated 5- or 6-membered ring which can be carbocyciic or heterocyciic, in which case it contains 1 or 2 heteroatoms selected from N, S and O, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein the Cy 1b group can be optionally substituted with one or more Ri.
  • the invention relates to the compounds of formula wherein Cyi represents a ring of formula Cy 1b
  • Cy 1b wherein ring A represents a saturated 5-membered heterocyclic ring which contains 1 or 2 heteroatoms selected from N, S and O 1 wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO 2 groups, and wherein the Cyt b group can be optionally substituted with one or more Ri.
  • the invention relates to the compounds of formula I wherein Cyi represents a ring of formula Cy-it
  • Cytb wherein ring A represents a saturated 5-membered heterocyclic ring which contains 1 N atom, wherein one or two C atoms of ring A can be optionally oxidized forming CO groups, and wherein the Cy- ⁇ b group can be optionally substituted with one or more R 1 .
  • the invention relates to the compounds of formula I wherein Cy-i represents a ring of formula Cy ie
  • Cy 1e wherein Cy te can be optionally substituted with one R-i at the NH group.
  • the invention relates to the compounds of formula 1 wherein Cyi represents a 5- or 6-membered aromatic heterocycle bonded to the NH group through a C atom, which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyciic or heterocyclic ring, wherein Cy i contains from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms of the optional 5- or 6-membered fused ring can be optionally oxidized forming CO, SO or SO2 groups, and wherein Cyi can be optionally substituted with one or more Ri.
  • the invention in another embodiment, relates to the compounds of formula I 1 wherein Cy 1 represents a 5-membered aromatic heterocycie bonded to the NH group through a C atom, wherein Cyi contains from 1 to 3 heteroatoms selected from N, O and S, and wherein Cyi can be optionaliy substituted with one or more
  • the invention in another embodiment, relates to the compounds of formula I, wherein Cyi represents a 5-membered aromatic heterocycie bonded to the NH group through a C atom, wherein Cy 1 contains from 1 to 3 heteroatoms selected from N and S, and wherein Cy -i can be optionally substituted with one or more Ri.
  • the invention relates to the compounds of formula I, wherein Cyi represents a 5-membered aromatic heterocycie bonded to the NH group through a C atom, wherein Cy 1 contains from 1 to 2 heteroatoms selected from N and S, and wherein Cy 1 can be optionally substituted with one or more R 1 , preferably with one or two R-s, and more preferably with one R 1 .
  • the invention relates to the compounds of formula I, wherein Cy 1 represents 3-isothyazolyi, 4-isothyazoly ⁇ 0 5-isothyazolyl, which can be optionally substituted with one or more R 1 , preferably with one R 1 .
  • Cy 1 represent a 2-pyrroiy! 0 3-pyrrolyl, which can be optionally substituted with one or more R 1 , preferably with one R 1 .
  • the invention relates to the compounds of formula I, wherein Cy 1 represents 2-thienyi or 3-thienyi, which can be optionally substituted with one or more R 1 , preferably with one R 1 .
  • the invention relates to the compounds of formula f, wherein Cy 1 represents 3-thienyl, which can be optionally substituted with one R 1 , in another embodiment the invention relates to the compounds of formula 1, wherein Cyi represents a ring of formula Cy ⁇
  • Cy 1d In another embodiment, the invention relates to the compounds of formula ⁇ wherein each R 1 independently represents Ci -4 alkyl, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 31 -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 2 R 2 , -SO 2 NR 4 COR 3 , -NR 2 R 2 , -NR 4 COR 2 , -NR 4 CO 2 R 3 or Cy 2 , wherein C 1-4 alkyi can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re- in another embodiment, the invention relates to the compounds of formula S wherein each R 1 independently represents C ⁇ aikyl, halogen, -CN, -COR 2 ,
  • Ci -4 aikyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula ⁇ wherein each Ri independently represents Ci -4 afkyl, -CN 1 -COR 2 , -CO 2 R 2 , -
  • NR 4 CO 2 R 3 or Cy 2 wherein can be optionally substituted with one or more R5 and Cy 2 can be optionally substituted with one or more RQ.
  • the invention relates to the compounds of formula f wherein each R 1 independently represents C-i ⁇ alkyl, -CN, -COR 2 , -CO 2 R 2 , -
  • NR 4 CO 2 R 3 or Cy 2 wherein C h alky! can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula I wherein each R t independently represents halogen, d ⁇ alkyi, -CN, -COR 2 , - CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 or -NR 4 CO 2 R 3 , wherein Ci -4 alkyl can be optionally substituted with one or more R 5 .
  • the invention relates to the compounds of formula I wherein each Ri independently represents C- ⁇ _ 4 a!kyl, -CN, -COR 2 , -CO 2 R 2 , - CONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 or - NR 4 CO 2 R 3 , wherein C 1-4 alky! can be optionally substituted with one or more R 5 .
  • the invention in another embodiment, relates to the compounds of formula I wherein each R-, independently represents Ci -4 a!kyi, -CN 1 -COR 2 , -CO 2 R 2 , - CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 or - NR 4 CO 2 R 3, wherein d -4 aikyl can be optionally substituted with one or more R 5 .
  • the invention relates to the compounds of formula i wherein each Ri independently represents C ⁇ aikyl, -CN, or -CONR 2 R 2 , wherein Ci. 4 alkyl can be optionally substituted with one or more R 5 .
  • the invention relates to the compounds of formula I wherein each R 1 independently represents C h alky!, -CN, or -CONR2R 2 , wherein C 1-4 alkyi can be optionally substituted with one R s .
  • the invention relates to the compounds of formula I wherein each Ri independently represents -CN, -CONR 2 R 2 or Ci -4 alkyl (preferably methyl) substituted with one R 5 .
  • the invention relates to the compounds of formula I wherein each Ri independently represents C h alky! ⁇ preferably methyl) optionally substituted with one R 5 .
  • the invention relates to the compounds of formula I wherein each Ri independently represents C 1-4 alkyl (preferably methy!) substituted with one R 5 .
  • the invention relates to the compounds of formula I wherein each Cy 2 independently represents Cy 2a , and Cy 2a represents a 5- or 6- membered saturated monocyclic heterocycie which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, with the proviso that Cy 2a is not morpholine, and wherein said Cy 23 can be optionally substituted with one or more R 6 .
  • the invention in another embodiment, relates to the compounds of formula S wherein each C ⁇ / 2 independently represents Cy 2b , and Cy 2b represents a 5- or 6- membered saturated monocyclic heterocycte which contains 1 or 2 heteroatoms selected from N and S 1 wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2b can be optionally substituted with one or more R 6 .
  • the invention in another embodiment, relates to the compounds of formula I wherein each Cy 3 independently represents Cy 3a , and Cy 3a represents a saturated 3- to 7-membered monocyciic or 6- to 11 -membered bicyciic heterocycie which can be carbocyclic or heterocyclic, in which case it contains from 1 to 4 heteroatoms selected from H, O and S, wherein Cy 33 can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, and wherein said Cy 3a can be optionally substituted with one or more R 7 .
  • the invention in another embodiment, relates to the compounds of formula I wherein each Cy 3 independently represents Cy 3b , and Cy 3b represents a saturated 3- to 7-membered (preferably 5- or 6-membered) monocyclic heterocycie which contains 1 or 2 heteroatoms selected from N, O and S 1 wherein Cy 3b can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, and wherein said Cy 3b can be optionally substituted with one or more R 7 .
  • each Cy 3 independently represents Cy 3b
  • Cy 3b represents a saturated 3- to 7-membered (preferably 5- or 6-membered) monocyclic heterocycie which contains 1 or 2 heteroatoms selected from N, O and S 1 wherein Cy 3b can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optional
  • the invention in another embodiment, relates to the compounds of formula I wherein each Cy 3 independently represents Cy 3c , and Cy 30 represents a saturated 5- or 6-membered monocyciic heterocycie which contains 1 N atom and optionally can contain one further heteroatom selected from N, O and S, and which is bonded to the rest of the molecule through any available N atom, and wherein said Cy 3c can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formula i wherein Cy 3 represents morpholin-4-yi. In another embodiment, the invention relates to the compounds of formula ⁇ wherein each R 3 independently represents C 1-4 alkyl or Cy 3 , wherein C 1-4 alkyl can be optionally substituted with one or more R s and wherein Cy 3 can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formula I wherein each R 5 independently represents halogen, -CN, -COR 8 , -CONR 8 Rs, - OR 8 , -SRe, -SOR 95 -SO 2 R 9 , -SO 2 NR 8 R 8 , -SO 2 NR 4 COR 9 , -NR 8 R 8 , -NR 4 COR 8 , - NR 4 SO 2 Rg or Cy 3 , wherein Cy 3 can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formula f
  • each R 5 independently represents halogen, -CONR 8 R 8 , -ORe, -SO 2 Rg, - SO 2 NR 8 R 8 , -NR 8 R 8 , -NR 4 COR 8 , -NR 4 SO 2 R 9 or Cy 3 , wherein Cy 3 can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formula I wherein each R 5 independently represents halogen, -CONR 8 Re, -ORs, -SO 2 R 9 , - SO 2 NR 8 RB, -NR 8 R 8 , -NR 4 COR 8 . -NR 4 SO 2 R 9 or Cy 3c , wherein Cy 30 can be optionally substituted with one or more R 7 .
  • each R 5 independently represents Cy 3 ; preferably Cy 3c ; and more preferably morphohn-4-yL
  • the invention relates to the compounds of formula ! wherein each R 10 independently represents halogen, -CN, -COR 8 , -CONR 8 R 8 , - ORs, -SR 8 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 8 R 8 , -SO 2 NR 4 COR 9 , -NR 8 R 8 , -NR 4 COR 8 or - NR 4 SO 2 R 9 .
  • the invention relates to the compounds of formula I wherein each Rn independently represents halogen, -CN 1 -COR 12, -CONRi 2 Ri 2 , - OR 12 , -SRi 2 , -SOR13, -SO 2 R 13 , -SO 2 NR 12 Ri 2 , -SO 2 NR 4 CORi 2 , -NR 12 R 12 , - NR 4 COR 12 or -NR 4 SO 2 R 13 .
  • the invention relates to the compounds of formula ! wherein:
  • Cyi represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring;
  • Ri represents C 1-4 alky(, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , - OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 2 R 2 , -SO 2 NR 4 COR 3 , -NR 2 R 2 , -NR 4 COR 2 , -NR 4 CO 2 R 3 or Cy 2 , wherein C 1-4 a!kyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R ⁇ ; and
  • Cy 2 represents Cy 2a
  • Cy 2a represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms seiected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO2 groups, with the proviso that Cy 2a is not morphofine, and wherein said Cy 2a can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula I wherein:
  • Cy 1 represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring;
  • R 1 represents C 1-4 aikyt, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -
  • Cy 2 represents Cy 2b
  • Cy 2b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the moiecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2b can be optionally substituted with one or more Re.
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents phenyl substituted with one R 1 which is placed at position 3 of the phenyl ring;
  • R 1 represents C 1-4 alkyi, halogen, -CN, -COR 2 , -CO 2 R 21 -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2, wherein C 1-4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re.
  • each Ri independently represents Ci -4 alkyl, halogen, -CN, -COR 2 , -CO 2 R 2 , -
  • each Cy 2 independently represents Cy 2a , and Cy 2a represents a 5- or 6- membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO 1 SO or SO 2 groups, with the proviso that Cy 2a is not morpho ⁇ ne, and wherein said Cy 2a can be optionally substituted with one or more Re-
  • each Ri independently represents Ci -4 aikyl, halogen, -CN, -COR2, -CO 2 R 2 , -
  • Ci -4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionaliy substituted with one or more R 6 ; and each Cy 2 independently represents Cy 2b , and Cy 2b represents a 5- or 6- membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecuie through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2 ⁇ can be optionally substituted with one or more Rg.
  • the invention relates to the compounds of formula I wherein:
  • Cy 1 represents phenyl substituted with one Ri which is placed at position 3 of the phenyl ring;
  • R 1 represents Chalky!, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2, wherein Ci_ 4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re; and
  • Cy 2 represents Cy 2a
  • Cy 2a represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, with the proviso that Cy 2a is not morpholine, and wherein said Cy 2a can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents phenyl substituted with one Ri which is placed at position 3 of the phenyl ring;
  • Ri represents C ⁇ alkyl, halogen, -CN 1 -COR 2 , -CO2R2, -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 . -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci- 4 aikyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re; and Cy 2 represents Cy 2 b, and Cy 2b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2b can be optionally substituted with one or more R 6
  • the invention relates to the compounds of formula 1 wherein:
  • Cyi represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring; Ri represents Ci -4 aikyi, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 ,
  • Ci-4a!kyi can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re;
  • Cy 2 represents Cy 2a
  • Cy 2s represents a 5- or 6-membered saturated monocyclic heterocycie which contains 1 or 2 heteroatoms selected from N, S and
  • the invention relates to the compounds of formula ! wherein:
  • Cyi represents phenyl substituted with one R 1 which is placed at position 4 of the phenyl ring;
  • R 1 represents C ⁇ alkyf, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci -4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Rg; and
  • Cy 2 represents Cy 2b
  • Cy 2b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2 b can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula I wherein:
  • Cy 1 represents phenyl substituted with one R 1 which is placed at position 3 of the phenyl ring;
  • R 1 represents C ⁇ alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , - OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2, wherein C 1- 4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re.
  • each R 1 independently represents C 1-4 alkyi, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR3, -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR4CO 2 R 3 or Cy 2 , wherein C- ⁇ alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and each Cy 2 independently represents Cy 2a , and Cy 23 represents a 5- or 6- membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized
  • each Ri independentiy represents Ci -4 alkyl, -CN, -COR2, -CO2R2, -CONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein C 1-4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R@; and each Cy 2 independently represents Cy 2 t > , and Cy 2b represents a 5- or 6- membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO
  • the invention relates to the compounds of formula I wherein:
  • Cy 1 represents phenyl substituted with one R 1 which is piaced at position 3 of the phenyl ring;
  • R 1 represents C 1-4 a!kyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , - OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2, wherein C 1- 4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and Cy 2 represents Cy 2a , and Cy 2a represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any avaifabie C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, with the provis
  • Cy 1 represents phenyl substituted with one R 1 which is placed at position 3 of the phenyl ring;
  • R 1 represents Chalky!, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , -
  • kyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ;
  • Cy 2 represents Cy 2 J 3
  • Cy 2 b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecuie through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2b can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula f wherein: Cyi represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring;
  • R 1 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , - OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci- 4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and
  • Cy 2 represents Cy 2a
  • Cy 2a represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO 1 SO or SO 2 groups, with the proviso that Cy 2a is not morpholine, and wherein said Cy 2a can be optionally substituted with one or more
  • the invention relates to the compounds of formula i wherein: Cyi represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring;
  • Ri represents C 1-4 aikyi, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , - OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein C 1- 4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and
  • Cy 2 represents Cy 2 b
  • Cy 2b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2 b can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents phenyl substituted with one R 1 which is placed at position 3 of the phenyl ring;
  • R 1 represents Ci -4 alkyl, -CN 1 -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 o Cy 2 , wherein Ci- 4 alkyS can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ,
  • each Ri independently represents Ci -4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 31 -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci -4 alkyi can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and each Cy 2 independently represents Cy 2a , and Cy 2a represents a 5- or 6- membered saturated monocyclic heterocycSe which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO
  • each Ri independently represents C- ⁇ -4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Chalky!
  • Cy 2 can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and each Cy 2 independently represents Cy 2b , and Cy 2b represents a 5- or 6- membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2b can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula ⁇ wherein:
  • Cyi represents phenyl substituted with one R 1 which is placed at position 3 of the phenyl ring;
  • R 1 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci -4 aiky[ can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re; and
  • Cy 2 represents Cy 2a
  • Cy 2a represents a 5- or 6-membered saturated monocyclic heterocycfe which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, with the proviso that Cy 2a is not morpholine, and wherein said Cy 28 can be optionally substituted with one or more
  • the invention in another embodiment, relates to the compounds of formula i wherein;
  • Cyi represents phenyl substituted with one Ri which is placed at position 3 of the phenyl ring;
  • R 1 represents C ⁇ alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein d ⁇ alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re', and
  • Cy 2 represents Cy 2 b, and Cy 2b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO 2 groups, wherein said Cy 2b can be optionally substituted with one or more R 6 .
  • the invention relates to the compounds of formula f wherein:
  • Cyi represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring;
  • R 1 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci -4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re; and
  • Cy 2 represents Cy 23
  • Cy 2a represents a 5- or 6-membered saturated monocyclic heterocycie which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO 2 groups, with the proviso that Cy 23 is not morphoJine, and wherein said Cy 2a can be optionally substituted with one or more
  • Cyi represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring;
  • R 1 represents C 1-4 aikyt, -CN 1 -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci -4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more RQ, and
  • Cy-i represents phenyl substituted with one R 1 which is placed at position 3 of the phenyl ring;
  • R 1 represents halogen, C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 or -NR 4 CO 2 R 3 .
  • C 1-4 a!kyl can be optionally substituted with one or more R 5 .
  • the invention relates to the compounds of formula I wherein:
  • Cy-i represents phenyl substituted with one R-i which is placed at position 4 of the phenyl ring;
  • Cyi represents a ring of formula Cy 10
  • R16, Ri7 or Ri 8 represents Chalky!, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 2 R 2 , -SO 2 NR 4 COR 3 , -NR 2 R 2 , -NR 4 COR 2 , -NR 4 CO 2 R 3 or Cy 2 , wherein C 1-4 alky!
  • R 5 can be optionally substituted with one or more R 5 , wherein Cy 2 can be optionally substituted with one or more Re; and the remainder of R- ⁇ 1 R ⁇ and Ri 8 as well as R 15 and Ri 9 are independently selected from hydrogen, halogen, Ci -4 aikyl, hydroxy and C 1-4 alkoxy.
  • the invention relates to the compounds of formula ! wherein:
  • Cy-i represents a ring of formula Cy- ⁇ c
  • R-I6, R17 or R 1 S represents Chalky!, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 31 -SO 2 NR 4 COR 3 , -NR4CO 2 R 3 or Cy 2 , wherein C 1-4 aikyi can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and the remainder of R-ie, R17 and R 18 as well as R 15 and R 19 are independently selected from hydrogen, halogen, C h alky!, hydroxy and C 1-4 a!koxy.
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents a ring of formula Cyi c
  • R 16 , R17 or R 18 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Chalky!
  • R 5 and Cy 2 can be optionally substituted with one or more R 6 ; and the remainder of R-ie, Ru and R 18 as weli as R 15 and R 19 are independently selected from hydrogen, halogen, C ⁇ alkyl, hydroxy and C- ⁇ alkoxy.
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents a ring of formula Cy 1c
  • R 16 , Ru or R 18 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 .
  • Ci -4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more Re; and the remainder of Rie, Ru and R 18 as well as R 15 and R 19 are independently selected from hydrogen, halogen, C h alky!, hydroxy and C 1-4 alkoxy.
  • the invention relates to the compounds of formula I wherein:
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents a ring of formula Cyi c
  • Ri 7 represents C 1-4 aikyl, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 ,
  • R 15 , R1 6 , R-i s and R19 are independently selected from hydrogen, halogen, C-
  • Cy-i represents a ring of formula Cyi c
  • R 17 represents Ci -4 alkyl, halogen, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR3, -OCONR3R3, -SR 2 , -SOR 3 , -SO2R3, -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2b , wherein C h alky! can be optionally substituted with one or more R 5 and Cy 2b can be optionally substituted with one or more R 6 ; and
  • R.15, R16. R18 and R19 are independently selected from hydrogen, halogen, Ci -4 alkyl, hydroxy and Ci -4 aikoxy.
  • R16 represents C ⁇ alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OR 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci -4 alkyl can be optionally substituted with one or more R 5 and Cy 2 can be optionaliy substituted with one or more Re; and Ri5, R17, R18, and R19 are independentiy selected from hydrogen, halogen, Ci -4 a!ky], hydroxy and Ci -4 alkoxy.
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents a ring of formuia Cyi c
  • R 16 , Ru or R 18 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR3, -OCONR3R3, -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2a , wherein C 1-4 a!kyl can be optionally substituted with one or more R 5 and Cy 2a can be optionally substituted with one or more R 6 ; and the remainder of R 16 , R17 and R 18 as well as R 15 and R 19 are independently selected from hydrogen, halogen,
  • the invention relates to the compounds of formula I wherein:
  • Cyi represents a ring of formula Cyi c
  • R16, Ru or R 18 represents Ci -4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2b , wherein Ci -4 alkyi can be optionally substituted with one or more R 5 and Cy 2b can be optionally substituted with one or more R 6 ; and the remainder of R ⁇ , R17 and Ri 8 as well as R 15 and R 19 are independently selected from hydrogen, halogen, C 1-4 alkyf ; hydroxy and Ci -4 a!koxy.
  • the invention relates to the compounds of formula ! wherein:
  • Cyi represents a ring of formula Cy- ⁇ c
  • R 16 represents C 1-4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2 , wherein Ci- 4 alky[ can be optionally substituted with one or more R 5 and Cy 2 can be optionally substituted with one or more RQ, and
  • R-I5, Ri7, R1 8 , and R-19 are independently selected from hydrogen, halogen, hydroxy and C f-4 aikoxy.
  • the invention relates to the compounds of formula ⁇ wherein:
  • Cyi represents a ring of formula Cy 1c
  • R 17 represents Ci -4 alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , -OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 , -NR 4 CO 2 R 3 or Cy 2a , wherein C 1-4 alkyi can be optionaiiy substituted with one or more R 5 and Cy 2a can be optionally substituted with one or more Re; and
  • R-I5, Ri6 > R-I8, and R19 are independently selected from hydrogen, halogen, C h alky!, hydroxy and Ci -4 aikoxy.
  • the invention relates to the compounds of formula ! wherein:
  • Cyi represents a ring of formula Cy- ⁇ c
  • Ci. 4 alkyl can be optionally substituted with one or more R 5 and Cy 2b can be optionally substituted with one or more Rg; and
  • Ri5, Ri6, R18, and R19 are independently selected from hydrogen, halogen, Ci -4 alkyi, hydroxy and Ci -4 a!koxy.
  • the invention relates to the compounds of formula i wherein:
  • Cy 1 represents a ring of formula Cyi 0
  • R 17 represents -CN, -CONR 2 R 2 or Chalky! (preferably methyf) substituted with one R 5 ;
  • R-15, Ri6, R-18, an d Ri9 are independently selected from hydrogen, halogen, hydroxy and in another embodiment, the invention relates to the compounds of formula ! wherein:
  • Cy 1 represents a ring of formula Cy 1c
  • R 17 represents C 1-4 alkyl (preferably methyl) substituted with one R 5 .; and Ri5, R16, Ri ⁇ . and R 1 Q are independently selected from hydrogen, halogen, Ci -4 alkyl, hydroxy and C ⁇ alkoxy. in another embodiment, the invention relates to the compounds of formula i wherein Cy 1 represents a ring of formula Cy 1c j
  • R 1 represents C ⁇ alkyl, -CN, -COR 2 , -CO 2 R 2 , -CONR 2 R 2 , -OCOR 3 , - OCONR 3 R 3 , -SR 2 , -SOR 3 , -SO 2 R 3 , -SO 2 NR 4 COR 3 or -NR 4 CO 2 R 3 , wherein C 1- 4 alkyl can be optionally substituted with one or more R 5 ; and
  • R 5 represents halogen, -CONR 8 R 3 , -OR 8 , -SO 2 R 9 , -SO 2 NR 8 R 8 , -NR 8 R 8 , - NR 4 COR 8 , -NR4SO2R9 or Cy 3c , wherein Cy 3c can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formuia I wherein Cy 1 represents a ring of formuia Cyi d
  • R 1 represents -CN, -CONR 2 R 2 or Ci -4 alkyl (preferably methyl) substituted with one R 5 ;
  • R 5 represents halogen, -CONR 8 R 8 , -OR 8 , -SO 2 R 9 , -SO 2 NR 8 R 8 , -NR 8 R 8 , - NR 4 COR 8 , -NR 4 SO 2 Rg or Cy 30 , wherein Cy 30 can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formula I wherein Cy 1 represents a ring of formula Cy 1c i
  • R 1 represents Chalky! (preferably methyi) substituted with one R 5 ; and R 5 represents halogen, -CONR 8 Rs, -OR 8 , -SO 2 R 9 , -SO 2 NR 8 R 8 , -NR 8 R 8 , - NR 4 COR 8 , -NR 4 SO 2 Rg or Cy 3c , wherein Cy 3c can be optionally substituted with one or more R 7 .
  • the invention relates to the compounds of formula I wherein Cyi represents a ring of formula Cyi e
  • Cyi e can be optionally substituted with one Ri at the NH group
  • R 1 represents C- ⁇ 4 alkyl which can be optionally substituted with one or more R 5 .
  • the invention relates to a compound of formula I selected from the list of compounds described in examples 1 to 25, In another embodiment, the invention relates to a compound of formula ⁇ seiected from:
  • the invention relates to a compound of formula E selected from:
  • the invention relates to the compound (R)-4-[3- (W J W-d ⁇ methylarnino)pyrrolidin-1-yl]-2-[(4-morpholi ⁇ -4-ytmethyl)pheny!]arnino-7H- pyrro!o[2,3-d]pyrimidine or a salt thereof. in another embodiment, the invention relates to the compound (R)-4-[3-
  • the invention relates to the compound (R)-4-[3- (N,N-dimethylamino)pyrroiidin-1-yl]-2-(4-methyisulfony!pheny[)amino-7H- pyrrolo[2,3-d]pyrimidine or a salt thereof.
  • the invention relates to the compound (R)-4-[3-
  • the invention relates to the compound (R)-4-[3- (A/,/V-dimethyiamino)pyrrolidin-1-yl]-2-(2-isopropylisoindolinone-5-yl)amino-7H- pyrroio[2,3-d]pyrimidine or a salt thereof.
  • the invention relates to the compound (R)-2-[2-(S)- sec-butylaminocarbonyl)-1"methyipyrrole-4-yl3amino-4-[3-( ⁇ /, ⁇ /- dimethylamino)pyrroiidin-1-yl3-7H-pyrrolo[2,3-c/]pynmidine or a salt thereof.
  • the invention relates to the compound (R)-4-[3- ( ⁇ /,N-dimethylamino)pyrrolidin-1-yi]-2-[2-(morpho[ ⁇ n-4-yimethyl)thiophen-4- yl]amino-7H-pyrrolo[2,3-d]py ⁇ midine or a salt thereof,
  • the invention relates to the compound (R)-4-[3- ( ⁇ / J ⁇ /-dimethylamino)pyrrolidin-1-yl]-2-[(3-dimethylaminosu[fonyimethyl)-(4- morpholin-4-y!)phenyf]amino-7H-pyrroio[2 I 3-d]pyrimidine or a salt thereof.
  • the invention relates to the compound (R ⁇ -2-[3-
  • the invention relates to the compound (R)-4-[3- ( ⁇ /, ⁇ /-dimethylamino)pyrroiidin-1 -yl]-2 ⁇ (3-methylisothiazote-5-yl)amino-7H- pyrrolo[2,3-c/]py ⁇ midsne or a salt thereof.
  • the invention relates to a compound of formula S which provides more than 50% inhibition of JAK3 activity at 10 ⁇ M, more preferably at 1 ⁇ M and still more preferably at 0.1 ⁇ M, in a JAK3 assay such as the one described in example 26.
  • the compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids.
  • salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and sa!ts with organic acids such as methanesuifonic acid, trifluoromethanesuifonic acid, ethanesulfonic acid, benzenesuifonic acid, p- toiuenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maieic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, giycoiic acid, succinic acid and propionic acid, among others.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid
  • organic acids such as methanesuifonic acid, trifluoromethanesuifonic
  • Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases.
  • these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginsne, ⁇ /-methylgiucamine, procaine and the iike.
  • pharmaceutically acceptable salt represents those salts which are, according to medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.
  • the compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula S or a salt thereof) and a solvent.
  • solvents include pharmaceutically acceptable solvents such as water, ethanol and the like.
  • a complex with water is known as a hydrate.
  • Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.
  • the compounds of formula 1 may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula i, including all polymorphic forms ("polymorphs") thereof, are included within the scope of the invention. Some of the compounds of the present invention may exist as several diastereoisomers and/or several optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • protecting groups Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene T.W. and Wuts P. G. M 1 "Protecting Groups in Organic Synthesis", John Wiley & Sons, 3 rd edition, 1999).
  • protecting group of an amino function the ferf-butoxycarbonyl (BOC) group can be used. Whenever a protecting group is present, a later deprotection step will be required, which can be performed under standard conditions in organic synthesis, such as those described in the above- mentioned reference.
  • step a the reaction between a compound of formula Ii and a compound of formula Hi may be carried out in the presence of a base such as triethylamine, K 2 CO 3 , Cs 2 CO 3 or diisopropylethylamine, a solvent such as ethanol, tetrahydrofuran/H 2 O or any polar solvent, and heating preferably at reflux to obtain a compound of formuia fV.
  • Step b may be carried out by the reaction between a compound of formula
  • step b may be carried out by the reaction between a compound of formula IV and an amine of formula V in the presence of 4M dioxane/HCl ( g) solution, a solvent such as n-butanol or methoxyethanol, and irradiating with a microwave oven preferably at around 170 0 C to obtain a compound of formula I.
  • the amino groups of the compounds of formula fl and/or JV may be protected in order to prevent the formation of side products.
  • Any suitable protective group may be used, such as for example a p- toluylsulfonyi group.
  • the compounds of formula IS and/or IV are used in protected form (i.e. when the respective amino groups of the compounds of Ei and/or IV are protected)
  • a subsequent deprotection step may be necessary to obtain a compound of formula I, which is carried out under standard conditions.
  • the protective group is p-toluylsulfonyl
  • the deprotection can be conducted directly upon the crude product obtained by adding a solution of a strong base such as sodium hydroxide in a suitable solvent such as methanol.
  • any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature.
  • these interconversion reactions can be carried out upon the compounds of formula I as well as upon any suitable synthesis intermediate thereof.
  • the compounds of formula Ii and II! are commerciaily available.
  • the compounds of formula V are commercially available or can be prepared by well- known methods described in the literature starting from commercialty available compounds using interconversion reactions such as those described above for a compound of formula i, and can be protected with suitable protecting groups.
  • the compounds of the present invention act by inhibiting JAK/STAT signaling pathways, particularly by inhibiting JAK3 activity. Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases in which JAKs, particularly JAK3, play a role in mammals, including human beings. These diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative disorders (see e.g. O'Shea JJ. et ai, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).
  • diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative disorders (see e.g. O
  • Acute or chronic transplant rejection reactions that can be treated or prevented with the compounds of the present invention include any kind of cell, tissue or organ xenotransplants or allografts, such as of heart, lung, liver, kidney, pancreas, uterus, joints, pancreatic islets, bone marrow, limbs, cornea, skin, hepatocytes, pancreatic beta cefls, piuripotential cells, neuronal cells and myocardial ceils, as well as graft-versus-host reactions (see e.g. Rousvoal G. et al, Transpl. int. 2006, 19(12):1014-21 ; Borie DC.
  • Immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of the present invention include among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and inflammatory bowel diseases (e.g.
  • ulcerative colitis and Crohn's disease scleroderma, type I diabetes and complications from diabetes, type B hepatitis, type C hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, suppression of HIV repiication, infertility of autoimmune origin, autoimmune thyroid disease (Grave's disease), interstitial cystitis, and mast cell- mediated a ⁇ ergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis (see e.g.
  • Neurodegenerative diseases that can be treated or prevented with the compounds of the present invention include, among others, amyotrophic lateral sclerosis and Alzheimer's disease (see e.g. Trieu VN. et al ⁇ Biochem. Biophys. Res, Commun. 2000, 267(1 ):22-5).
  • Proliferative disorders that can be treated or prevented with the compounds of the present invention inciude, among others, leukemias, lymphomas, glioblastoma multiforme, colon carcinoma, as well as thromboembolic and allergic complications associated with these diseases (see e.g. Sudbeck EA. et ai, Clin. Cancer Res. 1999, 5(6):1569-82; Naria RK.
  • Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3, are well known in the art.
  • a compound to be tested can be incubated in the presence of JAK3 to determine whether inhibition of JAK3 enzymatic activity occurs, as described in the assay of example 26.
  • Other in vitro useful assays that can be used to measure JAK3- inhibitory activity include cellular assays, for example IL-2-induced proliferation of human T lymphocytes.
  • the immunosuppressive activity of the compounds of the invention can be tested using standard in vivo animal models for immune and autoimmune diseases, which are well known in the art, For example, the following assays can be used: delayed-type hypersensitivity (DTH) (see e.g.
  • DTH delayed-type hypersensitivity
  • testing at 10 ⁇ M must result in an activity of more than 50% inhibition of JAK3 activity in the test provided in example 26. More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 ⁇ M, and still more preferably, they should exhibit more than 50% inhibition at 0.1 ⁇ M.
  • the present invention also relates to a pharmaceutical composition that comprises a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients.
  • the excipients must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasai, ocular, rectal and topical administration.
  • Solid compositions for oral administration include tablets, granulates and capsules.
  • the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients.
  • excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitoi or calcium hydrogen phosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethy! starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or taic.
  • Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability.
  • the active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents.
  • Soft gelatin capsules are aiso possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.
  • Powders and granulates for the preparation of oral suspensions by the addition of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives.
  • Other excipients can also be added, for example sweetening, flavoring and colouring agents.
  • Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as purified water, ethanoi, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol.
  • Said compositions can aiso contain coadjuvants such as wetting, suspending, sweetening, flavoring agents, preservatives and buffers.
  • injectable preparations, according to the present invention, for parenteral administration comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions, which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout ail the manufacturing process.
  • coadjuvants such as wetting, emulsifying, dispersing agents and preservatives.
  • the active compound can be preferably formulated as a suppository on an oily base, such as for example vegetable oils or solid semisynthetic giycerides, or on a hydrophi ⁇ c base such as polyethylene glycols (macrogol).
  • an oily base such as for example vegetable oils or solid semisynthetic giycerides
  • a hydrophi ⁇ c base such as polyethylene glycols (macrogol).
  • the compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract.
  • Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
  • the compound for the nasal administration or for inhalation, can be formulated as an aerosol and it can be conveniently released using suitable propeliants.
  • the dosage and frequency of doses wilt depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors.
  • a representative exampSe of a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.
  • DIPEA W, ⁇ /-diisopropylethyJamine
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium (0)
  • PyBOP (Benzotriazol ⁇ 1-yloxy)tripyrroiidinophosphonium hexafluorophosphate s: singlet
  • Method 1 Waters Acquity UPLC BEH C18 Column (1.7 ⁇ m, 2.1 x 50 mm), temperature 40 0 C, flow rate: 0.5 mL/min, efuent: AcN(A) / Ammonium bicarbonate 1 O mM (B), gradient: 0 min 10% A - 3.75 min 90% A.
  • the desired compound was obtained following a similar procedure to that described in example 6, but using the compound obtained in the previous section instead of the solution of example 5, and 50 mg of desired compound were obtained (yield: 67%).
  • the crude product was diluted with H 2 O and extracted thrice with CH 2 CI 2 .
  • the combined organic phases were separated, dried over Na 2 SO 4 and the solvent was evaporated.
  • the crude product thus obtained was purified by column chromatography over silica gel, using hexane/EtOAc mixtures of increasing polarity as eluent, and 60 mg of the desired compound were obtained (yield: 48%).
  • the crude product was diluted with 0.5 M HCl aqueous solution and extracted thrice with CH 2 CI 2 .
  • the combined organic phases were separated, dried over
  • the foliowing compound was obtained by following a similar procedure to that described in reference example 31 , but using the corresponding starting compound instead of 2-methyl-1 -propanediol:
  • the titie compound was obtained following a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section (292 mg, 1.44 mmoi) (yield: 95%).
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction crude obtained was evapporated to dryness, it was dissolved in CHCI 3 (3 mL) and then imidazole (94 mL, 1.382 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated to dryness.
  • the reaction crude thus obtained was heated to 8O 0 C for 3 hours in a mixture of MeOH (2 mL) and 1 N NaOH (2 mL). The MeOH in the mixture was evaporated and the aqueous phase was extracted thrice with CHCI 3 . The combined organic phases were separated, dried over Na 2 SO 4 ⁇ and the solvent was evaporated to dryness.
  • JAK3 kinase activity was determined in 384-well assay microplates using the Z'-Lyte ® Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogen (Ref: PV4122), following the manufacturer's instructions.
  • the compounds of all examples showed more than 50% inhibition of JAK3 activity at 1 ⁇ M in this assay.
  • Arthritis was induced in 8-weekoid male DBA/1 mice by the intradermal administration at the base of the tail of 0.1 mL of an emulsion containing 100 ⁇ g of type Il chicken collagen in complete Freund's adjuvant (CFA) (100 ⁇ g M. Tuberculosis).
  • CFA complete Freund's adjuvant
  • the animals received an injection booster consisting in 0.1 mL of an emulsion containing 100 ⁇ g of type Ii chicken collagen in incomplete Freund's adjuvant (IFA).
  • IFA incomplete Freund's adjuvant
  • the compound to be tested was administered orally during the following 21 consecutive days at the dose of 15 mg/kg/bid dissolved in 0,2% carboxymethylceliulose + 1 % Tween ® 80 (10 mL/kg). Untreated arthritic animals (control) received only the vehicle. The arthritic index was assessed according to the following scale:
  • Each limb was graded from 0 to 4, and the result for each one was added up to obtain the arthritic index, which therefore lies between 0 and 16.
  • the efficacy of the tested compounds was determined by assessing the inhibition of the increase in the arthritic index with respect to the untreated arthritic animals (control).

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des dérivés (R)-3-(N,N-diméthylamino)pyrrolidine de formule (I), la signification de Cy1 étant telle que décrite dans la description. Ces composés sont utiles comme inhibiteurs de la JAK3 kinase.
PCT/EP2009/062322 2008-09-23 2009-09-23 Dérivés (r)-3-(n,n-diméthylamino)pyrrolidine WO2010034740A1 (fr)

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WO2012022045A1 (fr) * 2010-08-20 2012-02-23 Hutchison Medipharma Limited Composés pyrrolopyrimidiniques et leurs utilisations
WO2013042006A1 (fr) * 2011-09-22 2013-03-28 Pfizer Inc. Dérivés de pyrrolopyrimidine et de purine
CN105452238A (zh) * 2013-05-24 2016-03-30 株式会社柳韩洋行 含嘧啶环的二环衍生物及其制备方法
JP2016537382A (ja) * 2013-11-21 2016-12-01 ファイザー・インク ２，６−置換プリン誘導体および増殖性障害の治療におけるそれらの使用
JP2017524703A (ja) * 2014-07-25 2017-08-31 シャンハイ ハイヤン ファーマシューティカル テクノロジー カンパニー リミテッドＳｈａｎｇｈａｉ Ｈａｉｙａｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． ２，４−二置換７Ｈ−ピロロ［２，３−ｄ］ピリミジン誘導体、その製造方法および医薬における使用
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10913744B2 (en) 2015-02-13 2021-02-09 Dana-Farber Cancer Institute, Inc. LRRK2 inhibitors and methods of making and using the same
CN114426542A (zh) * 2020-10-29 2022-05-03 苏州亚宝药物研发有限公司 取代的二芳基胺化合物及其药物组合物、制备方法和用途
CN114728972A (zh) * 2019-11-13 2022-07-08 拉普特医疗公司 C-c趋化因子受体4型拮抗剂的结晶形式及其用途

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WO2007089768A2 (fr) * 2006-01-30 2007-08-09 Exelixis, Inc. 4-aryl-2-amino-pyrimidines ou 4-aryl-2-aminoalkyl-pyrimidines utilisées comme modulateurs de la jak-2 et leurs procédés d'utilisation
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Cited By (18)

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Publication number Priority date Publication date Assignee Title
WO2012022045A1 (fr) * 2010-08-20 2012-02-23 Hutchison Medipharma Limited Composés pyrrolopyrimidiniques et leurs utilisations
WO2013042006A1 (fr) * 2011-09-22 2013-03-28 Pfizer Inc. Dérivés de pyrrolopyrimidine et de purine
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
US9040547B2 (en) 2011-09-22 2015-05-26 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
AU2014269229B2 (en) * 2013-05-24 2017-03-02 Yuhan Corporation Bicyclic derivative containing pyrimidine ring, and preparation method therefor
EP3006439A4 (fr) * 2013-05-24 2016-11-02 Yuhan Corp Dérivé bicyclique contenant un cycle pyrimidine, et procédé de synthèse permettant de l'obtenir
CN105452238A (zh) * 2013-05-24 2016-03-30 株式会社柳韩洋行 含嘧啶环的二环衍生物及其制备方法
JP2016520098A (ja) * 2013-05-24 2016-07-11 ユーハン・コーポレイションＹＵＨＡＮ Ｃｏｒｐｏｒａｔｉｏｎ ピリミジン環を含む二環式誘導体及びその製造方法
JP2016537382A (ja) * 2013-11-21 2016-12-01 ファイザー・インク ２，６−置換プリン誘導体および増殖性障害の治療におけるそれらの使用
JP2017524703A (ja) * 2014-07-25 2017-08-31 シャンハイ ハイヤン ファーマシューティカル テクノロジー カンパニー リミテッドＳｈａｎｇｈａｉ Ｈａｉｙａｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． ２，４−二置換７Ｈ−ピロロ［２，３−ｄ］ピリミジン誘導体、その製造方法および医薬における使用
US10913744B2 (en) 2015-02-13 2021-02-09 Dana-Farber Cancer Institute, Inc. LRRK2 inhibitors and methods of making and using the same
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
CN114728972A (zh) * 2019-11-13 2022-07-08 拉普特医疗公司 C-c趋化因子受体4型拮抗剂的结晶形式及其用途
CN114426542A (zh) * 2020-10-29 2022-05-03 苏州亚宝药物研发有限公司 取代的二芳基胺化合物及其药物组合物、制备方法和用途
JP7522315B2 (ja) 2020-10-29 2024-07-24 蘇州亜宝薬物研発有限公司 置換ジアリールアミン化合物及びその医薬組成物、製造方法と用途

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