WO2010034740A1 - (r)-3-(n,n-dimethylamino)pyrrolidine derivatives - Google Patents

(r)-3-(n,n-dimethylamino)pyrrolidine derivatives 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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French (fr)
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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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Publication of WO2010034740A1 publication Critical patent/WO2010034740A1/en

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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).

Abstract

(R)-3-(N,N-Dimethyiamino)pyrrolidine derivatives of formula (I), wherein the meaning for Cy1 is as disclosed in the description. These compounds are useful as JAK3 kinase inhibitors.

Description

(/?)-3-(W,/V-dimethylamino)pyrrolidiπe derivatives
Field of the invention
The present invention relates to a new series of (R)S-(N1N- dimethylamino)pyrrolidine derivatives, as weil as to processes for their preparation, to pharmaceutical compositions comprising them and to their use in therapy.
Background of the invention
The Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that play pivotal roles in pathways that modulate cellular functions in the lympho- hematopoietic system that are critical for cell proliferation and cell survival. JAKs are involved in the initiation of cytokine-triggered signaling events by activating through tyrosine phosphorylation the signal transducers and activators of transcription (STAT) proteins. 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.
Four members of the JAK family have been identified so far: JAK1 , JAK2, JAK3 and Tyk2. Unlike JAK1 , JAK2 and Tyk2, whose expression is ubiquitous, JAK3 is mainly found in hematopoietic ceils. JAK3 is associated in a non-covalent manner with the γc subunit of the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL- 15. These cytokines play an important role in the proliferation and differentiation of T lymphocytes. JAK3~deficient mouse T cells do not respond to ΪL-2. This cytokine is fundamental in the regulation of T lymphocytes. In this regard, it is known that antibodies directed against the IL-2 receptor are able to prevent transplant rejection. In patients with X severe combined immunodeficiency (X-SClD), very low levels of JAK3 expression as well as genetic defects in the γc subunit of the receptor have been identified, which indicates that immunosuppression is a consequence of an alteration in the JAK3 signaling pathway. Animal studies have suggested that JAK3 not only plays a critical role in T and B lymphocyte maturation, but also that JAK3 is required to maintain lymphocyte function. Modulation of the immunological activity through this new mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.
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. in conclusion, 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
M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrije M. et al, Arch.
Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).
Accordingly, it would be desirable to provide 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.
Description of the invention
One aspect of the invention relates to a compound of formula f
Figure imgf000005_0001
wherein:
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
6-membered saturated, partially unsaturated or aromatic carbocycSic or heterocyclic ring, wherein Cyi 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 SO2 groups, and wherein Cy 1 can be optionally substituted with one or more Ri; each Ri independently represents Chalky!, C2-4alkenyt, C^alkynyi, halogen, -CN, -NO2, -COR2, -CO2R2, -CONR2R2, -COCONR2R2, -OR2, -OCOR3, -OCONR3R3, -OCO2R3, -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CONR2R2, -NR4CO2R3, -C(=N-OH)R3 or Cy2, wherein Ci-4alkyl, C2-4aikenyi and C2-4alkynyl can be optionaliy substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; each R2 independently represents hydrogen or R3; each R3 independently represents Chalky!. C^alkenyl, C2-4afkynyi, or Cy3, wherein d^alkyl, C2-4alkenyl and C2»4alkyny[ can be optionally substituted with one or more R5 and Cy3 can be optionally substituted with one or more R7; each R4 independently represents hydrogen or Chalky!; each R5 independently represents halogen, -CN, -NO2, -COR8, -CO2R8, -CONR8R8, -OR8, -OCOR9, -OCONR9R9, -OCO2R9, -SR8, -SOR9, -SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8, -NR4CONR8R8, -NR4CO2R9, -NR4SO2R9, -Cf=N-OH)R9 or Cy3, wherein Cy3 can be optionally substituted with one or more R7; each R6 independently represents C1-4aiky! that can be optionally substituted with one or more Ri0, or R6 represents any of the meanings described for R11; each R7 independently represents Ci-4aikyl, haloCi-4alkyl, Ci-4alkoxyCi. 4aikyl, hydroxyCi-4alkyl,
Figure imgf000006_0001
or any of the meanings described for Ri1; each Rs independently represents hydrogen or R9; each Rg independently represents Chalky!, haioC-^alkyl, Ci-4alkoxyC-|. 4alkyi, hydroxyC1-4alkyl, cyanoCi-4a!kyl, Cy4-Ci.4alky! or Cy3, wherein Cy3 can be optionally substituted with one or more R7; each R-io independently represents halogen, -CN, -NO2, -COR8, -CO2Rs1 -CONR8R8, -OR8, -OCOR9, -OCONR9R9, -OCO2R9, -SR8, -SOR9, -SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8, -NR4CONR8R8, -NR4CO2R9, -NR4SO2R9, or -C(^N-OH)R9; each R-n independently represents halogen, -CN, -NO2, -CORi2, -CO2R12, -CONR12R12, -ORi2, -OCOR13, -OCONR13Ri3, -OCO2Ri3, -SRi2, -SORi3, -SO2R13, -SO2NR12Ri2, -SO2NR4CORi2, -NRi2Ri2, -NR4COR12, -NR4CONRI2R12, -NR4CO2R13, -NR4SO2Ri3 or -C(=N-OH)Ri3; each Ri2 independently represents hydrogen or Ri3; each Ri3 independently represents C^alkyl, haioC^alkyi, Ci^aIkOXyC1- 4aikyl or hydroxyCi-4alkyl; or two Ri2 groups or two Ri3 groups on the same N atom can be bonded completing, together with the N atom, a 5- or 6-membered saturated ring, which can additionally contain one or two heteroatoms selected from N, S and O, and which can be optionally substituted with one or more
Figure imgf000006_0002
groups; each Cy2 and Cy3 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, wherein each Cy2 and Cy3 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 CO1 SO or SO2 groups; each Cy4 independently represents a ring selected from (a)-(c):
Figure imgf000007_0001
(a) (b) (c) ; and
each R14 independently represents hydrogen or Ci-4alkyl; 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/Jpyrimidinef
(R)-4-[3-(A/;Λ/-dimethylamino)pyrrolidin-1 -y!]-2-[3- (phenylamino)phenyf]amino-7W-pyrrolo[2,3-d]pyrimidine,
(R)-4-[3-(Λ/,Λ/-dimethyiamino)pyrroiidin-1 -yl]-2-[4-(morpholin-4- yl)pheny!]amino-7H-pyrroio-[2,3-cfjpyrimidine,
(f?)-4-[3-fΛ/;A/-dimethy!amino)pyrroiidin-1 -yl]-2-(3-fluoro-4- methoxyphenyl)amino-7H-pyrroio-[2,3-c/]pyrimidine, (/?)-4-[3-(W,/V-dimethylam/no)pyrrolidin~1 -yl]-2-(3- methylaminosulfony!phenyl)amino-7H-pyrrolo[2,3-Gf3pyrimidine)
(R)-2-(3-aminosυlfonylpherιyi)amino~4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1- yl]-7H-pyrroJo[2,3-c/]pyrimfdine.
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. Thus, another aspect of the invention relates to a compound of formuia
Figure imgf000008_0001
or a salt thereof, wherein: 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 Cy1 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 SO2 groups, and wherein Cyi can be optionally substituted with one or more Ri; each Ri independently represents Ci-4alkyl, C2-4alkenyl) C≤^alkynyl, halogen, -CN, -NO2, -COR2, -CO2R2, -CONR2R2, -COCONR2R2, -OR2, -OCOR3, -OCONR3R3, -OCO2R3, -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CONR2R2, -NR4CO2R3, -C(=N-OH)R3 or Cy2, wherein Ci-4alkyl, C2-4alkenyi and C2-4alkynyi can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; each R2 independently represents hydrogen or R3; each R3 independently represents Chalky!, C2-4alkenyl, C2,4alkynyl, or Cy3, wherein Chalky!, C2-4alkenyl and C2-4alkyny! can be optionally substituted with one or more Rs and Cy3 can be optionally substituted with one or more R7; each R4 independently represents hydrogen or Ci-4alkyi; each R5 independently represents halogen, -CN, -NO2, -CORg, -CO2R8, -CONR8R8, -OR8, -OCOR9, -OCONR9R9, -OCO2R9, -SR8, -SOR9, -SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8, -NR4CONR8R8, -NR4CO2Rg, -NR4SOaRg, -C(=N-OH)R9 or Cy3, wherein Cy3 can be optionalty substituted with one or more R7; each Rg independentϊy represents C^alkyl that can be optionally substituted with one or more R1Q, or Re represents any of the meanings described for R11; each R7 independently represents C1-4alky[, haioC1-4aJkyi, Ci-4aikoxyC-ι. 4alky!,
Figure imgf000009_0001
cyanoCi-4alkyi or any of the meanings described for R11; each R8 independently represents hydrogen or Rg; each Rg independently represents Ci-4alkyl, haioCi-4alkyi,
Figure imgf000009_0002
4alkyS,
Figure imgf000009_0003
cyanoC-μ4alkyl, Cy4-Ci -4a Iky! or Cy3, wherein Cy3 can be optionally substituted with one or more R7; each R10 independently represents halogen, -CN, -NO2, -CORs, -CO2Rs5 -CONR8R8, -OR8, -OCOR9, -OCONR9R9, -OCO2R9, -SR8, -SOR9, -SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8, -NR4CONR8R8, -NR4CO2R9, -NR4SO2R9, or -C(=N-OH)R9; each R11 independently represents halogen, -CN, -NO2, -COR12, -CO2Ri2, -CONR12R12, -OR12, -QCOR13, -OCONR13R13, -OCO2R13, -SR12, -SORi3, -SO2R13, -SO2NR12Ri2, -SO2NR4COR12, -NR12R12, -NR4COR12, -NR4CONR12R12, -NR4CO2R13, -NR4SO2Ri3 or -C(=N-0H)R13; each Ri2 independently represents hydrogen or Ri3; each R13 independently represents C-^alkyl, haloC^alkyi, C-i-4alkoxyCi. 4a!kyl or hydroxyC-^aikyl; or two Ri2 groups or two R13 groups on the same N atom can be bonded completing, together with the N atom, a 5- or 6-membered saturated ring, which can additionally contain one or two heteroatoms selected from N, S and O, and which can be optionally substituted with one or more Ci-4alkyl groups; each Cy2 and Cy3 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 O5 wherein each Cy2 and Cy3 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 SO2 groups; each Cy4 independently represents a ring selected from (a)-(c):
Figure imgf000010_0001
each Ru independently represents hydrogen or Ci-4alkyl; with the proviso that the foliowing compounds are excluded:
(R)-2-(3-acetylaminophenyJ)aminθ"4-[3~(A/,/V-dimethy[amino)pyrroiidin-1-yi]- 7H-pyrro!o[2,3-d]pyrimidine, (R)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1-yl]-2-[3-
(phenylamino)phenyl]amino-7/-/-pyrrolo[2,3-d]pyrimidine,
(/?)-4-[3-(Λ/,/V-dtmethy!amino)pyrrolidin-1-yl]~2~[4-(morphoiin-4- y!)phenyi]amino-7H-pyrrolo-[2,3-d]pyrimidine,
(R)-4-[3~fΛ/,W-dimethyiamino)pyrroiidin-1-yi]-2-(3-fluoro-4- methoxyphenyl)amino-7H-pyrroio-[2;3-Gθpyπmidine,
(R)-4-[3-(W,Λ/-dsmethyiamino)pyrroiidin-1-yi]~2-(3- methyiaminosulfonylphenyl)amino-7H-pyrrolo[2,3-c0pyrimidine,
(R)-2-(3-aminosu!fonyiphenyl)amino-4-[3-(/V,/V-dimethyiamino)pyrrolidin-1- yi]-7H-pyrroio[2,3-d]pyrimidinβ, for use in therapy.
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. In a preferred embodiment, 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.
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. In a preferred embodiment, 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 ceiS-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. In a preferred embodiment, 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 f or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, muitipie scierosis, 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 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. In a preferred embodiment, 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.
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)
Figure imgf000013_0001
SV V wherein Cy 1 has the meaning described in claim, followed if necessary by the removal of any protecting group that may be present; or (b) converting, in one or a plurality of steps, a compound of formula ! into another compound of formula I.
In the above definitions, the term C1-4 alkyi, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyi, butyl, isobutyl, sec-butyi and te/Y-butyl.
A C2-4alkenyi 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 C2-4alkynyl 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.
A Ci-4alkoxy group, as a group or part of a group, means a group of formula -OCi-4alkyi, wherein the C^aikyi moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxγ. Haiogen or its abbreviation halo means fluoro, chloro, bromo or iodo.
A Ci-4alkoxyCi.4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci-4alkyl group with one or more C1-4alkoxy 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, tβrt- butoxymethyl, dimethoxymethyl, 1-methoxyethy!, 2-methoxyethyl, 2-ethoxyethyl,
1 ,2-diethoxyethy!, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2- butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-terf-butoxypropyl and 4-methoxybutyl. A
Figure imgf000014_0001
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
(i.e. fluoro, chioro, bromo or iodo), which can be the same or different. Examples include, among others, the groups trifiuoromethyl, fiuorornethyl, 1-chloroethyl, 2- chloroethyl, 1 -fiuoroethyl, 2-fluoroethyl, 2-bromoethy!, 2-iαdoethyi, 2,2,2- trifluoroethyl, pentafiuoroethyl, 3-fiuoropropyi, 3-chloropropyl, 2,2,3,3- tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluoro butyl, nonafluorobutyl, 1-chloro-2-fluoroethyi and 2-bromo-1-chioro-1-fluoropropyi.
A hydroxyC1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a
Figure imgf000014_0002
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^4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci-4alkyl 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 Cy4-Ci,4aikyl group means a group resulting from the replacement of one hydrogen atom from a
Figure imgf000014_0003
group with one Cy4 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-yl)methy!, 2-{1 ,1 -dioxotiomorphofin-4-yi)ethyl, 3-{1 ,1-dioxothiomorpholin-4- yi)propyl and 4-(1 ,1-dioxothiomorpholin-4-yl)butyI.
The term 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. When the second ring, i.e. 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 SO2 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. Examples of 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, benzothiazolyl, quinolinyi, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxaiinyi, cinolinyl, naphthyridinyl, indazoiyl, imidazopyridinyl, pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyf, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyrazinyi, pyrazoSopyridinyl, pyrazoiopyrimidinyl, benzo[1 ,3]dioxoiyl, phtalimidyS, 1 -oxo-1 ,3- dihydroisobenzofuranyl, 1 ,3~dioxo-1 ,3-dihydroisobenzofuranyl, 1-oxo-indanyi, 2- oxo-2,3-dihydro-1 H-indolyl, 1 -oxo-2,3-dihydro-1 H-isoindolyl, 1 ,2,3,4- tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyi, 1 -oxo-1 ,2,3,4- tetrahydroisoquinolinyl, 1 -oxo-1 ,2-dihydroisoquinolinyl, 4-oxo-3,4- dihydroquinazoiinyl, 3-oxo-4W-benzo[1 ,4]oxazonyl and 2-oxo-1 H-pyrido[2,3- b][1 ,4]oxazonyS.
The term Cy2 or Cy3 refers to a 3- to 7-membered monocyclic or 6- to 11- membered bicycfic carbocyciic or heterocyclic ring. When 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 Cy2 or Cy3 group can be saturated, partially unsaturated or aromatic. Cy2 and Cy3 can be bonded to the rest of the molecule through any available C or N atom, in Cy2 or Cy3 one or more C or S atoms of a saturated or partially unsaturated ring can be optionally oxidized forming CO, SO or SO2 groups. Cy2 and Cy3 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. Examples of Cy2 or Cy3 groups include, among others, cycSopropyl, cyclobutyl, cyciopentyl, cyclohexyl, cycloheptyϊ, 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, thiazolinyl, pyrazolinyl, imidazoiinyl, isoxazolinyl, isothiazolinyl, 2-oxo-pyrrolidiπyl, 2-oxo-piperidinyl, 4-oxo-pipeπdiny!, 2-oxo- piperazinyl, 2-oxo-1 ,2-dihydropyridiny1, 2-oxo-1 ,2-dihydropyrazinyi, 2-oxo-1 ,2- dihydropyrimidinyi, 3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyi, furyl, pyrrolyi, thiazolyl, isothiazolyi, oxazolyl, isoxazolyl, imidazolyS, pyrazoiy!, 1 ,2,3- triazolyl, 1 ,2,4-triazolyl, tetrazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,4-thiadiazolyl, pyridy!, pyrazinyi, pyrimidinyl, pyridazinyi, benzimidazolyl, benzooxazolyl, benzofuranyi, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, quinoliny!, isoquinoϋnyl, phtaiazinyl, quinazolinyS, quinoxaiinyi, cinoϋnyf, naphthyridinyi, indazolyi, imidazopyridinyl, pyrroiopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyi, pyrazoiopyraziny!, pyrazolopyridinyl, pyrazoiopyrimidinyϊ, benzo[1 ,3]dioxolyl, phtalimidyf, 1-oxo-1 ,3~dihydroisobenzofuranyl, 1 ,3-dioxo-1 ,3- dihydroisobenzofuranyl, 2-oxo-2,3-dihydro-1 H-indoiyϊ, 1 -oxo-2,3-dihydro-1 H- isoindoiyl, perhydroquinoiinyi, i-oxo-perhydroisoquinoiinyl, 1-oxo-1 ,2- dihydroisoquinoliπyl, 4-oxo-3,4-dihydroquinazolinyl, 2-aza-bicyclo[2.2.1]heptanyl, 5-aza-bicyclo[2.1.1]hexanyl, 2H~spiro[benzofuran-3I4!-piperidinyl], 3H- spiro[tsobenzofυran-1 ,4'-piperidinyi], 1-oxo-2,8-diazaspiro[4.5]decanyl and 1-oxo- 2,7-diazaspiro[4.5]decanyl.
In the above definitions of Cy1, Cy2 and Cy3 when the examples fisted refer to a bicycle in general terms, ail possible dispositions of the atoms are included. Thus, for example, 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-έ>]pyrazinyl, imidazo[1 ,2-a]pyrazinyi and imtdazo[1 ,5~a]pyrazinyt and the term pyrazolopyrimidinyl can include groups such as 1 H-pyrazo!o[3,4-d]pyrimidinyl, 1H- pyrazo!o[4,3-d]pyrimidinyi, pyrazoio[1 ,5-a]pyrimidiny! and pyrazoio[1 ,5- c]pyrimidinyl.
When in the definitions used throughout the present specification for cyclic groups the examples given refer to a radical of a ring in genera! terms, for example pyridyi, thienyl or indoiyl, all the available bonding positions are included, unless a limitation is indicated in the corresponding definition for said cyclic group, for example that the ring is bonded through a G atom in Cy-s, in which case such limitation applies. Thus for example, in the definitions of Cy2 and Cy3, which do not include any limitation regarding the bonding position, the term pyridyi includes 2- pyridyl, 3-pyridyl and 4-pyridyl; thienyl includes 2-thienyl and 3-thienyl; and indolyϊ includes 1-indoSyS, 2-indofyl, 3-indo!yi, 4-indotyl, 5-indoiyi, 6-indoiyl and 7-indoiyl.
The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 1 , 2 or 3 substituents, and stil! more preferably with 1 or 2 substituents, provided that said group has enough positions susceptible of being substituted. The substituents can be the same or different and can be placed on any available position.
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. Likewise, 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:
Figure imgf000018_0001
Figure imgf000018_0002
When in the definition of a substituent two or more groups with the same numbering are indicated (e.g. -NR4CONR2R2, -NR8R8, -CONR12Ri2, etc.), this does not mean that they must be the same. Each of them is independently selected from the list of possible meanings given for said group, and therefore they can be the same or different. in certain embodiments of the invention, Cy1 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
3 and 4, positions 4 and 5 or positions 3 and 5 of the phenyl ring.
In certain embodiments of the invention, Cy1 represents a ring of formula Cy1 e which can be optionally substituted with one R-t group at the NH group. This means that Cyiθ is either unsubstituted, or substituted with one Ri group placed at the N atom of the Cyie ring replacing the hydrogen atom of the NH group.
Throughout the present specification, by the term "treatment" is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention 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).
As used herein, "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. In another embodiment, 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
C atom, which contains from 1 to 3 heteroatoms selected from N, O and S; or c) a ring of formula Cy-tb
Figure imgf000019_0001
wherein 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 SO2 groups, and wherein Cy1 can be optionally substituted with one or more R1.
In another embodiment, 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
Figure imgf000019_0002
c) a ring of formula Cyie
Figure imgf000020_0001
Cy 1e wherein Cyie can be optionally substituted with one Ri at the NH group. In another embodiment, the invention relates to the compounds of formula wherein Cy-i represents phenyl, pyridyl or a ring of formula Cyia
Figure imgf000020_0002
Cy1 a wherein Y represents C or N; ring A represents a 5- or β-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 SO2 groups, and wherein the phenyl, pyridyl and Cyia groups can be optionally substituted with one or more R-).
In another embodiment, the invention relates to the compounds of formula I wherein Cyi represents phenyl or a ring of formula Cy1b
Figure imgf000020_0003
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 H1 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 Cyib groups can be optionally substituted with one or more R-j.
In another embodiment, the invention relates to the compounds of formula S wherein Cy 1 represents phenyl or a ring of formula Cy1b
Figure imgf000021_0001
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 Cyib groups can be optionally substituted with one or more R-i. in another embodiment, the invention relates to the compounds of formula \ wherein Cy-i represents phenyl or a ring of formula Cy^
Figure imgf000021_0002
Cyib 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 SO2 groups, and wherein the phenyl and Cyib groups can be optionally substituted with one or more R1,
In another embodiment, the invention relates to the compounds of formula ! wherein Cyi represents phenyl or a ring of formula Cy-ib
Figure imgf000022_0001
Cyib 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 phenyl and Cy-ιb groups can be optionally substituted with one or more Ri.
Sn another embodiment, the invention relates to the compounds of formula I wherein Cyi represents: a) phenyl optionally substituted with one or more R1; or b) a ring of formula Cy-ιe
Figure imgf000022_0002
wherein Cy1e can be optionally substituted with one Ri at the NH group. in another embodiment, the invention relates to the compounds of formula f wherein Cy i represents phenyl optionally substituted with one or more R-i.
In another embodiment, the invention relates to the compounds of formula I wherein Cyi represents phenyl substituted with one or more Ri.
In another embodiment, 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.
Sn another embodiment, 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. In another embodiment, 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. in another embodiment, the invention relates to the compounds of formula I wherein Cy1 represents phenyl substituted with one Ri which is placed at position
3 of the phenyi ring. in another embodiment, 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 phenyi ring. in another embodiment, the invention relates to the compounds of formula I wherein Cyi represents a ring of formula Cy<|b
Figure imgf000023_0001
Cyib wherein ring A represents a 5- or 6-rnembered saturated, partially unsaturated or aromatic ring which can be carbocycϋc 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 SO2 groups, and wherein the Cyib group can be optionally substituted with one or more R1.
In another embodiment, the invention relates to the compounds of formula I wherein Cyi represents a ring of formuia Cyib
Figure imgf000023_0002
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 SO2 groups, and wherein the Cy1b group can be optionally substituted with one or more Ri. in another embodiment, the invention relates to the compounds of formula wherein Cyi represents a ring of formula Cy1b
Figure imgf000024_0001
Cy1b wherein ring A represents a saturated 5-membered heterocyclic ring which contains 1 or 2 heteroatoms selected from N, S and O1 wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO2 groups, and wherein the Cytb group can be optionally substituted with one or more Ri. in another embodiment, the invention relates to the compounds of formula I wherein Cyi represents a ring of formula Cy-it
Figure imgf000024_0002
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-ιb group can be optionally substituted with one or more R1.
In another embodiment, the invention relates to the compounds of formula I wherein Cy-i represents a ring of formula Cyie
Figure imgf000024_0003
Cy 1e wherein Cyte can be optionally substituted with one R-i at the NH group. in another embodiment, 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. in another embodiment, the invention relates to the compounds of formula I1 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
in another embodiment, 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 Cy1 contains from 1 to 3 heteroatoms selected from N and S, and wherein Cy -i can be optionally substituted with one or more Ri. In another embodiment, 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 Cy1 can be optionally substituted with one or more R1, preferably with one or two R-s, and more preferably with one R1.
In another embodiment, the invention relates to the compounds of formula I, wherein Cy1 represents 3-isothyazolyi, 4-isothyazolyϊ 0 5-isothyazolyl, which can be optionally substituted with one or more R1, preferably with one R1.
En otra realizaciόn, Ia invenciόn se refiere a ios compuestos de formula i donde Cy1 representa 2-pyrroiy! 0 3-pyrrolyl, which can be optionally substituted with one or more R1, preferably with one R1. in another embodiment, the invention relates to the compounds of formula I, wherein Cy1 represents 2-thienyi or 3-thienyi, which can be optionally substituted with one or more R1, preferably with one R1.
In another embodiment, the invention relates to the compounds of formula f, wherein Cy1 represents 3-thienyl, which can be optionally substituted with one R1, in another embodiment the invention relates to the compounds of formula 1, wherein Cyi represents a ring of formula Cy^
Figure imgf000026_0001
Cy1d In another embodiment, the invention relates to the compounds of formula \ wherein each R1 independently represents Ci-4alkyl, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R31 -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CO2R3 or Cy2, wherein C1-4alkyi can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re- in another embodiment, the invention relates to the compounds of formula S wherein each R1 independently represents C^aikyl, halogen, -CN, -COR2,
-CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3,
-NR4CO2R3 or Cy2. wherein Ci-4aikyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6.
In another embodiment, the invention relates to the compounds of formula \ wherein each Ri independently represents Ci-4afkyl, -CN1 -COR2, -CO2R2, -
CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -
NR4CO2R3 or Cy2, wherein
Figure imgf000026_0002
can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more RQ.
In another embodiment, the invention relates to the compounds of formula f wherein each R1 independently represents C-i^alkyl, -CN, -COR2, -CO2R2, -
CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -
NR4CO2R3 or Cy2, wherein Chalky! can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula I wherein each Rt independently represents halogen, d^alkyi, -CN, -COR2, - CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3, wherein Ci-4alkyl can be optionally substituted with one or more R5. In another embodiment, the invention relates to the compounds of formula I wherein each Ri independently represents C-ι_4a!kyl, -CN, -COR2, -CO2R2, - CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or - NR4CO2R3, wherein C1-4alky! can be optionally substituted with one or more R5. in another embodiment, the invention relates to the compounds of formula I wherein each R-, independently represents Ci-4a!kyi, -CN1 -COR2, -CO2R2, - CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or - NR4CO2R3, wherein d-4aikyl can be optionally substituted with one or more R5.
In another embodiment, the invention relates to the compounds of formula i wherein each Ri independently represents C^aikyl, -CN, or -CONR2R2, wherein Ci.4alkyl can be optionally substituted with one or more R5. in another embodiment, the invention relates to the compounds of formula I wherein each R1 independently represents Chalky!, -CN, or -CONR2R2, wherein C1-4alkyi can be optionally substituted with one Rs. In another embodiment, the invention relates to the compounds of formula I wherein each Ri independently represents -CN, -CONR2R2 or Ci-4alkyl (preferably methyl) substituted with one R5.
In another embodiment, the invention relates to the compounds of formula I wherein each Ri independently represents Chalky! {preferably methyl) optionally substituted with one R5.
In another embodiment, the invention relates to the compounds of formula I wherein each Ri independently represents C1-4alkyl (preferably methy!) substituted with one R5. in another embodiment, the invention relates to the compounds of formula I wherein each Cy2 independently represents Cy2a, and Cy2a 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 SO2 groups, with the proviso that Cy2a is not morpholine, and wherein said Cy23 can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula S wherein each C\/2 independently represents Cy2b, and Cy2b represents a 5- or 6- membered saturated monocyclic heterocycte which contains 1 or 2 heteroatoms selected from N and S1 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula I wherein each Cy3 independently represents Cy3a, and Cy3a 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 Cy33 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, and wherein said Cy3a can be optionally substituted with one or more R7. in another embodiment, the invention relates to the compounds of formula I wherein each Cy3 independently represents Cy3b, and Cy3b 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 S1 wherein Cy3b 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, and wherein said Cy3b can be optionally substituted with one or more R7. in another embodiment, the invention relates to the compounds of formula I wherein each Cy3 independently represents Cy3c, and Cy30 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 Cy3c can be optionally substituted with one or more R7.
In another embodiment, the invention relates to the compounds of formula i wherein Cy3 represents morpholin-4-yi. In another embodiment, the invention relates to the compounds of formula \ wherein each R3 independently represents C1-4alkyl or Cy3, wherein C1-4alkyl can be optionally substituted with one or more Rs and wherein Cy3 can be optionally substituted with one or more R7. In another embodiment, the invention relates to the compounds of formula I wherein each R5 independently represents halogen, -CN, -COR8, -CONR8Rs, - OR8, -SRe, -SOR95 -SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8, - NR4SO2Rg or Cy3, wherein Cy3 can be optionally substituted with one or more R7. In another embodiment, the invention relates to the compounds of formula f
- wherein each R5 independently represents halogen, -CONR8R8, -ORe, -SO2Rg, - SO2NR8R8, -NR8R8, -NR4COR8, -NR4SO2R9 or Cy3, wherein Cy3 can be optionally substituted with one or more R7.
In another embodiment, the invention relates to the compounds of formula I wherein each R5 independently represents halogen, -CONR8Re, -ORs, -SO2R9, - SO2NR8RB, -NR8R8, -NR4COR8. -NR4SO2R9 or Cy3c, wherein Cy30 can be optionally substituted with one or more R7.
In another embodiment the invention relates to the compounds according to formula \ wherein each R5 independently represents Cy3; preferably Cy3c; and more preferably morphohn-4-yL
In another embodiment, the invention relates to the compounds of formula ! wherein each R10 independently represents halogen, -CN, -COR8, -CONR8R8, - ORs, -SR8, -SOR9, -SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8 or - NR4SO2R9. In another embodiment, the invention relates to the compounds of formula I wherein each Rn independently represents halogen, -CN1 -COR12, -CONRi2Ri2, - OR12, -SRi2, -SOR13, -SO2R13, -SO2NR12Ri2, -SO2NR4CORi2, -NR12R12, - NR4COR12 or -NR4SO2R13.
In another embodiment, 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 C1-4alky(, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, - OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CO2R3 or Cy2, wherein C1-4a!kyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Rε; and
Cy2 represents Cy2a, and Cy2a 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 Cy2a is not morphofine, and wherein said Cy2a can be optionally substituted with one or more R6.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cy1 represents phenyl substituted with one Ri which is placed at position 4 of the phenyl ring; R1 represents C1-4aikyt, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -
OCOR3, -OCONR3R31 -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CO2R3 or Cy2, wherein Ci-4aikyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and
Cy2 represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more Re. In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents phenyl substituted with one R1 which is placed at position 3 of the phenyl ring; and
R1 represents C1-4alkyi, halogen, -CN, -COR2, -CO2R21 -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re.
In another embodiment, the invention relates to the compounds of formula I wherein: each Ri independently represents Ci-4alkyl, halogen, -CN, -COR2, -CO2R2, -
CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, - NR4CO2R3 or Cy2, wherein Chalky! can be optionally substituted with one or more Rs and Cy2 can be optionaify substituted with one or more Re; and each Cy2 independently represents Cy2a, and Cy2a 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 CO1 SO or SO2 groups, with the proviso that Cy2a is not morphoϋne, and wherein said Cy2a can be optionally substituted with one or more Re-
In another embodiment, the invention relates to the compounds of formula I wherein: each Ri independently represents Ci-4aikyl, halogen, -CN, -COR2, -CO2R2, -
CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, - NR4CO2R3 or Cy2> wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionaliy substituted with one or more R6; and each Cy2 independently represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2^ can be optionally substituted with one or more Rg. In another embodiment, 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;
R1 represents Chalky!, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci_4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and
Cy2 represents Cy2a, and Cy2a 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 SO2 groups, with the proviso that Cy2a is not morpholine, and wherein said Cy2a can be optionally substituted with one or more R6.
In another embodiment, 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, -CN1 -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3. -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4aikyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and Cy2 represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6.
In another embodiment, 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-4aikyi, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3,
-OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4a!kyi can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and
Cy2 represents Cy2a, and Cy2s 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 SO2 groups, with the proviso that Cy2a is not morpholine, and wherein said Cy2a can be optionally substituted with one or more R6. fn another embodiment, the invention relates to the compounds of formula ! wherein:
Cyi represents phenyl substituted with one R1 which is placed at position 4 of the phenyl ring;
R1 represents C^alkyf, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Rg; and
Cy2 represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cy 1 represents phenyl substituted with one R1 which is placed at position 3 of the phenyl ring; and
R1 represents C^alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1- 4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re. In another embodiment, the invention relates to the compounds of formula S wherein: each R1 independently represents C1-4alkyi, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C-^alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and each Cy2 independently represents Cy2a, and Cy23 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 SO2 groups, with the proviso that Cy23 is not morphoiine, and wherein said Cy2a can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula 1 wherein: each Ri independentiy represents Ci-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R@; and each Cy2 independently represents Cy2t>, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more RQ.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cy1 represents phenyl substituted with one R1 which is piaced at position 3 of the phenyl ring;
R1 represents C1-4a!kyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1- 4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and Cy2 represents Cy2a, and Cy2a 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 SO2 groups, with the proviso that Cy23 is not morphoiine, and wherein said Cy2a can be optionally substituted with one or more
Rein another embodiment, the invention relates to the compounds of formula I wherein:
Cy1 represents phenyl substituted with one R1 which is placed at position 3 of the phenyl ring;
R1 represents Chalky!, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -
OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1-
4a!kyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and
Cy2 represents Cy2J3, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6.
In another embodiment, 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;
R1 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci- 4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and
Cy2 represents Cy2a, and Cy2a 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 CO1 SO or SO2 groups, with the proviso that Cy2a is not morpholine, and wherein said Cy2a can be optionally substituted with one or more
R6-
In another embodiment, 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 C1-4aikyi, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1- 4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and
Cy2 represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents phenyl substituted with one R1 which is placed at position 3 of the phenyl ring; and
R1 represents Ci-4alkyl, -CN1 -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 o Cy2, wherein Ci- 4alkyS can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6,
In another embodiment, the invention relates to the compounds of formula I wherein: each Ri independently represents Ci-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R31 -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4alkyi can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and each Cy2 independently represents Cy2a, and Cy2a 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, SO or SO2 groups, with the proviso that Cy2a is not morpholine, and wherein said Cy2a can be optionally substituted with one or more Re. In another embodiment, the invention relates to the compounds of formula I wherein: each Ri independently represents C-ι-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Chalky! can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and each Cy2 independently represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula ϊ wherein:
Cyi represents phenyl substituted with one R1 which is placed at position 3 of the phenyl ring;
R1 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4aiky[ can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and
Cy2 represents Cy2a, and Cy2a 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 SO2 groups, with the proviso that Cy2a is not morpholine, and wherein said Cy28 can be optionally substituted with one or more
R6. in another embodiment, 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;
R1 represents C^alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein d^alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re', and
Cy2 represents Cy2b, and Cy2b 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6. in another embodiment, 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;
R1 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and
Cy2 represents Cy23, and Cy2a 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 SO2 groups, with the proviso that Cy23 is not morphoJine, and wherein said Cy2a can be optionally substituted with one or more
Re. In another embodiment, 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;
R1 represents C1-4aikyt, -CN1 -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more RQ, and
Cy2 represents Cy2b, and Cy2b represents a 5- or 6-membered saturated monocyclic heterocycie 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6. in another embodiment, the invention relates to the compounds of formula S wherein:
Cy-i represents phenyl substituted with one R1 which is placed at position 3 of the phenyl ring; and
R1 represents halogen, C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3. wherein C1-4a!kyl can be optionally substituted with one or more R5.
In another embodiment, 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; and
R1 represents d-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3. wherein C1- 4alkyi can be optionally substituted with one or more R5.
In another embodiment, 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; and
R1 represents C1-4alkyl, -CN1 -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3. wherein Ci- 4alky{ can be optionally substituted with one or more R5.
In another embodiment, the invention relates to the compounds of formula i wherein:
Cyi represents a ring of formula Cy10
Figure imgf000039_0001
one of R16, Ri7 or Ri8 represents Chalky!, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CO2R3 or Cy2, wherein C1-4alky! can be optionally substituted with one or more R5, wherein Cy2 can be optionally substituted with one or more Re; and the remainder of R-^1 Rπ and Ri8 as well as R15 and Ri9 are independently selected from hydrogen, halogen, Ci-4aikyl, hydroxy and C1-4alkoxy. in another embodiment, the invention relates to the compounds of formula ! wherein:
Cy-i represents a ring of formula Cy-ιc
Figure imgf000040_0001
one of R-I6, R17 or R1S represents Chalky!, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R31 -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein C1-4aikyi can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and the remainder of R-ie, R17 and R18 as well as R15 and R19 are independently selected from hydrogen, halogen, Chalky!, hydroxy and C1-4a!koxy. In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents a ring of formula Cyic
Figure imgf000040_0002
one of R16, R17 or R18 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Chalky! can be optionafly substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6; and the remainder of R-ie, Ru and R18 as weli as R15 and R19 are independently selected from hydrogen, halogen, C^alkyl, hydroxy and C-^alkoxy.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents a ring of formula Cy1c
Figure imgf000041_0001
one of R16, Ru or R18 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2. wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more Re; and the remainder of Rie, Ru and R18 as well as R15 and R19 are independently selected from hydrogen, halogen, Chalky!, hydroxy and C1-4alkoxy.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cy-i represents a ring of formula Cy-ic
Figure imgf000042_0001
one of R-I6, R17 or Ri8 represents Ci-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR31 -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3, wherein Chalky! can be optionally substituted with one or more R5; and the remainder of R16, R-17 and Riδ as well as R-15 and R19 are independently selected from hydrogen, halogen, Ci-4alkyi, hydroxy and Ci_4alkoxy.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents a ring of formula Cyic
Figure imgf000042_0002
Ri7 represents C1-4aikyl, halogen, -CN, -COR2, -CO2R2, -CONR2R2,
-OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2a, wherein C^alkyl can be optionally substituted with one or more R5 and Cy28 can be optionally substituted with one or more RQ, and
R15, R16, R-i s and R19 are independently selected from hydrogen, halogen, C-|.4a!kyl, hydroxy and C1-4a!koxy. in another embodiment, the invention relates to the compounds of formula ! wherein:
Cy-i represents a ring of formula Cyic
Figure imgf000043_0001
R17 represents Ci-4alkyl, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2b, wherein Chalky! can be optionally substituted with one or more R5 and Cy2b can be optionally substituted with one or more R6; and
R.15, R16. R18 and R19 are independently selected from hydrogen, halogen, Ci-4alkyl, hydroxy and Ci-4aikoxy.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents a ring of formula Cyic
Figure imgf000043_0002
R16 represents C^alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionaliy substituted with one or more Re; and Ri5, R17, R18, and R19 are independentiy selected from hydrogen, halogen, Ci-4a!ky], hydroxy and Ci-4alkoxy.
In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents a ring of formuia Cyic
Figure imgf000044_0001
one of R16, Ru or R18 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2a, wherein C1-4a!kyl can be optionally substituted with one or more R5 and Cy2a can be optionally substituted with one or more R6; and the remainder of R16, R17 and R18 as well as R15 and R19 are independently selected from hydrogen, halogen,
Figure imgf000044_0002
In another embodiment, the invention relates to the compounds of formula I wherein:
Cyi represents a ring of formula Cyic
Figure imgf000044_0003
one of R16, Ru or R18 represents Ci-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2b, wherein Ci-4alkyi can be optionally substituted with one or more R5 and Cy2b can be optionally substituted with one or more R6; and the remainder of R^, R17 and Ri8 as well as R15 and R19 are independently selected from hydrogen, halogen, C1-4alkyf; hydroxy and Ci-4a!koxy.
In another embodiment, the invention relates to the compounds of formula ! wherein:
Cyi represents a ring of formula Cy-ιc
Figure imgf000045_0001
R16 represents C1-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2, wherein Ci-4alky[ can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more RQ, and
R-I5, Ri7, R18, and R-19 are independently selected from hydrogen, halogen, hydroxy and Cf-4aikoxy.
In another embodiment, the invention relates to the compounds of formula \ wherein:
Cyi represents a ring of formula Cy1c
Figure imgf000046_0001
R17 represents Ci-4alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2a, , wherein C1-4alkyi can be optionaiiy substituted with one or more R5 and Cy2a can be optionally substituted with one or more Re; and
R-I5, Ri6> R-I8, and R19 are independently selected from hydrogen, halogen, Chalky!, hydroxy and Ci-4aikoxy.
In another embodiment, the invention relates to the compounds of formula ! wherein:
Cyi represents a ring of formula Cy-ιc
Figure imgf000046_0002
R17 represents Cv4a!ky[, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3,
-OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3, -NR4CO2R3 or Cy2b. wherein Ci.4alkyl can be optionally substituted with one or more R5 and Cy2b can be optionally substituted with one or more Rg; and
Ri5, Ri6, R18, and R19 are independently selected from hydrogen, halogen, Ci-4alkyi, hydroxy and Ci-4a!koxy.
In another embodiment, the invention relates to the compounds of formula i wherein:
Cy1 represents a ring of formula Cyi0
Figure imgf000047_0001
Cy1c
R17 represents -CN, -CONR2R2 or Chalky! (preferably methyf) substituted with one R5; and
R-15, Ri6, R-18, and Ri9 are independently selected from hydrogen, halogen, hydroxy and
Figure imgf000047_0002
in another embodiment, the invention relates to the compounds of formula ! wherein:
Cy1 represents a ring of formula Cy1c
Figure imgf000047_0003
Cy10
R17 represents C1-4alkyl (preferably methyl) substituted with one R5.; and Ri5, R16, Riβ. and R1Q are independently selected from hydrogen, halogen, Ci-4alkyl, hydroxy and C^alkoxy. in another embodiment, the invention relates to the compounds of formula i wherein Cy1 represents a ring of formula Cy1cj
Figure imgf000048_0001
Cyid;
R1 represents C^alkyl, -CN, -COR2, -CO2R2, -CONR2R2, -OCOR3, - OCONR3R3, -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3, wherein C1- 4alkyl can be optionally substituted with one or more R5; and
R5 represents halogen, -CONR8R3, -OR8, -SO2R9, -SO2NR8R8, -NR8R8, - NR4COR8, -NR4SO2R9 or Cy3c, wherein Cy3c can be optionally substituted with one or more R7.
In another embodiment, the invention relates to the compounds of formuia I wherein Cy1 represents a ring of formuia Cyid
Figure imgf000048_0002
R1 represents -CN, -CONR2R2 or Ci-4alkyl (preferably methyl) substituted with one R5; and
R5 represents halogen, -CONR8R8, -OR8, -SO2R9, -SO2NR8R8, -NR8R8, - NR4COR8, -NR4SO2Rg or Cy30, wherein Cy30 can be optionally substituted with one or more R7.
In another embodiment, the invention relates to the compounds of formula I wherein Cy1 represents a ring of formula Cy1ci
Figure imgf000048_0003
Cyid;
R1 represents Chalky! (preferably methyi) substituted with one R5; and R5 represents halogen, -CONR8Rs, -OR8, -SO2R9, -SO2NR8R8, -NR8R8, - NR4COR8, -NR4SO2Rg or Cy3c, wherein Cy3c can be optionally substituted with one or more R7.
In another embodiment, the invention relates to the compounds of formula I wherein Cyi represents a ring of formula Cyie
Figure imgf000049_0001
wherein Cyie can be optionally substituted with one Ri at the NH group, and R1 represents C-μ4alkyl which can be optionally substituted with one or more R5.
Furthermore, the present invention covers aif possible combinations of the particular and preferred embodiments described above.
In all the embodiments described above the following compounds are excluded:
(R)-2-(3-acetylaminopheny!)amino-4-[3-(W,/V-dimethylamino)pyrrolidin-1-ylj-7W- pyrrolo[2,3-d]pyrimidine,
(f?)-4-[3-(Λ/,Λ/-dimethyiam!no)pyrroiidin-1-yl]-2-[3-(phenylamino)phenyl]amino-7/-/- pyrroio[2,3-d]pyrimidinβ, (R)-4-[3-(Λ/,Λ/-dimethyiamino)pyrroIidin-1-yl]-2-[4-(morpholin-4-yl)phenyi]amino-7/-/- pyrrolo-[2,3-c/]pyrirnidine,
(R)-4-[3-(Α/,W-dimethylamino)pyrrotidin-1-yi]-2-(3-fluoro-4-methoxyphenyi)amino-
7H-pyrroio-[2,3-αf]pyrimidine,
{/?)-4-[3-(Λ/;W-dimethytamino)pyrrolidin-1-y!]-2-(3- methyiaminosulfonylphenyl)amino-7H-pyrro!o[2,3-c/jpyrimidine,
(f?)-2-{3-aminosulfonylphenyl)amtno-4-[3-(Λ/,Λ/-dimethylamino)pyrroiidin-1-y!]-7/-/- pyrro!o[2,3-c/]pyrimidine.
In another embodiment, 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 ϊ seiected from:
(R)-4-[3-(/V,Λ/-dimethyiamino)pyrro[idin-1-y!]-2-[(4~morphoiin-4- ylmethyl)phenyi]amino-7H-pyrrolo[2,3-c/jpyrimidine, (R)-4-[3-(Λ/,N-dimethylamino)pyrrolidin-1 -y!]-2-[(4-hydroxymethyl) phenyljamino-
7H-pyrrofo[2,3-c/] pyrimidine,
(R)-4-[3-(N,A/-dimethy!amino)pyrrolidin-1-yl]-2-[4-(1 ,1-dioxothiomorphoiin-4- yl)phenyi]amino-7H-pyrroio[2,3-o]pyrimidine,
(R)-2-[(3~aminosulfonyl-4-methy!)phenyl]amino-4-[3-(Λ/;/V- dimethylamino)pyrrolidin-1 -yn-yH-pyrrolo^^-dlpyrimidine,
(/?)-2-(4-aminosuffonyfphenyl)amino-4-[3-(Λ/JΛ/-dimethylamino)pyrrolidin-1-yl]- 7W- pyrrolo[2,3-c/|pyrimidine,
(R)-4-[3-{Λ/,/V-dimethylamino)pyrroiidin-1-yl]-2-(4-methyisulfonylphenyl)amino~7H- pyrrolo[2,3-c(]pyπmidine, (^^-[{S-aminosuifonyl^-methoxyJphenyOamino^-^Λ/^- dimethyiamino)pyrroiidin-1-yl]- 7H-pyrro(o[2,3-c/|pynmidine,
(R)-2-[(3-aminosulfonyimethyi)phenyl]amino-4-[3-(A/;Λ/-dimethytamino)pyrroitdin-1- yl]-7H-pyrrolo[2,3-tfjpyrimidinet
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrroiidin-1-yi]-2-[4-(((1-methylpyrroiidin-2- yi)ethyt)aminosulfoπyl)phenyl]amino-7H-pyrroto[2,3-d]pyπmidiπe,
(R)-4-[3-{A/,Λ/-dimethyfamino)pyrrol(din-1-yl]-2-[(3- methylsu!fonylamino)phenyl]amino-7H-pyrroio[2,3-c/]pyπmidine,
{R)-4-[3-(W,N-dimethyiamino)pyrro!idin-1 -yl]-2-[(1 -oxo-2,3-dihydro)-1 H-inden-5- yl]amino~7/-/-pyrrolo[2,3-c/]pyrimidine, (R)-4-[3-(W,W-dimethyiamino)pyrrolidin-1 -yl]-2-[1 -(methyisulfonyl)-indoltne-5- yi]amine-7H-pyrroJo[2,3-c(]pyπmidine,
(R)-4-[3-(/VJΛ/-dimethylamino)pyrroi!din-1-yl]-2-[3-fJuoro-4-(4-methylpiperazin-1 - yl)phenyl]amino-7H-pyrrolo[2,3-c/]pyrimidine,
(R).4_[3.(/\/jΛ/-dimethylamino)pyrro!idin-1 -yl]-2-[3-fluoro-4-(morpho[in-4- ylmethyi)phenyl]amino-7H-pyrroto[2,3-cf]pyrimidine,
(R)-4-[3-(/VJΛ/-dimethylamino)pyrroitdin-1-yf]-2-[3-fluoro-4-(morphofin-4- y!)phenyl]amino-7H-pyrrolo[2,3-c(jpyrinnidine, (R^-^-f^acetyipiperazin-i-yiJphenyljamino-^CS-f/V.Λ/KiimethylaminoJpyrrolidin- 1-yl]- 7H-pyrrolo[2,3-GT|pyrimidine,
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrroiidtn-1-yl]-2-[1-(isopropylsulfonyl)-indoiine-5- yl]amino-7H-pyrro!o[2,3-d3pyrimidine, (R)-4-[3-(A/JW-dimethylamino)pyrroi'idin-1-yl]-2-[1 -(ethyisu!fonyl)-indoline-5- yl]amine-7H-pyrroio[2,3-c/]pyrirnidine,
(R)-4-[3-(N,W-dimethyiamino)pyrrotidin-1 -yl]-2-[1 -(Λ/, W- dimethylaminosulfonyl)indoline-5-yl]amine-7H-pyrrolo[2,3-a']pyrimidine,
(R)-4-[3-(/VJW-dimethylamino)pyrroitdin-1-yi]-2-[4-(2-{pyrrolidin-1- yi)ethoxy)phenyi]amino-7H-pyrrolo[2,3-c/]pyrimidine,
(f?)-4-[3-(W,W-dimethylamino)pyrrolidin-1-yl]-2-[4-(4-methylpiperaztn-1- ylmethy[)phenyl3amine-7/-/-pyrrolo[2,3-d]pyπmidine,
(R)-4-[3-(NJW-dimethytamino)pyrrolidin-1-yl]-2-[3-(morpho!in-4-yl)phenyl]amine-7H- pyrrolo[2,3-d]pyr!mid!ne, (R)-2-(benzofuran-5-yi)amino-4~[3-(/V,W-dimethylamino)pyrrolidin-1 -yl]-7H- pyrrolo[2,3-d]pyrimidine,
(/?)-4-[3-(A/,W-dimethylamino)pyrrolidsn-1 -yl]-2-(3-fiuorophenyi)am!no-7H- pyrroio[2,3-d]pyrimidine,
(R)-4-[3-(N,N-dimethylamino)pyrroiidin-1-yl]-2-(4-tnfSuoromethoxyphenyl)amsne- 7H-pyrroio[2,3-rfjpyrimidine,
{R)-4-[3-(Λ/,A/-dimethylamino)pyrroiidin-1 -yl3-2-[3-(2-oxo-pyrrolidirι-1- yl)phenyl]amine-7W-pyrroto[2,3-d3pyrimidine1
(R)-2-(3-acetylphenyi)amino-4-[3-(Λ/JW-dirnethyiamino)pyrrolidin-1 -yl]--7/-/- pyrrolo[2,3-d]pyrimidine, (R)-4-[3-(Λ/,N-dimethylamino)pyrroiidin-1-yl]-2-(3-isopropoxyphenyl)amine-7/~/- pyrrolo[2,3-d]pyrimidine,
(R)-4-[3-{W.,W-dimethylamino)pyrrolidin-1-yl]-2-(4-trifiuoromethylphenyl)amine-7H- pyrrolo[2,3-c/jpyrimidine,
(R)-4-[3-(W,A/-dimethyiamino)pyrrolidin-1-yl]-2-[(4-fiuoro-3-methoxy)phenyl]amine- 7H-pyrrolo[2,3-d]pyπmidine,
(R)-2-[(2,4-difiuoro-3-methoxy)phenyl]amino-4-[3-(W,/V-dimethyiamJno)pyrroiidin-1- yl]-7H-pyrro[o[2,3-d]pyrimidine, (R)-4-[3-(W,W-dimethylamino)pyrrolidin-1 -yl]-2-[3-(1 ,1 ,2,2- tetrafluoroethoxy)phenyI]amine-7H-pyrroϊo[2,3-c/]pyπmidine, fR)-2-(4-cyanophenyl)amino-4-[3-(Λ/,N-dimethyiamino)pyrrolidin-1-yl]-7H- pyrrolo[2,3-c/3pyrimidine, fR)-2-(3-cyano-4-fluoropheny!)amino-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidtn-1-yl]-7H- pyrrolo[2,3-d]pyrimjdlne,
(R)-4-[3-(Λ/,Λ/-dimethyiamino)pyrroiidin-1 -yi}-2-{3-methylsulfonylphenyi)amino-7H- pyrro Io [2 , 3-d] pyri m id tne ,
(f?)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1-y[]-2-[(3-methyisuiphany!)phenyl]am!no- 7H-pyrroio[2,3-d]pyrimtdine,
(R)-4-[3-{Λ/,Λ/-dimethylamino)pyrrolidin-1 -yl]-2-[{4-fluoro-3-methyi)phenyl]amino-
7H-pyrrolo[2,3-c/jpyrimidineI
(/?)-2-(Φter^butylphβπyi)amfno-4-[3-{Λ/,/V-dimethy[arnino)pyrroiidin-1-y[]-7H- pyrrolo[2,3-c/]pyπm(dine, (R)-2-[1 -(2H)-oxo-3,4-dihydronaphthaien~6-yi]amiπo-4-[3-(Λ/,/V- dimethylamino)pyrroitdin-1-yl]-7W-pyrrofo[2,3-c/jpynmidine,
(R)-4-[3-(Λ/,W~dimethyiamino)pyrroiidin-1-yl]-2-(2-oxo-1-methylindoline-5-yl)amine-
7H-pyrrolo[2,3-c/]pyπmidine,
(R)-4-[3-(Λ/}N-dimethy!amino)pyrro[idin-1 -yS]-2-(2-oxoindoline-5-yl)amino-7H- pyrroSo[2,3-d]pyrimidtne,
(R)-2-(4-cyc!opropyimethoxy-3-fluorophenyl)amino-4-[3-(W,/V- dimethyiamino)pyrrolidin-1-yi]-7H-pyrroio[2,3-c/]pyrimidine!
{R)-4-[3-(W,N-dsmethytamino)pyrroHdin-1-yl]-2-(4-ethoxycarbonySphenyl)amine-7H-
[2,3-cdpyrimidine, 2-(2H-2-methyl-3(4H)-oxobenzo[£)][1 ,4]oxacin-6-yl)amino-4-[3-(RHW,W- dimethySamino)pyrrolidin-1-yi]-7/-/~pyrroio[2!3-d]pyrimidine,
(R)-2-(2H-4-methyl-3(4H)-oxobenzo[b][1 ,4]-oxazin-6-yl)amino-4-[3-(W,/V- dimethyiamino)pyrroifdin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine,
(R)-2-(2H-3(4H)-oxobenzo[b][1 !4]-oxazin-6-yl)amino-4-[3-(Λ/,Λ/- dimethylamino)pyrrolidin-1-y!]-7f-/-pyrroio[2,3-d3pyπmidine!
(R)-4-[3~(Λ/!/V-dimethy!amino)pyrro[idin-1 -yi]-2-[4-(2~ methoxyethyl)aminosuifonylphenyl]amino-7H-pyrro!o[2,3-c/]pyrimidine, (R)-2-(3-aminosulfonyl-4-fiuorophenyi)amino-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidtn-1- yl]-7H-pyrro!o[2,3-of]pyπmidine,
(R)-4-[3-(Λ/,A/-dimethylamino)pyrrolidin-1-yi]-2-[4~({morpholin-4- yimethy!)carbonylamino)pheny[]amino-7H-pyrrolo[2,3-c/]pyrimJdine, (R)-4-[3-(Λ/,Λ/-dimethyiamino)pyrroltdin-1-yl]-2-(2-methylbenzoxazoi-6-yl}amino-
7H-pyrro!o[2,3-d]pyrimidine,
(R)-4-[3-(Λ/,W-dimethylamino)pyrrolidin-1-yl]-2-[3-(imidazo-1- ytmethyl)phenyl]amino-7H-pyrrolo[2,3-c/]pyπmidine,
(R)-4-[3-(Λ/,/V-dimethyiarnino)pyrro!idin-1-yi]-2-[4-(piperidin-1-yl)pheny!]amino-7/-/- pyrrolop.S-cfjpyrimsdine,
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrro!idin-1-y!]-2-[4-(2,6-dimethylmorphoiin-4- yl)phenyi]amino-7H-pyrrolo[2,3-d3pyrimidine,
(R)-4-[3-(/VJΛ/-dimethylamino)pyrrolidin-1-yl]-2-[3-fluoro-4-(2-(pyrroiidin-1 - yl)ethoxy)phenyl]amino-7H-pyrrolo[2,3-d]pyrimidine1 (R)-4-[3-(A/,W-dimethylamino)pyrrolidin-1 -yi]-2-[3-(2-hydroxyethy!)pheny[]amino-
7H-pyrrolo[2,3-c/jpyπmidine1
(/?)-2-[3-chloro-4-(morpholin-4-yl)phenyl]amino-4-[3-(Λ/,/V- dimethylamJno)pyrroiidin-1-y!]-7H-pyrrolof2,3-cf|pyrimidine,
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1 -yi]-2-[4-(2-hydroxyethyJ)pheny!]amino- 7H-pyrrolo[2!3-d]pyrimidine,
(R)-4-[3-(Λ/J/V~dimethy[amino)pyrroiidin-1 -yl3-2-[3-
(isopropyicarbonylamino)phenyl]amino-7H-pyrrolo[2,3-d]pyrimidine,
(R)-4-[3-(A/,/V-dimethylamino)pyrroiidin~1 -yl]-2~[4-{4-ethoxycarbonyipiperidin-1 - yl)phenyl]amino-7H-pyrroio[2,3-d]pyrimidine, (f?)-2-[4-(2-cyanoethylsulfonyi)pheny!]amtno-4-[3-(Λ/;Λ/-dimethyiamino)pyrroiidin-1- yl]-7H-pyrro!o[2,3-d]pyrimidine1
{/?)-2-[2,2-dimethyl-4H-3-oxopyrido[3,2-b][1 ,4]oxazin-7-yl]amino-4-[3-(Λ/,W- dimethylamino)pyrroiidtn-1 -yl]-7/-/-pyrroio[2,3-d]pyrimidine!
(R)-4-[3-(N,N-dimethylamino)pyrroiidin-1 -yl]-2-[1-(isopropyfcarbonyl)-indoline-5- y!]amino-7H-pyrrolo[2,3-d]pyrimidine,
(f?)-4-[3-(N,N-dimethyiamino)pyrroiidin-1-y!]-2-[1-(phenyisulfony[)-indoiine-5~ y[]amino-7H"pyrrolo[2,3-d]pyrimidine, (/?)-4-[3-(A/,Λ/-dimethyiamino)pyrroiidin-1-yl]-2-[(4- methy!aminosulfoπyimethy!)phenyi]amino-7/-/-pyrroloE2,3-d]pyrimiclin, (R)-2-[(4-cyclopentylsulfonyl)phenyl]amino-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1- yI]-7H-pyrro!o[2,3-d]pyrimidine, {R)-4-[3-(/V,Λ/-dimethyiamino)pyrroiid!n-1-yi]-2-[4-((2- hydroxyethyl)sulfonyf)phenyl]amino-7/-/-pyrrolo[2,3-c/lpyπmfdine, (R)-4-[3-(/V,W-dimethylamino)pyrrolidin-1-y]]-2-[(4-isopropylsulfony!)phenyl]arnino- 7H-pyrrolo[2,3--c(]pyrirnidine,
(R)-4-[3-(Λ/7/V-dimethylamino)pyrrolidin-1--yl]-2-[3~(hydroxymethy[)phenyi]amirio- 7H-pyrrolo[2,3-d]pyrimidine,
(f?)-4-[3-{/\/;N-dimethylamino)pyrrolidin-1-yl]-2-[4-(piperidiri-1 - ylmethyi)phenyi]amino-7H-pyrroio[2,3-d]pyrimidine,
(R)-4-[3-(Λ/,W-dimethylamino)pyrro!idin-1-yl]-2-[4-{4-hydroxypiperidin-1- ylmethyl)phenyi]amino-7H-pyrrolo[2,3-GGpyπmidine, (R)-2-t4-{4-acetylam!nopiperidin-1-ylrnethy!)pheny!3amino-4-[3-(Λ/,Λ/- dimethylamino)pyrrolidin-1 -yl]-7H-pyrrolo[2,3~cyjpyπmidine,
(R)-4-[3-(/V;Λ/-dimethy!amino)pyrrolidin-1-yI]-2-[4-(pyrroiidin-1- ylmethyOphenylJamino^H-pyrrolo^.S-djpyrimidine,
(R)-4-[3-{Λ/,/V-dimethylamino)pyrrolidin-1 -yl]-2-[4-(1 ,1-dioxothiomorphoIin-4- ySmethyOphenyljamino^H-pyrroiop^-cdpyπmidine,
4-[({3R)-A/7Λ/-dimethyiamino)pyrroifdin-1-yl]-2-E4-({3S)-methylpfperazin-1- yl)methyl)phenyi]amino- 7H-pyrro(o[2,3-c/|pyrimidine,
(R)-4-[3-{Λ/JΛ/-dimethylamino)pyrroiidin-1-y[]-2-[4-{4-methy![1 ,4]diazepan-1 -yl methy[)pheny!]amino-7H-pyrrolo[2!3-Qrlpyπm!dine! 2-[4-((R)-1 ,4-diazabicyclo[4.3.0]nonan-4-ylmethyl)phθnyl]amino-4-[(3R>(Λ/,Λ/- dtmethylamino)pyrro!idin-1-yi]-7H-pyrrolo[2,3-c/}pyrimidine!
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrroNdin-1 -yl]-2-[4-(imidazo-1 - ylmethylJphenyljamino^H-pyrrolop.S-djpyrimidine, fR)-4-[3-(Λ/,/V-dimethylamino)pyrroiidin-1-yl]-2-[4-(4-fluoropιperidin-1- ylmethyS)pheny!]amino-7H-pyrroSo[2i3-c(lpyrimidine,
(R)~4-[3-{/V,W-dtmethylamino)pyrrolidin-1-y!]-2-[4-(4-methoxypfperidin-1- ylmethyl)phenyl]amino-7H-pyrrolo[2,3-c']pyrimidine, (R)-2-(4-carboxyphθnyl)amino-4-[3-(Λ/,Λ/-dimethyIamino)pyrroiidin-1-yl]-7H- pyrrolo[2,3-d]pyrimidine,
(R)-4-[3-(/V,Λ/-dimethylamino)pyrrolidin-1-yl]-2-[4-(morphoiin-4- ylcarbony!)pheny!]amino-7H-pyrrolo[2,3-djpyrimidine, (/?)-4-[3-(Λ/,A/-dimethy!amino)pyrroiidin-1-yl]-2-[4-(4-methylpiperazin-1- ylcarbonyl)phenyl]amino-7H-pyrrolo[2,3-d]pyrimidine,
(f?)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1-yl]-2-[4-(piperidin-1- ylcarbonyi)phenyi]amino-7H-pyrroio[2,3-d]pyrimidine,
(R)-4-[3-(Λ/.W-dimethylamino)pyrrolidin-1-yI]-2-[4-(1 !1-dioxomorphoiin-4- yicarbonyl)phenyl]amino-7H-pyn-o!o[2,3-c/lpyrimiciine,
(R)-4-[3-(A/,A/-dimethyiamino)pyrrolidtn-1-yl]-2-[4-
(isopropylaminocarbonyl)phenyl3amino-7/-/-pyrrolof2,3-of]pyπmidine,
(R)-2-[4-(dimethyiaminocarbonyl)phenyl3amino-4-[3-(Λ/,Λ/- dimethylamino)pyrroiidin-1-y[]-7/-/-pyrrolo[2,3-c/]pyrimidine, (R)-4-[3-(W,Λ/-dimethylamino)pyrrolidin-1-yl]-2-[4-
(methylaminocarbonyi)phenyl]amtno-7H-pyrrolo[2,3-c/jpyrimidine,
(R)-4-[3-(Λ/,Λ/-dimethy!amino)pyrro[idin-1-yl]-2-[4~(piperazin-1- yimethy[)phenyi]amino-7H-pyrrolo[2,3-d]pyrimidine,
(R)~4-[3-(W,A/-dimethylamino)pyrroiidin-1"yt]~2-[3- (methy!sulfonyimβthy[)phenyf]amino-7H-pyrroio[2,3-cfjpyrimidine,
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1-yi]-2-[4-(piperidin-4- ylmethyl)phenyl]amino-7H-pyrrolo[2,3-c/]pyπmidine1
(/?)-4~[3-(/V,A/-dimethylamino)pyrroiidin-1-yi]~2-[4-(piperazin-1-yl)phenyl]amino-7W- pyrroio[2,3-d]pyrimidine, (R)-4-[3-(/VI/s/-dimethyiamino)pyrrolidin-1-yf]-2-[4-(2-morpholin-4- ylethyl)phenyl]amino-7H-pyrrolo[2,3-c/lpyrimidine,
(R)"2-[4-(4-carboxypiperidfn-1 -y!)phenyi]amino-4-f3-(A/,Λ/-dimethylamino)pyrro!idin-
1 -yl]- 7H-pyrroio[2,3-d]pyrimidine,
(/?)-4-[3-(WJΛ/-dimethylamino)pyrrolidin-1-yl]-2-[4-(4-methylaminocarbony!piperidin- 1 -yl)phenyi]amino-7H-pyrroio[2,3~d]pyrimidine,
(f?)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1-yi]-2-[4-(1-methyipiperidin-4- ylmethyI)phenyl]amino-7H-pyrrolo[2,3-c/]pyrimidine> (R)-4-E3-(Λ/,Λ/-dimethy!amino)pyrrolidin-1-yl]-2-[4-(1-methylsutfonyipiperidirι-4- yimethyi)pheny!]amino-7/-/-pyrrolo[2,3-c/]pyrimidine! and
(R)-2-[4-(1-acetyipipeπdin-4-ylmethyl)phenyi]amino-4-[3-(N?W- dimethyiamino)pyrrolidin-1-yl]-7H-pyrrolo[2,3-cdpyrimidine, or a sait thereof.
In another embodiment, the invention relates to a compound of formula E selected from:
{/?)-4-[3-(Λ/;W-dimethylamino)pyrrolidin-1-yl]-2-[(4-morpholin-4- ylmethyl)phenyl]ammo-7H-pyrrolo[23-c/]pyrimidine; (R)-4-[3-(Λ/JA/-dimethylamino)pyrroiidin-1-yl]-2-[4-(1 !1-dioxothiomorpholin-4- yl)pheny!]amino-7H-pyrrolo[2,3-c/3pyrimidine;
{R)-4-[3-(Λ/,W-dimethylamino)pyrrolidin-1 -yl]-2-(4-methytsulfonylpheny])amino-7H- pyrroio[2,3-c/]pyrirnidine;
(R)-4-[3-(Λ/,Λ/-dimethyiamino)pyrrolidin-1 -yf]-2-[3-fluoro-4-(morpholin-4- y!)phenyi]amino-7H~pyrroJo[2,3-d]pyrimidine;
(/?)-4-[3-{W,A/-dimethy[am!no)pyrrolidin-1-y[]-2-(2-isopropy[isoindolinone-5- y!)amino-7H-pyrrolo[2,3-c(]pyrimidtne;
(/^^-^-{SJ-sec-butylarninocarbonyO-i -rnethyipyrrole^-yflarnino^-IS-fWj/V- dimethy[amtno)pyrroiidin-1-yi]-7H-pyrrolo[2,3-c/]pyrimidine; {R}-4-[3-(N!W-Dimethyiamino)pyrrolidin-1--yl]-2-[2-(morpholin-4-y!methyl)thiophen-
4-y[]amino-7/-/-pyrrolo[2,3-c/|pyrimidine;
(R)-4-[3-(Λ/JΛ/-dimethylamino)pyrrolidin-1-y!]-2-t(3-dimethytaminosu!fony(methyl)-
(4-morpho!in-4-yI)pheny!]amino-7H-pyrrolo[2,3-d]pyrimidine;
(R)-2-[3-(azetidin-1 -yl)suifonylmethylρhenyl]amino-4-[3»(A/,A/- dimethyiamino)pyrrolidin-1-yi]- 7H-pyrroio[2I3-d]pyrimidine; and
(R)-4-[3-(Λ/,Λ/-dimethylamino)pyrroiidin-1-yl]-2-(3-methyiisothiazo[e-5-yl)amino-7H- pyrrolo[2,3-c(]pyrimidine, or a salt thereof.
In another embodiment, the invention relates to the compound (R)-4-[3- (WJW-dϊmethylarnino)pyrrolidin-1-yl]-2-[(4-morpholiπ-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-
(N,N»dimethylamino)pyrrolidin-1 -yl]-2-[4-(1 , 1 -dtoxothiomorphoHn-4- yi)phenyl]ammo-7H-pyrro!o[2,3-d]pyrimidine or a salt thereof. in another embodiment, 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. In another embodiment, the invention relates to the compound (R)-4-[3-
(Λ/,Λ/-dinnethyJamino)pyrrolidin-1 -yl]-2-[3-fiuoro-4-(morpholin-4-yl)phenyl]aminθ"7H- pyrrolo[2,3-c/jpyrimidine or a salt thereof.
In another embodiment, 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.
In another embodiment, the invention relates to the compound (R)-2-[2-(S)- sec-butylaminocarbonyl)-1"methyipyrrole-4-yl3amino-4-[3-(Λ/,Λ/- dimethylamino)pyrroiidin-1-yl3-7H-pyrrolo[2,3-c/]pynmidine or a salt thereof.
In another embodiment, the invention relates to the compound (R)-4-[3- (Λ/,N-dimethylamino)pyrrolidin-1-yi]-2-[2-(morpho[ϊn-4-yimethyl)thiophen-4- yl]amino-7H-pyrrolo[2,3-d]pyπmidine or a salt thereof,
Sn another embodiment, the invention relates to the compound (R)-4-[3- (Λ/JΛ/-dimethylamino)pyrrolidin-1-yl]-2-[(3-dimethylaminosu[fonyimethyl)-(4- morpholin-4-y!)phenyf]amino-7H-pyrroio[2I3-d]pyrimidine or a salt thereof. tn another embodiment, the invention relates to the compound (R}-2-[3-
(azetidin-1-yi)suifonySmethylphenyl]amino-4-[3-(NrN-dimethyiamino)pyrroiidin-1-yl]- 7H-pyrrolo[2,3-d]pyrimidine or a salt thereof.
In another embodiment, the invention relates to the compound (R)-4-[3- (Λ/,Λ/-dimethylamino)pyrroiidin-1 -yl]-2~(3-methylisothiazote-5-yl)amino-7H- pyrrolo[2,3-c/]pyπmidsne or a salt thereof.
In another embodiment, the invention relates to a compound of formula S which provides more than 50% inhibition of JAK3 activity at 10 μM, more preferably at 1 μM and still more preferably at 0.1 μM, 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. Examples of these 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. Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases. Examples of 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, Λ/-methylgiucamine, procaine and the iike.
There is no iimitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when they are used for therapeutic purposes. The term 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 salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid or base to give the salt in the conventional manner. The salts of the compounds of formula S can be converted into other salts of the compounds of formula S by ion exchange using ionic exchange resins.
The compounds of formula S and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention. All salts of the compounds of formula ! are included within the scope of the invention.
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. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula S or a salt thereof) and a solvent. Examples of 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. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of formula I. Optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them. The compounds of formula i can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups with conventional 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. M1 "Protecting Groups in Organic Synthesis", John Wiley & Sons, 3rd edition, 1999). As an example, as 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.
Unless otherwise stated, in the methods described below the meanings of the different substituents are the meanings described above with regard to a compound of formula !.
In general, compounds of formula i can be obtained in two steps by the method described in Scheme 1 :
Figure imgf000060_0001
III IV V
Scheme 1
Figure imgf000060_0002
wherein Cyi has the meaning previously described in relation with a compound of formula I. in a first step (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, K2CO3, Cs2CO3 or diisopropylethylamine, a solvent such as ethanol, tetrahydrofuran/H2O 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
IV and an amine of formuia V in the presence of a Pd catalyst such as Pd2(dba)3, a phoεphine such as 2-dicydohexylphosphino-2\4',6'-triisopropylbiphenyl, and a base such as potassium carbonate, in a solvent such as tert-butanol, and heating preferably at reflux to obtain a compound of formula ϊ. Alternatively, 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 0C to obtain a compound of formula I.
In certain instances, before conducting the reaction between the compounds of formula it and Ht, or IV and V, 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. When 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. When 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.
Furthermore, some compounds of the present invention can also be obtained from other compounds of formula S by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the standard experimentaS conditions. Said transformations can be carried out upon Cyi and include, for example: the reduction of a nitro group to give an amino group, for example by treatment with hydrogen, hydrazine or formic acid in the presence of a suitable catalyst such as Pd/C; or by treatment with sodium borohydride in the presence of NiCi2, or SnCI2; the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cya no borohydride or sodium tπacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionaliy in the presence of catalytic amounts of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or pyridine; the conversion of an amine into an amide, carbamate or urea under standard conditions; the alkylation of an amide by treatment with an alkylating agent under basic conditions; the conversion of an aScohoi into an ether, ester or carbamate under standard conditions; the alkylation of a thiol to give a thioeter under standard conditions; the partial or total oxidation of an alcohol to give ketones, aldehydes or carboxyiic acids under standard oxidizing conditions; the reduction of an aldehyde or a ketone to an alcohol by treatment with a reducing agent such as sodium borohydride; the reduction of a carboxyiic acid or a carboxyiic acid derivative to an alcohol by treatment with a reducing agent such as diisobutylaluminium hydride or LiAIH4;
** the reduction of an amide to an amine by treatment with a reducing agent such as LiAlH4; the oxidation of a thioeter to a sulfoxide or sulfone under standard conditions; the conversion of an alcohol into a halogen by reaction with SOCi2, PBr3, tetrabutylammonium bromide in the presence of P2O5, or PI3; the conversion of a halogen atom into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating; the conversion of a primary amide into a -CN group or vice versa, under standard conditions.
Likewise, 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.
Some of these interconversion reactions are explained in greater detail in the examples.
As it will be obvious to those skilled in the art, 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.
As mentioned above, 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).
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. et al, Transplantation 2005, 79(7):791-801 ; Paniagua R. et a!, Transplantation 2005, 80(9):1283-92; Higuchi T. et al, J. Heart Lung Transplant. 2005, 24(10): 1557-64; Saemann MD. et al, Transpl int. 2004, 17(9):481-89; Suva Jr HT. et al, Drugs 2006, 66(13):1665-1684).
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 aϋergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis (see e.g. Sorbera LA. et al, Drugs of the Future 2007, 32(8):674-680; O'Shea JJ, et a!, Nat. Rev. Drug. Discov. 2004, 3(7);555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Muiler-Ladner U. et al, J. Immunol. 2000, 164(7): 3894-3901 ; Walker JG. et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Milici AJ. et ai, Arthritis Rheum .2006, 54 (9, Suppϊ): abstr 789; Kremer JM. et al, Arthritis Rheum. 2006, 54, 4116, presentation no. L40; Cetkovic-Cvrlje M. et al, Arch Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82; Maiaviya R. et al, J. Pharmacol. Exp. Ther. 2000, 295(3):912-26; Maiaviya R. et al, J. Biol. Chem. 1999, 274(38):27028-38; Wilkinson B et al, Ann. Rheum. Dis. 2007, 66(SuppS 2): Abst. THU0099; Matsumoto M. et al, J. Immunol, 1999, 162(2):1056- 63).
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 alτ 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. et aS, Clin. Cancer Res. 1998, 4(10):2463-71 ; Lin Q. et al, Am J. Pathol. 2005, 167(4):969-80; Tibbies HE. et al, J. Biol. Chem. 2001 , 276(21 ):17815-22).
Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3, are weil known in the art. For example, 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. the method disclosed in Kudiacz E. et al, Am J. Transplant. 2004, 4(1 ):51-7, the contents of which are incorporated herein by reference), rheumatoid arthritis models such as collagen-induced arthritis (see e.g. the method disclosed in the assay of example 27), multiple sclerosis models such as experimentai autoimmune encephalomyelitis (EAE) (see e.g. the method disclosed in Gonzalez-Rey et al, Am. J. Pathol. 2006, 168(4): 1179-88, the contents of which are incorporated herein by reference) and transplant rejection models (see e.g. the various animal models disclosed in the references listed above in relation to the treatment of transplant rejection, incorporated herein by reference).
For selecting active compounds, testing at 10 μM 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 μM, and still more preferably, they should exhibit more than 50% inhibition at 0.1 μM.
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. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients. These 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. These 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.
For the rectal administration, 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 hydrophiϋc 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.
For the nasal administration or for inhalation, the compound 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.
The following examples illustrate the scope of the invention.
Examples
The following abbreviations have been used in the examples:
AcN: acetonitrile
BINAP: 2,2!-bisdiphenylphosphino-1 ,1 '-btnaphtyl d. doublet
DIPEA: W,Λ/-diisopropylethyJamine
DMAP: 4~(dimethylamino)pyridine
DME: 1 ,2-dimethoxyethane
DMF: Λ/,Λ/-dimethylform amide DMSO: dimethylsulphoxide
EDC: Λ/-[3-(dimethylamino)propyl-Λ/'-ethyicarbodiimide
EtOAc: ethyl acetate
EtOH: ethanol
HATU:o-(7-azabenzotriazol-1 -yl}-/V,Λ/,Λ/',ΛT- tetramethyluroniumhexafluorophosphate
HOBT: 1-hydroxybenzotriazole
HPLC: High Performance Liquid Chromatography
LC-MS: Liquid Chromatography-Mass Spectrometry m: muitipiet
MeOH: methanol
NMR: nuclear magnetic resonance
Pd2(dba)3: tris(dibenzylideneacetone)dipalladium (0) PyBOP: (Benzotriazol~1-yloxy)tripyrroiidinophosphonium hexafluorophosphate s: singlet
TEA: triethylamine
THF: tetrahydrofurane
TMS: tetramethyisyiane IR: retention time
X-Phos: 2-dicyciohexyiphosphino-2',4',6'-triisopropylbiphenyS
One of the following methods was used to determine the LC-MS spectrums:
Method 1 : Waters Acquity UPLC BEH C18 Column (1.7μm, 2.1 x 50 mm), temperature 40 0C, 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.
Method 2: YMC Column, 3 μm (50 mm x 4.6), temperature: 30 0C, flow rate: 2.6 mL/min, eluent A = H2O (0.1 % HCOOH) B = AcN (0.1% HCOOH), gradient: 0 min
5% B; 4.8 min 95% B; 6 min 95% B.
Method 3: Column Xbridge C18 (4.6 mm x 50 mm, 5μm), flow: 2.0 mL/min, eiuent: A = AcN, B = NH4HCO3 (pH=8), gradient: 0 min A 5%; 7 min A 100 %.
REFERENCE EXAMPLE 1 fRj-a-ChSoro-^S-CNjN-dimethyiaminoipyrrolidiπ-i-ylJ-TW-pyrrofoia^- αf]pyrimidine
1.2 g of (R)-3-{N, Λ/-dimethyiamino)pyrrolidine (10.6 mmol) and TEA (2.9 ml_, 21.2 mmoi) were added over a 2I4-dichloro-7W-pyrro!o[2I3-c/]pyrimidine solution (2.0 g,
10.6 mmol) in 1 ,4-dioxane (22 mL). The reaction mixture was stirred at reflux temperature for 18 h. The resulting mixture was allowed to cool to room temperature and the solvent evaporated to dryness. The crude product obtained was purified by column chromatography over silica gel, using CHCI3/MeOH mixtures of increasing polarity as eiuent, and 1.48 g of the desired compound were obtained (yield: 52%).
LC-MS (Method 1 ): tR = 1.41 min; m/z = 266 (MH+). REFERENCE EXAMPLE 2 fR)-2-Chϊoro-4-[3-(Λf,W»dimethy[amino)pyrrolidin-1-yl]-7-[(4-toiLfy!)suifony!ϊ- pyrτolo[2,3-d]pyrimidine a) 2,4-Dichloro-7-[(4-toiuyl)suJfonyI]-pyrro[o[2t3-d|pynmidine 6.39 g of NaH 60 % (158 mmol) were slowly added at 0 0C over a 2,4-dichloro-7H- pyrrolo[2,3-d]pyrimidine solution (15 g, 78.9 mmol) in THF (300 mL). The reaction mixture was stirred at room temperature for 1 h. After this time p-toluensulfonyl chloride (16.4 g, 86 mmoi) was added and it was stirred at room temperature for 18 h. The solvent was evaporated to dryness, the crude product was diluted with H2O and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and the solvent evaporated to dryness. The desired compound was obtained in quantitative yield and used without further purification. LC-MS (Method 1 ): tR = 2.72 min; m/z = 340 (MH"). b} Title compound The title compound was obtained following a procedure similar to that described in reference example 1 but starting from the compound obtained in the previous section (yield: 54 %), LC-MS (Method 1 ): tR = 2.44 min; m/z = 418 (MH").
REFERENCE EXAMPLE 3 (R)-4-[3-(Af,Af-Dimethyiamino)pyrrolidin-1-yll-2-E(4- hydroxymethyJ)phβnyfϊamϊno-7-[{4-toIuyl)suifonyi3-pyrrofo[2,3-dlpyrimidine 1.44 g of K2CO3 (10.47 mmoi), X-Phos (0.28 g, 0.47 mmol), Pd2(dba)3 (0.22 g, 0.23 mmol) and (4-aminophenyl)methanoi (0.70 g, 5.57 mmol) were added to a solution of reference example 2 (2.0 g, 4.76 mmol) in terf-butanol (71 mL). The reaction mixture was stirred under an Ar atmosphere at 100 0C overnight. The crude product obtained was diluted with MeOH and filtered over Ceiite®. The filtered solution was evaporated to dryness and purified by column chromatography over silica gel using CHCVMeOH mixtures of increasing polarity as eluent. 1.93 g of the desired compound were obtained (yield: 80%). LC-MS (Method 1): tR = 2.22 min; m/z = 507 (MH+).
REFERENCE EXAMPLE 4
4-Amino-W-[2-(1-methylpyrrolidin-2-yS)ethyI]benzenesulfonamide a) Λf-[2-(1-MethySpyrrolidm-2-yl)ethyl]-4-πstrobenzenesulfoπamide 1.0 g of 4-nitrobenzenesuifony! chloride (4.51 mmol) in THF (5 mL) were slowiy added at 0 0C over a solution of 2-(1-methylpyrroiidin-2~yl)ethylamine (3.2 mL, 27 mmol) in THF (23 mL). The reaction mixture was stirred at room temperature overnight. The crude product obtained was diluted with a saturated aqueous solution of NaCi and extract thrice with EtOAc. The combined organic phases were separated, dried over Na2SC>4 and the solvent was evaporated to dryness. 1.18 g of the desired compound were obtained (yield: 81 %). LC-MS (Method 2): tR - 1.33 min; m/z = 314 (MH+). b) Title compound 118 mg of 10% Pd/C were added to a solution of the compound obtained in the previous section (1.18 g, 3.76 mmol) in MeOH (38 mL). The reaction mixture was stirred under an H2 atmosphere at room temperature overnight. The crude product obtained was filtered over Celite® and the solution was evaporated to dryness. The desired compound was obtained in quantitative yield and used without further purification.
LC-MS (Method 2): tR = 0.75 min; m/z = 284 (MH+).
REFERENCE EXAMPLE 5 3-Fluoro-4-(nnorpho[ϊn-4-ylmethy[)phenyiarτiine a) 4-Bromomethyl-3-fSuoronitrobeπzene 6.97 g of /V-bromosuccinimide (39.15 mmol) and benzoyl peroxide (1.72 g, 7.11 mmol) were added to a solution of 2-fiuoro-4-nitrotoluene (5.52 g, 35.58 mmoi) in CCI4 (210 mL). The reaction mixture was stirred under irradiation by a 250 W lamp at reflux temperature for 18 h. The crude product obtained was cooled in an ice bath for 45 min and the solid formed was filtered. The filtered solution was evaporated to dryness. The desired compound was obtained in quantitative yield and used in next step without further purification. b) 3-Fiuoro-4-(morphofiπ-4-ytmethyS)nitrobenzene
2.3 g of K2CO3 (16.3 mmol) and morpholine (0.66 mL, 10.9 mmol) were added to a solution of the crude obtained in the previous section (1.53 g, 6.53 mmol) in acetone (6.5 mL), The reaction mixture was stirred at reflux temperature overnight. The crude product obtained was diluted with a saturated aqueous solution of NaCI and extract thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated to dryness. The crude product thus obtained was purified by column chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eiuent, and 480 mg of the desired compound were obtained (yield: 31 %). LC-MS (Method 1 ): tR - 1 ,83 min; m/z = 241 (MH+). c) Title compound
748 mg of SnCI2-2H2O (3.30 mmoϊ) in 37% aqueous HCI (0.9 mL) were added dropwise to a solution of the compound obtained in the previous section (202 mg, 0.841 mmol) in EtOH (1.8 mL). The reaction mixture was stirred at reflux temperature for 10 min. The crude product obtained was cooled to O0C, a 2 M KOH solution was added up to pH = 10 and it was extracted thrice with CHCI3. The combined organic phases were separated, dried over Na2SO4 and evaporated to dryness. The crude product thus obtained was purified by column chromatography over silica gel using EtOAc/MeOH mixtures of increasing polarity as eiuent, and 100 mg of the desired compound were obtained (yield; 57%). LC-MS (Method 1 ): tR = 1.17 min; m/z = 211 (MH+).
The following compound was obtained by following a similar procedure to that described in reference example 5, but using the corresponding starting compound:
Figure imgf000071_0001
REFERENCE EXAMPLE 6 5-Amino-1-isopropy!sulfonylindofine a) 1-isopropy!sulfonyf~5-πitroindoline
1 mL of TEA (7.61 mmol) and isopropylsulfonyl chloride (0.5 mL, 4.57 mmoi) were added at 0 0C to a solution of 5-nitroindoline (0.5 g, 3.05 mmol) in CH 2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 48 h and then at reflux temperature for 18 h. The crude product obtained was diluted with a saturated aqueous solution of NaHCOs and extracted thrice with CH2Cl2. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated to dryness. The desired compound was obtained in quantitative yield and used in next step without further purification. b) Title compound
0.47 g of Raney nickel solution in EtOH (9.62 mmoi) and hydrazine monohydrate (3 g, 72 mmol) in EtOH (3 mL) were added at 0 0C to a soiution of the compound obtained in the previous section {1.3 g, 4.81 mmoi) in EtOH (40 mL). The reaction mixture was stirred at 50 0C for 1 h. The crude product obtained was diluted with H2O and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and the soivent was evaporated to dryness. The desired compound was obtained in quantitative yieid and used in without further purification.
LC-MS (Method 2): tR = 1.00 min; m/z = 241 (MH+).
The following compounds were obtained by following a procedure similar to that described in reference example 6, but using in each case the corresponding starting compounds:
Figure imgf000072_0001
REFERENCE EXAMPLE 7 4-fsopropyfsulfonylphenyf amine a) i-fsopropySsuSphanyl-4-nitrobβnzene 0.69 g (7.09 mmo!) of sodium 2-propanethiolate were added to a solution of 1 - fluoro-4-nitrobenzene (0.80 g, 5.70 mmo!) in DMF (5 mL). The reaction mixture was stirred at 9O0C overnight. The solvent was then evaporated to dryness and the crude product was diluted with H2O and extracted thrice with EtOAc. The combined organic phases were separated and washed with 1 N NaOH, then with H2O and finaiiy with 1 N HCl. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated to dryness. The crude thus obtained was purified by column chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, and 816 mg (4.13 mmol) of the desired compound were obtained (yield: 72%). b) 1-fsopropyisulfony[-4-nitrobenzeπe
2.54 g of Oxone® (4.13 mmol) in water (26 mL) were added at 0 0C to a solution of the compound obtained in the previous section (816 mg, 4.13 mmol) in MeOH (26 mL). The reaction mixture was stirred at room temperature for 2 h. The crude product obtained was diluted with H2O and extracted thrice with CH2CI2. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated to dryness. The desired compound was obtained and used in the next step without further purification. c) Title compound The title compound was obtained with a quantitative yieid by following a similar procedure to that described in reference example 5, section c, but starting from the compound obtained in the previous section.
LC-MS (Method 1 ): tR = 1.22; m/z = 241 (MH+).
The following compound was obtained by following a similar procedure to that described in reference example 7, but using the corresponding starting compound:
Figure imgf000073_0001
REFERENCE EXAMPLE 8 4-CyciopentySsulfonytphβnyiarnine a) i-CyclopentylsulphaπyE-4-nitrobenzeπe
775 mg of K2CO3 (5.55 mmol), and cyclopentylmercaptane (579 mg, 5.55 mmol) were added to a solution of 1-fiuoro-4-nitrobenzene (800 mg, 5.55 mmol) in AcN (6 ml_). The reaction mixture was stirred at room temperature overnight. The crude product obtained was diluted with H2O and ethylic ether and the phases were separated. The organic phase was washed with 1 N NaOH, then with H2O and finally with 1 N HCl. The combined organic phases were separated, dried over Na2SO4 and evaporated to dryness. The desired compound was obtained and used in the next step without further purification. b) i-CyclopentyfsuIfonyf-4-nitrobeπzene
The title compound was obtained following a simiiar procedure to that described in reference example 7, section b, but starting from the compound obtained in the previous section. c) Title compound 11 mL of glacial acetic acid and 5% Pd/C (91 mg) were added to a solution of the product obtained in the previous section (915 mg, 3.37 mmol) in MeOH (2 mL). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 48 hours. The crude product obtained was diluted wilth MeOH, filtered over Celite® and evaporated to dryness. The crude thus obtained was purified by column chromatography over silica gel using CHCS3/MeOH/NH3 mixtures of increasing polarity as eluent, and 104 mg (0.46 mmol) of the desired compound were obtained (yield: 8%). LC-MS (Method 1 ): tR = 1.52; m/z = 226 (MH+). The following compound was obtained by following a procedure similar to that described in reference example 8, but using the corresponding starting compound:
Figure imgf000074_0001
REFERENCE EXAMPLE 9 5-Amino-2-fiuorobenzenesuffonamide a) 2-Fluoro-5-nitrobenzenesulfonamide
4.03 ml. of chlorosulfonic acid (60.33 mmol) were added at O0C dropwise for 5 min to 1-fiuoro-4-nttrobenzene (1.06 g, 7.54 mmol). The reaction mixture was stirred at 110 0C for 24 h. The crude product obtained was allowed to cool at room temperature and was siowiy added over water/ice mixture. The resulting aqueous phase was extracted thrice with diethyl ether, the combined organic phases were separated, dried over Na2SO4, and the solvent was evaporated to dryness. The reaction crude thus obtained was dissolved in EtOAc (38 mL), cooled at 0 0C and a 30% aqueous solution of NH3 (38 mL) was added. The resulting mixture was stirred between O0C and 50C for 4 h. The organic phase was separated and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were separated, dried over Na2SO4, and evaporated to dryness. The reaction crude thus obtained was purified by column chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, and 607 mg (2.76 mmoi) of the desired compound were obtained (yield: 37%). LC-MS (Method 1 ): tR = 1.11 ; m/z = 219 (MH'). b) Title compound
A 0.05 M solution of the compound obtained above (0.606 g, 2.75 mmol) in MeOH was hydrogenated using the H-cube® continuous flow hydrogenation reactor. The solution was pumped at a continuous rate of 0.8 mL/min through the hydrogenation reactor working in its "full hydrogen mode", corresponding to a pressure of 1 bar and a temperature of 25 0C. The solution was pumped through the catalytic cartridge of the appliance loaded with 10% Pd/C. The resulting solution was collected and the solvent was evaporated to dryness. 460 mg of the desired compound were obtained (yield: 88%). LC-MS (Method 1 ): tR = 0.50; m/z = 189 (MH").
REFERENCE EXAMPLE 10
3-(Λ/,W-Dimethylaminosulfonylmethyi)phenylarmne a) 3-(N,W-E3imethylaminosulfonyimethyl)nitrobenzeπe
668 mg of K2CO3 (4.83 mmol), and 2,0 M Λ/,Λ/-dimethylamine solution in THF (3,22 mL, 6,45 mmol) were added to a solution of (3- chiorosulfony!methyl)nitrobenzene (380 mg, 1 ,61 mmoi) in AcN (17 mL). The reaction mixture was stirred at 65 0C for 48 h. The crude product obtained was filtered and evaporated to dryness, and 282 mg of the desired compound were obtained (yield: 90%).
LC-MS (Method 1 ): tR = 1.67; m/z = 243 (MH"). b) Title compound
The title compound was obtained with 78% yield by following a similar procedure to that described in reference example S1 section c, but starting from the compound obtained in the previous section. LC-MS (Method 1 ): tR = 1.01 ; m/z = 215 (MH+).
The following compounds were obtained by following a similar procedure to that described in reference example 10, but using in each case the corresponding starting compounds:
Figure imgf000076_0001
Figure imgf000077_0001
REFERENCE EXAMPLE 11 4-[{1,1-Dioxothiomorphoϊin-4-y!}sulfony!]phenyEamine a) 1-[{1,1-Dioxothiomorphoiϊn-4-y!)suffony[3-4-nitrobenzeπe
55 mg of 4-dimethyiaminopyridine (0.45 mnnoϊ), TEA (1.25 mL, 9.02 mmol) and 4- nitrobenzenesuifony! chloride (1.0 g, 4.51 mmol) were added to a solution of 1 ,1 - dioxothiomorpholine (732 mg, 5.41 mmof) in CH2CI2 (45 mL). The reaction mixture was stirred at room temperature overnight. The crude product obtained was diluted with NaHCO3 saturated aqueous solution and extracted thrice with CHCI3. The collected solids were dried and 1.04 g of the intendeed compound were obtained (yield: 71 %). LC-MS (Method 1 ): tR = 1.60 min; m/z = 319 (MH+). b) Title compound
The title compound was obtained following a similar procedure to that described in reference example 5, section c, but using the compound obtained in the previous section (yield: 21 %). LC-MS (Method 1 ): tR = 1.01 min; m/z = 289 (MH").
REFERENCE EXAMPLE 12
Ethyl 4-amino-1 -cyclopentyImethyI-1 H-pyrrofo-2-carboxylate a) Ethyl 1-cyclopentyimethyS-4-nitro-1H-pyrrolo-2-carboxy!ate
261 mg (5.97 mmol) of sodium hydride were added at 0 0C to a solution of ethyl 4- nitro-1H-pyrrolo-2-carboxylate (1.00 g, 5.43 mmol) in DMF (8 ml_). The reaction mixture was stirred at room temperature 15 minutes, then 1.25 g (5.97 mmol) of iodomethylcyclopentane were added. The reaction mixture was stirred at 90 0C for 48 h. The solvent was then evaporated to dryness and the crude product thus obtained was diluted with NaHCO3 saturated aqueous solution and extracted thrice with CHCI3. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated to dryness. The crude product btained was purified by column chromatography over silica gel, using hexane/EtOAc mixtures of increasing polarity as eluent, and 842 mg of the desired compound were obtained, (yield: 58%). b) Title compound
20 mg of 50% Raney nickel solution in EtOH (0.114 mmol) were added to a solution of the compound obtained in the previous section (500 mg, 1.88 mmol) in THF/MeOH (1 :1 ) (4 mL). The reaction mixture was stirred under H2 atmosphere at room temperature overnight. The reaction mixture was filtered through a plug of Celite® and the solvent was evaporated to dryness. The desired compound was obtained and used in the next step without further purification.
REFERENCE EXAMPLE 13 4-Amino-1 -cyclopentyimethyi-2-fsobutylaminocarbonyl-1 H-pyrrole a) 4-Nitro-1-cycSopentylmethyl-2-isobutylaminocarbony!-1f/-pyrrole 2 mL (20 mmoi) of isobutylamine were added to the reference example 12 (108 mg, 0.406 mmoi). The reaction mixture was stirred at 100 0C for 48 h. The solvent was then evaporated to dryness and the crude product was diluted with H2O and extracted thrice with CHCI3. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated. The crude product thus obtained was purified by column chromatography over silica gel, using hexane/EtOAc mixtures of increasing poiarity as eluent. 80 mg of the desired compound were obtained (yield: 67%). b) Title compound
The title compound was obtained following a similar procedure to that described in reference example 12, section b, but using the compound obtained in the previous section. LC-MS (Method 1 ): tR = 1.96 min; m/z = 264 (MH+).
REFERENCE EXAMPLE 14
2-Amiπo-5-(morpho!sn-4-yfcarbonyf)thiophene trifluoroacetate a) 5-Carboκy-2-tø/t-butoxycarbonylaminothiophene
1.45 mL (10.4 mmol) of TEA, and 1.11 ml_ (5.2 mmol) of diphenylphosphory! azide were added to a solution of thiophene-2,5-dicarboxylic acid (895 mg, 5.2 mmol) in terf-butanoi (30 mL). The reaction mixture was stirred at 82 0C for 5 h. The solvent was then evaporated to dryness. The desired compound was obtained and used in next step without further purification. b) 2-fe/t-Sutoxycarbonylamino~5-(morphoIin-4-yfcarboπyf)thiophene
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%).
LC-MS (Method 1 ): tR = 1.71 min; m/z = 313 (MH+). c) Title compound
1 mL (13.1 mmol) of trifluoroacetic acid were added to a solution of the compound obtained in previous section (50 mg, 0.160 mmol) in CH2Ci2 (9 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was then evaporated to dryness, and the desired compound was obtained and used in next step without further purification.
LC-MS (Method 1 ): tR = 0.80 min; m/z = 213 (MH+).
REFERENCE EXAMPLE 15 2-Amino-5-methySarninocarbonylthiophene a) 5-Nitrothiopheπe-2-carbonyl chloride
2.89 mL (5.78 mmol) of 2.0 M oxaiyl chloride solution in CH2CI2 were added to a solution of 2-nitro-5-thiophene carboxylic acid (500 mg, 2.89 mmol) in THF (29 mL). The reaction mixture was stirred at room temperature for 4 h. The solvent was then evaporated to dryness, and the desired compound was obtained and used in next step without further purification. b) 2-Methylaminocarbonyϊ-5-nϊtro-thiophene 2.00 mL (11.56 mmol) of DlPEA, and 2.5 mL (4.33 mmol) of 2.0 M methylamine soiution in THF were added to a solution of the compound obtained in previous section (515 mg, 2,89 mmol) in CH2CI2 (19 mL). The reaction mixture was stirred at room temperature overnight. The crude product obtained was diluted with 1 M HCI aqueous solution and extracted thrice with CHCb. "The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated. 410 mg of the desired compound was obtained and used in next step without further purification (yield: 76%). c) Title compound
1 mL of 50% Raney nickel solution in EtOH (5.7 mmol) , and 0.80 mL (16.53 mmol) of hydrazine monohydrate were added to a solution of the compound obtained in previous section (205 mg, 1.10 mmoi) in EtOH (5 mL). The reaction mixture was stirred at 50 0C for 40 min. The reaction mixture was filtered through a plug of Ceiite® and the solvent was evaporated to dryness. The desired compound was obtained and used without further purification. LC-MS (Method 2): tR = 0.65 min; m/z = 157 (MH+).
REFERENCE EXAMPLE 16 5-Amino-2-isopropyfisoindofin-1-one a) 2-isopropyi-5-nitroisoindolin-1-one 0.23 mL (1.64 mmoi) of TEA, and 65 mg (1.09 mmol) of isopropyl amine were added to a solution of methyl 2-bromomethyl-4-nitrobenzenecarboxylate (300 mg, 1.09 mmol) in methanol (2.25 mL). The reaction mixture was stirred in a seaied tube at 100 0C for 2 h. After cooling the reaction mixture, the solid formed was filtered, washed with diethyl ether and dried. The desired compound was obtained and used in next step without further purification. b) Title compound
The title compound was obtained with 92% yield by following a similar procedure to that described in reference example 5, section c, but using the crude product obtained in the previous section, and using acetic acid instead of EtOH and concentrated HCI aqueous solution. LC-MS (Method 1 ): tR = 1.13; m/z = 191 (MH+).
The following compounds were obtained by following a similar procedure to that described in reference example 16, but using in each case the corresponding starting compounds:
Figure imgf000081_0001
REFERENCE EXAMPLE 17
6-Am!no-2-cyciopropy!«3,4-drhyclroisoquinofin-1(2W)-one a) β-Bromo-2-cyclopropyϊ-3!4-dihydroisoquino!in-1(2H)-one
0.93 mL (6.64 mmol) of TEA, 0.85 mL (10.6 mmol) of pyridine, 480 mg (2.7 mmol) of copper(ϋ) acetate, and 340 mg (4,0 mmol) of cyciopropyl boron ic acid were added to a solution of 6-bromo-3!4-dihydroisoquinolin-1 (2H)~one (300 mg, 1.33 mmol) in THF (13.3 mL). The reaction mixture was stirred at 70 0C for 7 days. The crude product was diluted with NaHCOs saturated aqueous solution and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 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 122 mg of the desired compound were obtained (yield: 35%). b) 2-Cycfopropyf-(6-N-diphenylmethyleneamino}-3,4-dihydroJsoquinolin-
1(2W)-one
61 mg (0.63 mmol) of sodium te/t-butoxide, 8 mg (0.008 mmol) of Pd2(dba)3, 16 mg (0.025 mmol) of BINAP, and 0.084 mL (0,50 mmol) of benzophenone imine were added to a solution of the compound obtained in previous section (112 mg, 0.42 mmol) in toluene (10.5 mL). The reaction mixture was heated to 80 0C overnight. The reaction crude thus obtained was diluted with EtOAc and filtered over Celite®. The filtered solution was concentrated to dryness, and the desired compound was obtained and used without further purification. c) Title compound
0.9 mL of 50% hydroxylamine aqueous solution (14.7 mmol), were added to a solution of the compound obtained in previous section (242 mg, 0.66 mmol) in methanol (1.8 mL). The reaction mixture was stirred at room temperature for 2 h.
The crude product was diluted with H2O and extracted thrice with CH2CI2. The combined organic phases were separated, dried over Na2SO4 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%).
LC-MS (Method 2): tR = 1.91 ; m/z = 203 (MH+).
REFERENCE EXAMPLE 18 5-Amino-2-(/V-terf-butoxycarbonySa2etidin-3-yi)isoindofinone a) 5-Nitro-2-(/V-fert-butoxycarbonylazetidiπ-3-y!)isoindolinone The title compound was obtained by following a similar procedure to that described in reference example 16, section a, but using terf-butyl 3- aminoazetidine-1-carboxyiate instead of isopropylamine. b) Title compound
1 mL of 50 % Raney nickel solution in EtOH (5.7 mmol) , and 0.30 mL (10.95 mmol) of hydrazine monohydrate were added to a solution of the compound obtained in previous section (243 mg, 0.73 mmo!) in EtOH (10 mL). The reaction mixture was at 50 0C for 40 min. The reaction mixture was filtered through a plug of Celite® and the solvent was evaporated to dryness. The desired compound was obtained in quantitative yield and used without further purification. LC-MS (Method 2): tR = 2.13; m/z = 304 (MH+).
The following compounds were obtained by following a similar procedure to that described in reference example 18, but using in each case the corresponding starting compounds:
Figure imgf000083_0001
REFERENCE EXAMPLE 19 5-Amino-1-isopropySsuIfonyl-1W-iπdole a) 1-lsopropyIsulfonyi-5-nitro-1W-indofe 2.12 mL (15.2 mmol) of TEA, 37 mg (0.30 mmo!) of DMAP, and 1.36 ml_ (12.2 mmoi) of isopropylsuifony! chloride, were added to a solution of 5-nitroindole in CH2Cb (100 mL). The reaction mixture was stirred at 50 0C for 48 h. The crude product was diluted with NaHCO3 saturated aqueous solution and extracted thrice with CH2Cl2. The combined organic phases were separated, dried over Na2SO4 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 eiuent, and 325 mg of the desired compound were obtained (yield: 20%). b) Title compound The title compound was obtained with 49% yield by following a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section. LC-MS (Method 1 ): tR = 1.70; m/z = 239 (MH+).
REFERENCE EXAMPLE 20 6-Amino-2-isopropyl-3,4-dihydroisoquiπoliπ-1(2H)-one a) 6-Bromo-2-isopropyl"3s4-dihydroisoquinoSin-1 (2H)-one 0.26 mL (2.76 mmoi) of 2-bromopropane, and 88 mg (2.2 mmol) of NaH were added to a solution of 6-bromo-3,4-dihydroisoquinoiin-1 (2H)-one (250 mg, 1.10 mmol) in DMF (2 mL). The reaction mixture was stirred at 100 0C overnight. The crude product was diluted with H2O and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 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 87 mg of the desired compound were obtained (yield: 29%). b) 6-Diphenylmethyleneamino-2-isopropyi-3,4-dihydroisoqu[nofin-1(2H}-one The title compound was obtained by following a similar procedure to that described in reference example 17, section b, but using the product obtained in the previous section. c) Title compund
The title compound was obtained by following a similar procedure to that described in 17, section c, but using the product obtained in the previous section. 1H NMR (200 MHZ, CDCI3) δ (TMS): 1.5 (d, 6H), 2.5 (m, 2H), 2.7 (m, 2H), 4.6 (m, 1 H), 6.5 (m, 2H), 6.9 (m, 1 H).
The following compounds were obtained by following a similar procedure to that described in reference example 20, but using in each case the corresponding starting compounds:
Figure imgf000084_0001
REFERENCE EXAMPLE 21
(3-N,N-Dϊmethy\am\no)sulfonyimethyl-4-(morphorm~4-yl}pheny\amϊne a) 1-(2-Fiuoro-5~nitrophenyl)methanesu!fonic acid
4.37 g (34.7 mmoi) of sodium sulphite were added to a solution of (2- bromomethyl)-1-fiuoro-4-nitrobenzene (8.11 g, 34.7 mmol) in H2O:AcN (6:4) (100 mL). The reaction mixture was stirred at room temperature overnight. The crude product obtained was evaporated to dryness. The desired compound was obtained and used in the next step without further purification. b) 1-(2-FSuoro-5-nitrophenyl)methanesulfontc chloride
2.05 g (9.85 mmol) of PCis were added to a solution of the compound obtained in previous section (2.5 g, 10.45 mmol) in POG3 (22 ml_). The reaction mixture was stirred at 115 0C overnight. The crude product was diluted at 0 0C with H2O and extracted thrice with CH2Cl2. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated. 1.52 g of the desired compound (yield: 29%) were obtained and used in the next step without further purification. c) N,N-Dϊmethyl 1-(2-fiuoro-5-nitrophenyI)methanesulfonarnide
0.785 mL (1.6 mmol) of dimethylamine solution 2.0M in THF were added at -20 0C to a solution of the compound obtained in previous section (300 mg, 1.25 mmo!) in
CH2CI2 (4 mL), The reaction mixture was stirred at room temperature for 30 min.
The crude product was diluted with 0.5 M HCl aqueous solution and extracted thrice with CH2CI2. The combined organic phases were separated, dried over
Na2SO4 and the solvent was evaporated. 224 mg of the desired compound (yield: 70%) were obtained and used in the next step without further purification. d) W, W-Dimethyl 1 ~(2-morphoiϊn-4-yl-5-nitropheny!)methanesulfonamide 0.50 mL (5.72 mmol) of morpholine were added to the compound obtained in previous section (224 mg, 0.855 mmol). The reaction mixture was stirred at 70 0C for 3 h. The reaction mixture was evaporated to dryness. The crude product thus obtained was purified by column chromatography over silica gel, using CH2Ci2/MeOH mixtures of increasing polarity as eluent, and 200 mg of the desired compound were obtained (yield: 71 %). e) Title compund
The title compound was obtained with quantitative yield by following a simiiar procedure to that described in reference example 4, section b, but using the product obtained in the previous section.
LC-MS (Method 1 ): tR = 1.38; m/z = 300 (MH+).
The following compounds were obtained by following a similar procedure to that described in reference example 21 , but using in each case the corresponding starting compounds:
Figure imgf000085_0001
Figure imgf000086_0001
^ pyrrolidine instead of morphoiine was used in section d
(b> piperϊdine instead of morphoiine was used in section d
<c) 2.0M dimethylamine solution in THF instead of morphoiine was used in section d
(d) section d was not performed
REFERENCE EXAMPLE 22 3-{Λ/-PropylsulfonySaminomethyf)phenylamine a) N-(3-nϊtrophenyImethy!)propanesuHbnamide
453 mg of propanesulfonyl chloride (3.18 mmoi) were added over a solution of (3- nitropheny[)methanamine hydrochloride (300 mL, 1.59 mmol) in pyridine (15 mL). The reaction mixture was stirred at room temperature overnight. The crude product was diluted with NaHCO3 saturated aqueous solution and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and the solvent was evaporated. 360 mg of the desired compound (yield: 88%) were obtained and used in the next step without further purification. b} Title compound
The title compound was obtained in 55% yieid by following a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section.
LC-MS (Method 1 ): tR = 1.37; m/z = 229 (MH+).
The following compounds were obtained by following a similar procedure to that described in reference example 22, but using in each case the corresponding starting compounds:
Figure imgf000087_0001
REFERENCE EXAMPLE 23 3-((3-Fluoroazetidin-1-y[su[fony!)methy!)phenylamine a) 3-Fluoro-1-(3-nitrobenzylsu!fony[)azetidine
The title compound was obtained in 74% yield by following a similar procedure to that described in reference example 10, section a, but using 3-fluoroazetidine instead of 2.0 M dimethyiamine solution in THF. b) Title compound
The title compound was obtained by following a similar procedure to that described in reference example 9, section b, but using the product obtained in the previous section. LC-MS (Method 1 ): tR = 1.65; m/z = 258 (MH+). The following compounds were obtained by following a similar procedure to that described in reference example 23, but using in each case the corresponding starting compounds:
Figure imgf000088_0001
REFERENCE EXAMPLE 24
4-[4-{2-Hydroxy-2-methyϊ-1-oxopropyl)pipera2in-1-ylmethy!]phenyiamine a) 4"[4~(2-Methyi-2-hydroxy-1-oxopropyl)piperazin-1-ylmethylJnitrobenzene
The desired compound was obtained following a similar procedure to that described in example 6, section a, but using 4-(piperazin-1~y!methy!)nitrobenzene and 2-hydroxyisobutyric acid instead of the corresponding starting materials. b) Title compound
The title compound was obtained by following a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section. LC-MS (Method 1 ): tR = 1.13; m/z = 278 (MH+).
REFERENCE EXAMPLE 25 4-{Morpholin-4-yI)-3-cyanomethylphenySamine a) 4-(Morphof!Si-4-yf}-3-cyanomβthyfπrtrobenzene
The desired compound was obtained foilowing a similar procedure to that described in example 4, but using 4-(morpholin-4-yi)-3-hydroxymethylnitrobenzene instead of reference example 3, and sodium cyanide instead of imidazole. b) Title compound
The title compound was obtained by following a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section. LC-MS (Method 1 ): tR = 1.33; m/z = 218 (MH+).
REFERENCE EXAMPLE 26 4-{1-Morpholin-4-ySethy!)phenyϊamine a) 4-{1-Bromoethyl)nitrobenzene
The desired compound was obtained following a similar procedure to that described in reference example 5, section a, but using 4-ethylnitrobenzene instead of 2-fluoro-4-nitrotouene. b) 4-(1-Morpholin-4-ytethyi)nitrobenzene
The desired compound was obtained following a similar procedure to that described in reference example 5, section b, but using the product obtained in the previous section. c) Title compound
The title compound was obtained by following a similar procedure to that described in reference example 6, section b, but using the product obtained in the previous section. LC-MS (Method 1 ): tR = 1.18; m/z = 207 (MH+).
REFERENCE EXAMPLE 27 (S)-4-{1-(Morphoiin-4-y!)ethyS)phenylamine a) (S)-4-{1 -(Morphof in-4-y!)ethyl)nitrobenzeπe
0.341 mL (2.71 mmoi) of 2-bromoethyi ether, and 1.51 mL (8.68 mmol) of TEA were added to a solution of 1-(S)-(4-nitrophenyl)ethylamine hydrochloride (440 mg, 2.17 mmol) in DMF (8 mL). The reaction mixture was stirred at 100 0C overnight. The reaction mixture was evaporated to dryness. The crude product thus obtained was purified by column chromatography over silica gel, using
EtOAc/MeOH mixtures of increasing polarity as eiuent, and 64 mg of the desired compound were obtained (yield: 12%). b) Title compound The title compound was obtained in 77% yieid by following a similar procedure to that described in reference example 4, section b, but using the product obtained in the previous section.
LC-MS (Method 1 ): tR = 1.18; m/z - 207 (MH+). REFERENCE EXAMPLE 28
Methyl 2-(4-amlnophenyl)-2-(morpholϊn-4-yl)acetate a) Methyl 2-chioro-2-{4-nitropheπyl)acetate
1.8 mL (17.9 mmol) of methyl 2,2-dichloroacetate, and 5.5 g (49 mmol) of potassium fe/t-butoxide were added at -150C to a solution of nitrobenzene (2.0 g, 16.25 mmol) in DMF (60 mL). The reaction mixture was stirred at -150C for 4 h. The crude product was diluted with 10% HCI aqueous solution and extracted thrice with CH2CI2. The combined organic phases were separated dried over Na2SO4 and the solvent was evaporated. 3.5 g of the desired compound (yieid: 94%) were obtained and used in the next step without further purification. b) Methyl 2-(4-nitrophenyl)-2-(morphoHn-4-yE)acetate
0.47 mL (5.4 mmol) of morpholine, and 0.4 g (1 ,09 mmol) of tetrabutylammonium iodide were added to a soiution the compound obtained in previous section (500 mg, 2.17 mmol) in toluene (5 mL). The reaction mixture was stirred at room temperature overnight. The crude product was evaporated to dryness. The crude product thus obtained was purified by column chromatography over sitica gel, using EtOAc/MeOH mixtures of increasing polarity as eiuent, and 255 mg of the desired compound were obtained (yield: 42%). c) Title compound The title compound was obtained in 75% yieid by foilowing a similar procedure to that described in reference example 6, section b, but using the product obtained in the previous section.
1H NMR (200 MHZ, CDCI3) δ (TMS): 2.4 (m, 4H), 3.67 <s, 3H)1 3.73 (m, 4H), 3,86 (s, 1 H), 6.64 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz1 2H).
REFERENCE EXAMPLE 29 3-(2-Methoxyethyl)suSfoπy!methyi-(4-morpholin-4-yS)phenylamine a) 1-Mitro-3-(2-hydroxyethytthiomethyl)-4-morpho!in-4-yϊbenzene The desired compound was obtained by following a similar procedure to that described in example 3, but using 3-hydroxymethy!-2-(rnorpholin~4-y[)-5- nitrobenzene and 2-mercaptoethano! as starting materials. b) 3-{2-Hydroxyethy[sulfonylmethyl}-4-(morphofin-4-yl}-1-nitrobenzene The desired compound was obtained (450 mg, 1.36 mmoi) (yield: 32%) by following a similar procedure to that described in reference example 7, section b, but using the compound obtained in the previous section. c) 3-(2-metboxyethylsulfony!methyl)-4-(morphotin-4-yl)"1-nitrobenzene
16 mL (16 mmoi) of 1 N NaOH aqueous solution were added to a solution of the compound obtained in the previous section (440 mg, 1.36 mmoi) in MeOH (36 mL). The reaction mixture was stirred at 100 0C overnight. The crude poduct was diluted in an H2O/CHCI3 mixture, the phases were separated and the aqueous phase was extracted with CHCI3. The combined organic phases were dried over
Na2SO4, filtered and evaporated to dryness, and 435 mg (1.26 mmoi) of the desired compound were obtained (yield: 85 %), d) Title compound
The title compound was obtained (175 mg, 0.55 mmo!) (yield: 44 %) by foliowing a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section. LC-MS (Method 1 ): tR = 1.27 min; m/z = 315 (MH+).
REFERENCE EXAMPLE 30 (3-!sobuty!suIfonyimetbyf)phenylamine a) (3-isobuty!thiomethyI)-1 -nitrobenzene
353 mg of NaHCO3 (4.19 mmoi), and 0.391 mL of 2-methyl-1 -propanethio! (3.49 mmoi) were added to a solution of 3-nitrobenzyl chloride (500 mg, 2.91 mmoi) in
MeOH (5 mL). The reaction mixture was stirred at 60 0C overnight. The solvent was evaporated to dryness and the residue was diluted with H2O and extracted thrice with CH2CI2. The combined organic phases were separated, dried over
Na2SO4 and evaporated to dryness. The desired compound was obtained and used in the next step without further purification (yield: 76%). b) (3-isobutylsulfonylmethy!)-1 -nitrobenzene The desired compound was obtained following a simifar procedure to that described in reference example 7, section b, but using the compound obtained in the previous section (yield: 79 %), LC-MS (Method 1 ): tR = 1.89 min; m/z = 256 (MH-). c) Title compound
The title 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. LC-IVIS (Method 1 ); tR = 1.45 min; m/z = 228 (MH+).
The following compounds were obtained by following a similar procedure to that described in reference example 30, but using the corresponding starting compounds:
Figure imgf000092_0001
REFERENCE EXAMPLE 31 3-!sobutyisuffonylmethyl-4-(morpholin-4-yi)phenyiamine a) 3-isobuty!thiomethyS-4-(morpholin~4-yl)-1~nitroben∑βne
The desired compound was obtained following a similar procedure to that described in example 3, but using 3-hydroxymethyl-2-(morpholin-4-yl)-5- nitrobenzene and 2-methyl-1 -propanediol as starting materials. b) 3-isobutyisulfony!methyl-4-(morpholin-4-yi)-1 -nitrobenzene
The desired compound was obtained following a similar procedure to that described in reference example 7, section b, but using the compound obtained in the previous section. LC-MS (Method 1 ): tR = 2.03 min; m/z = 343 (MH+). c) Title compound
The title compound was obtained following a similar procedure to that described in reference exampie 5, section c, but using the product obtained in the previous section (yield: 37%).
LC-MS (Method 1 ): tR = 1.63 min; m/z = 313 (MH+).
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:
Figure imgf000093_0001
REFERENCE EXAMPLE 32
3-Aminosu!fonylmethyS-(4-morpholin-4-yl)phenyIamine a) {2-FSuoro-5-nJtropheπyl)methanesulfonamide
39 ml_ of 0.5 N NH3 solution in dioxane were added at 0 0C to the compound obtained in reference example 21 , section b (391 mg, 1.63 mmol) in CH2Ci2 (3 mL). The reaction mixture was stirred at room temperature overnight. After 24 h and 72 h 30 mL (15 mmol) of 0.5 N NH3 solution in dioxane was added at 0 0C. The reaction mixture was stirred at room temperature overnight and 1 N HCl aqueous solution (60 rnL) was added. The phases were separated and the aqueous phase was extracted twice with CH2Ct2. The combined organic phases were separated, dried over Na 2SO4 and evaporated to dryness. 307 mg of the desired compound were obtained (yield: 56%). b) 2-{MorphoHn-4-yiH5-nitrophenyl}methanesulfonamide
0.15 mL of morpholine (1.71 mmo!) were added to the product obtained in the previous section (150 mg, 0.64 mmol). The reaction mixture was heated at 120 0C for 2 h. The crude poduct was evaporated to dryness and purified by column chromatography over silica gel using CH2CI2/MeOH mixtures of increasing polarity as eiuent, 105 mg (0.35 mmol) of the desired compound were obtained (yield: 54%). c) Title compound
The title compound was obtained following a similar procedure to that described in reference example 9, section b, but using the product obtained in the previous section at 30 0C (54 mg, 0.199 mmol) (yield: 57%). LC-MS (Method 1 ): tR = 0.92 min; m/z = 272 (MH+).
REFERENCE EXAMPLE 33
3-Acetylamino~(5-methy(suIfonylmethyl)phenylamine a) 3,5-Dinitromethyisulfonylmethylbenzene 1.032 g of methanesuiphinic acid sodium salt (10.12 mmol) were added to a solution of 3,5-dinitrobenzyl chloride (730 mg, 3.37 mmo!) in MeOH (8 mL)..The reaction mixture was stirred at 65 0C for 2 h. The reaction crude was diluted with H2O and extracted thrice with CHCI3. The combined organic phases were separated, NaHCO3 saturated aqueous solution. The desired compound was obtained and used in next step without further purification (yield: 96%). b) 3-{Methyisulfonylmethyf}-5-πϊtropheny!amine
2.45 ml of 20% ammonium sulphide aqueous solution (7.20 mmol) were added to a solution of the compound obtained in the previous section (625 mg, 2.40 mmol) in MeOH (30 mL). The reaction mixture was srirred at 100 0C for 5 h. The reaction crude was cooled and the solid formed was filtered. 2M HC! aqueous solution was added up to pH = 1 , The solution was diluted with NaHCO3 saturated aqueous solution and extracted thrice with Et2θ. The combined organic phases were sparated, dried over Na 2SO4 and evaporated to dryness. The crude product thus obtained was purified by column chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent and 381 mg (1.65 mmol) of the desired compound were obtained (yield: 69%). c) 3-Acety!amino-(1-methy[suifonyϊmethyf}"5-nitrobenzene 9 mg of DMAP (0.07 mmol), 0.138 mL of DIPEA (0.78 mmol), and 0.05 mL of acetyl chloride (0.71 mmol) were added to a solution of the compound obtained in the previous section (150 mg, 0.65 mmol) in CH2Cl2 (6 mL). The reaction mixture was stirred at room temperature for 72 h. The crude poduct was diluted in a H2OZCH2CI2 mixture and NaHCO3 saturated aqueous solution was added up to pH = 8. The solid formed was filtered and dried, and 108 mg of the desired compound were obtained (yield: 61 %). cf) Title compound
The title compound was obtained following a similar procedure to that described in reference example 6, section b, but using the product obtained in the previous section {62 mg, 0.25 mmol) (yield: 65%). LC-MS (Method 1 ): tR = 0.46 min; m/z = 243 (MH+).
REFERENCE EXAMPLE 34 5-Fluoro-{3-methylsuIfonyImethy!)phenylamine a) 5-F!uoro-(3-hydroxymethy!)-1-nitrobenzene
1 ,29 ml_ of 2.0 N BH4Li solution in THF (2.58 mmol) were added to a soiution of ethyl 3-fiuoro-5-nitrobenzoate (50Qmg, 2.35 mmol) in Et2O (5 mL). The reaction mixture was stirred at room temperature for 2h. The crude product was diluted in
1 N HCI aqueous solution and the aqueous phase was extracted thrice with Et2O.
The combined organic phases were separated, dried over Na2SO4, and evaporated to dryness. The crude product thus obtained was purified by column chromatography over siiica gel using hexane/EtOAc mixtures of increasing polarity as eluent and 355 mg (2.07 mmol) of the desired compound were obtained (yieid:
74%). b) 5-Fluoro-3-nitroben∑yi bromide
707 mg of triphenylphosphine (2.69 mmol), and 1.03 g of CBr4 (3.11 mmol) were added to a solution of the compound obtained in the previous section (355 mg,
2.07 mmol) in CH2CI2 (5 mL). The reaction mixture was stirred at room temperature for 3 h. The crude product thus obtained was evaporated to dryness and purified by column chromatography over silica gel using CH2CI2/MeOH mixtures of increasing polarity as eiuent. 356 mg (1.52 mmol) of the desired compound were obtained (yieid: 73%). c) 5-Ffuoro-(3-methySsulfonyimethyf}-1 -nitrobenzene
The desired compound was obtained with quantitative yield following a similar procedure to that described in reference example 34, section a, but using the product obtained in the previous section. d) TitSe compound
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%). LC-MS (Method 1 ): tR = 0.99 rnin; m/z = 204 (MH+).
REFERENCE EXAMPLE 35 3-Acetyiamino-(4-morpho!in-4-yl)phenyiamine a) 2-Fluoro-5-nitro-1 -acetylaminobenzene Following a similar procedure to that described for reference example 34, section c, but using 2-fluoro-5~nitroaniline as starting material, the desired compound was obtained (223 mg, 1.12 mmol) (yield: 57%). b) 1-Acety!amino-(2-Morpholin-4-yf)-5-nitrobenzene
The desired compound was obtained following a similar procedure to that described in reference example 8, section a, but using the product obtained in the previous section (115 mg, 0.43 mmol) (yield: 86%). c) Title compound
The title compound was obtained with quantitative yield following a similar procedure to that described in reference example 6, section b, but using the product obtained in the previous section (102 mg, 0.43 mmol). LC-MS (Method 1 ): tR = 1.10 min; m/z = 236 (MH+).
REFERENCE EXAMPLE 36
S^WjW-DimethySaminomethylJ^morphoiin^-ylJphenyiamine a} {2-(Morpho[iπ-4~yl)-5-nϊtrophenyl}methanesulfonfC acid 0.81 mL of morphoϋne (9.35 mmol) were added to a solution of the product obtained in reference example 21 , section a (1.0 g, 4.25 mmoi) in DMSO (4 mL). The reaction mixture was heated at 100 0C for 4h. The reaction crude obtained was diluted with a Et2O/EtOAc mixture and the solid formed was filtered and dried. 1.10 g of the desired compound were obtained (yield: 90%). b) (3-chloromethyl)-4-(morphαIϊn-4-y!)-1 -nitrobenzene
1.41 mL of SOCI2 (19.35 mmol) were added to a solution of the product obtained in previous section (650 mg, 2.15 mmol) in CH2CI2 (50 mL). The reaction mixture was stirred at room temperature overnight. The reaction crude was dissolved in H2O and the aqueous phase was extracted thrice with CH2CI2.. The combined organic phases were separated, dried over Na2SO4 and evaporated to dryness. The desired compound was obtained and used in the next step without further purification. c} 3-{W,W-Dimethyfaminomethyl)-4-{morphofin-4-yl)-1 -nitrobenzene The desired compound was obtained in 56% yield following a similar procedure to that described for reference example 21 , section c, but using the compound obtained in previous section. c) Title compound The title compound was obtained with quantitative yield (49 mg, 0.20 mmol) following a similar procedure to that described in reference example 5, section c, but using the product obtained in the previous section.
LC-IvIS (Method 1 ): tR = 0,97 min; m/z = 237 (MH+),
REFERENCE EXAMPLE 37 3-Gyanomethylphenylaminβ
The title compound was obtained (212 mg, 1.60 mmol) (yield; 86 %) by foStowing a similar procedure to that described in reference example 5, section C5 but using 2-
(3-nitropheny!)acetonitrile as starting compound.
LC-MS (Method 1 ): tR = 1.11 min; m/z = 131 (MhT). EXAMPLE 1
(R)-4-[3-(/V,N-dimethyiamino)pyrroisdfn-1-yl]-2-[(4-morphoSin-4- ylmethyl}phenyl]amino-7H-pyrrolo[2,3-£flpyr«midine
The title compound was obtained foliowing a similar procedure to that described in reference example 3, but using reference example 1 instead of reference example 2 and 4-(morρholin-4-ylmethyS)phenylamine instead of (4-aminophenyl)methanol
(yield: 51 %).
LC-MS (Method 1 ): tR = 1.72 mm; m/z = 422 (MH+).
The following compounds were obtained by following a similar procedure to that described in example 1 , but using in each case the corresponding starting compounds:
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
(R)-4-[Z-(N,N- dιmethylamιno)pyrrolιdιn-1 -yl]-2-bu reference
[Λ/-(2-pyrrolidιn-1- 1 53 475 example 16a yϊethyi)isoindoitnone-5-yl]arnιrιo-
7H-pyrrolo[2,3-cθpyπmιdιne
(R)-A-[Z-(N1N- dιmethyiamιno)pyrrolιdιn-1 -yi]-2-bv [N-(2,2-dιmethy!-1 - reference
1 95 464 hydroxypropan-3-yl)isotndo[snone- example 18a
5-y!]amιπo-7f/-pyrroIo[2,3- cflpynmidine
(R)-A-[Z-(N, N- dimethylamino)pyrrolidin-1-yl]-2-bw [W-(2,2,2- reference
1 87 460 trifluoroethyl)isofndolinone-5- example 16b yl] amino-7 H-py rrolo[2 , 3- c/jpyπmidine
(R)-4-[3-(W,W- dsmethylamino}pyrrolιdιn-1-yl]-2-bx [W-(3- reference
1 62 436 hydroxypropy!)isoιπdoiιnone-5- example 18b yi]amino-7W-pyrrolo[2,3- cdpyrimidine
{R)-4-[3-(N,W- dιmethyiamιno)pyrro!ιd!n-1-yl]-2-by reference
{/V-ført-butylisoindolιrione-5- 1 95 434 example 16c yl)amιno-7H-pyrrolo[2,3- cf]pyrιmιd[ne
(R)-4-[3-(N,N- dιmethy!amιno)pyrrolsdtn-1-yi]~2-bz reference
{1-ιsoρropylsu!fonylιndole-5- 2 17 468 example 19 yl)amιno-7W-pyrrolo[2,3- c/]pyrιmιdιne
(R)A-[Z-(N, N- dimethylamιno)pyrrolιdιn-1-yi]-2-ca reference
(Λ/-methyi-3,4- 3 05 406 example 20a dshydrofSoquιnolιnone-6-yl)amino- 7H~pyrrolo[2,3-c/]pyrfmtdιne
Figure imgf000108_0001
(R)-A-[Z-(N1 N- d!methylamjno)pyrrolιd[n-1-y[]-2-cι reference
[3-dιmethyiamιnosυlfonylmethyl- 2 24 513 example 21 d
4-(pyrro!fdin-1-yl)phenyi]am)no-
7/7-pyrrolo[2,3-rf]pyrtmrdιne
(R)-4-[3-(N,N- dimethylamιno)pyrroltd!n-1-yl]-2-cj reference
[3-{4-methylpιpeπdιn-1 - 2.25 498 example 10b ylsulfonylmethyl)pheny[]amιno-
7H-pyrrolo[2(3-c/]pyrιm]dιne
(R)-2-[3-(N-cyclopropyl-W- methylammosulfonylmethyl)pheny ck reference l]amιno-4-[3-(Λ/,W- 1.94 471 example 10c d!methyiamjno)pyrrolιd!n-1-yl]-7W- pyrrolo[2,3-c(|pyπmιdιne
(R)-4-l3-(N,N- d!methylamιno)pyrrolιdιn-1-yl]-2-cl reference
[3-{2-(R)-methylpyrrolιdιn-1 - 2 02 484 example 10d ylsulfonyimethyl)phenyl]am!no-
7H-pyrrolo[2,3-d]pyπmιdιne
(R)-4-[3-{N,N- d!methylamιno)pyrrolιdfn-1-yl]-2-cm [3-(Λ/-(2-methoxyethyl }-W- reference
1 88 486 methylamιnosuifonylmethy[)pheny example 1 Oe l]amιπo-7W-pyrroio[2,3- djpyπmidsne
(R}-4-[3-(/V,/V- d(methylam!no)pyrroiιdιn-1-yl]-2-cn reference
[3-(3-(S)-hydroxypyrrolιd!n-1 - 1 59 486 example 10f yisulfonylmethyi)phenyl]arnιno~
7H-pyrrolo[2,3-c/]pyrjmidine
(R)-4-[3-(N,N- d!methyiamιno)pyrroiιdtn-1-yl]-2-co reference
[3-(3-{/?}-hydroxypιperidin-1 - 1 70 500 example 10g ylsulfonylmethyl)phenyl]amιno-
7W-pyrrolo[2,3-c()pyrιm!dine
_L
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
EXAMPLE 2
(/?}-4-[3-(W,W-Dimethylamino)pyrroiidin-1-yi]-2-{(4- methylarn»nosulfonylrnethyl)ρhenyi]amino-7H-pyrroϊo[2,3-d]pyrimidine a) (RH-[S-(W, W-Dimethylamino)pyrro!idin-1 -y[]-2-[(4- methylaminosulfonylmethyO-pheπyllamino-Z-^-toitiySJsuJfoπyfJ-pyrroiop^- c([pyrimidine Following a similar procedure to that described in example 1 but using 1-(4- aminopheπyl)-/V-methyImethanesulfonamide instead of 4-(morpholin-4- y!methy!)phenyjamiπe, and using reference example 2 instead of reference exampfe 1 , the reaction crude product thus obtained was used directly in the next step without further purification. LC-MS (Method 1 ): tR = 2,30; m/z = 584 (MH+). b) Title compound
9 ml_ of 1 N NaOH solution were added to a solution of the product obtained in the previous section (211 mg, 0.36 mmoi) in MeOH (22 mL), The mixture was stirred at reflux temperature for 3 hours. The crude product was concentrated to dryness and it was purified by column chromatography over silica ge! using EtOAc/MeOH mixtures of increasing polarity as an eluent, providing 49 mg of the desired compound (yield: 32%). LC-MS (Method 1 ): tR = 1.57; m/z = 430 (MH+).
The following compounds were obtained by following a similar procedure to that described in example 2, but using in each case the corresponding starting compounds:
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
EXAMPLE 3
(R}-4"[3-{Λ/,Λ?-dimethyiamino)pyrrolϊdin-1-yl]-2-[4-{pipeπd!n-1- ylmethy!)phenyi]amino-7H-pyrrolo[2,3-c0pynmidine 0.024 mL of thionyl chloride (0.328 mmol) were added to a solution of example 1a (50 mg, 0.142 mmol) in CHCi3 (4 mL}. The reaction mixture was stirred at 6O0C for 1 h. The crude product was evaporated to dryness. The reaction crude thus obtained was dissolved in CHCl3 (2 mL) and then piperidine (0.080 mL, 0.809 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The components of the mixture were evaporated to dryness and the reaction crude obtained was purified by column chromatography over silica gei using CHCi3/MeOH/NH3 mixtures of increasing polarity as eluent, providing 42 mg of the desired compound (yield: 71 %). LC-MS (Method 1 ): tR = 1.62 min; m/z = 420 (MH+).
The foilowing compounds were obtained by following a procedure similar to that described in example 3, but using in each case the corresponding starting compounds:
Figure imgf000119_0001
Figure imgf000120_0001
The reaction mixture was stirred at room temperature for 18 h.
EXAMPLE 4
(/?}-4-[3-{Nf/V-0imethyIamino}pyrrofidin-1-yi]-2-[4-(imic!azo-1- yimethyf)phenyl]amino-7H-pyrrolo[2,3-oOpyrimidine 0.030 mL of thiony! chloride (0.415 mmoS) were added to a solution of reference example 3 (100 mg, 0.197 mmol) in CHCI3 (5 mL). The reaction mixture was stirred at 6O0C for 1 h. The reaction crude obtained was evapporated to dryness, it was dissolved in CHCI3 (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 8O0C 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 CHCI3. The combined organic phases were separated, dried over Na2SO4ϊ and the solvent was evaporated to dryness. The crude product obtained was purified by column chromatography over silica gel using CHCVMeOH mixtures of increasing polarity as eluent, providing 10 mg of the title compound (yield; 13%). LC-MS (Method 1 ): tR = 1.60 min; m/z = 403 (MH+).
The following compounds were obtained by following a procedure similar to that described in example 4, but using in each case the corresponding starting compounds:
Figure imgf000121_0001
isopropanol was used instead of methanol in the last step of the procedure.
EXAMPLE 5
(^^-{^CarboxyphenylJamsno-^P-CWjW-dimethytaminoJpyrrolidin-i-ySl-TH- pyrrolo[2,3-£/]pyπmidine 106 mg of LiOH-H2O (2.5 mmol) in H2O (1.5 mL) were added to a solution of example l ap (200 mg, 0.50 mmo!) in DME (1.5 mL). The solution was stirred at room temperature for 72 h. A 1 N HCI solution was added at O0C up to pH = 4 and was extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and concentrated to dryness, providing 218 mg (yieid: 41 %) of the desired compound.
LC-MS (Method 2): tR = 1 ,05 min; m/z = 367 (MH+).
EXAMPLE 6 (R)-4-[3-{N,W-Dimethylamino)pyrrolidin-1-yl]-2-[4-(morpholin-4- yicarbonyS)phenyl]ammo-7H-pyrrolo[2,3-αf|pyrimidiπe 31 mg of HBOT (0.23 mmo!) were added to a solution of example 5 (56 mg, 0.15 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 1 h. 43 mg of EDC (0.23 mmoi) and morpholine (0.02 mL, 0.23 mmol) were added, and the mixture was stirred at room temperature overnight. The crude product obtained was evaporated to dryness and purified by column chromatography over silica gel using CHCVMeOH mixtures of increasing polarity as efuent. The obtained product was then partitioned between CHCi3 and a saturated soiution of NaHCO3 The combined organic phases were dried over Na2SO4 and concentrated to dryness, providing the desired compound (yield: 60%). LC-MS (Method 2): tR - 1.00 min; m/z - 436 (MH+).
The following compounds were obtained by following a procedure similar to that described in example 6, but using in each case the corresponding starting compounds:
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
"reaction ussπg PyBOP and DlEA instead of EDC and HOBT
EXAMPLE 7
(ff}-4-[3-(Λ/,Λ/-D!methyIamino)pyrroIidiπ-1"yf]-2-{4-(piperaziπ-1- ylmethyI)phenyl]amino-7H-pyrrolo[2,3-d]pyrimidine a) {/?)-2-[4-({4-ført-butoxycarbonyf)piperazϊπ-1-ylmethyi)phenyE]amino-4-[3-
{WjW-dϊmethylamϊnoJpyrroiidin-i-yil-TH-pyrrolo^jS-cflpyrimJdJne
Following a procedure similar to that described for example 4, but using N-tert- butoxycarbonylpiperazine instead of imidazole, and using isopropanol in the last step instead of methanol, the desired compound was obtained with quantitative yield.
LC-MS (Method 1 ): tR = 2.26 min; m/z = 521 (MH+). b) Title compound 8 ml_ of 4 M HCl solution in dioxane were added to a solution of the compound obtained in the previous section (200 mg, 0.384 mmo!) in MeOH (2 ml_). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to dryness and the reaction crude obtained was diluted with 0.5 N NaOH aqueous solution and was extracted thrice with EtOAc. The combined organic phases were separated, dried over Na 2SO4 and concentrated to dryness, providing 25 mg of the title compound (yield: 13%). LC-MS (Method 1 ): tR = 1.36 min; m/z = 421 (MH+).
EXAMPLE 8 (W)-4-[3-(Λ/,A/-dimethylamino)pyrrolϊdin-1-y[]-2-[3- (methylsuifonylmethyl)pheny[]amino-7W~pyrroIo[2,3-cf[pynmidine a) (R)-4-[3-(Λf,W-Dimethyfamino)pyrroiidin-1-yj]-2-i(3- hydroxymethyl)phenyi]amino-7-[(4-toluyi)sulfony[|-pyrroio[2,3-d|pynmidline Following a procedure similar to that described in reference example 3, but using (3-aminophenyl)methano! instead of (4-aminopheny!)methanol, the desired compound was obtained (yield: 35%).
LC-MS (Method 1 ): tR = 2.27 min; m/z = 507 (MH+). b) (R)-4^3K Af,W-Dimethyiamino)pyrrof idin-1 »y !}-2-[3- (methyIsuifonylmethy!)phenyI]-arnino-7-[(4-toluyl)sulfonyl3~pyrrolo[2,3- cfjpyrimidiπe 0.043 mL of TEA (0,309 mmol) were added to a solution of the compound obtained in the previous section (76 mg, 0.151 mmol) in CHCI3 (1.5 mL). The mixture was cooled at O0C and methanesulfonyl chloride (0.025 mL, 0,321 mmol) was added. The mixture obtained was stirred at room temperature for 1 h. The solvent was evaporated to dryness. The crude product was dissolved in DMF (3 mL) and sodium methanesuiphinate was added (300 mg, 2.94 mmol). The mixture was stirred at 6O0C for 18 h. The solvent was evaporated to dryness and the reaction crude thus obtained was used in next step without further purification. c) Title compound Following a procedure similar to that described in example 2, section b, but starting from the compound obtained in the previous section, 6.63 mg (yield: 11 %) of the title compound were obtained. LC-MS (Method 1 ): tR = 1.56 min; m/z = 415 (MH+). EXAMPLE 9
{/?)-.4-[3-(W,Λ/-Dϊmethylamino)pyrro!idin-1-yl}-2-[4-(piperidin-4- y!methyf)phenyI3amino-7W-pyrrolo[2f3-d}pyrimidine a) (/?)-4-[3~(/V,Λ/-Dimethylamϊno)pyrroisdin-1-y!l-2-[4-(1-ferf-butoxycarbony[- piperidine-4-ylmethy[)phenyiJamino-7-[(4-toluyl)suffonyI]pyrroio[2,3- cfjpyrimϊdiπe
Following a procedure simiiar to that described in reference example 3, but starting from 4-(Λ/-tørt-butoxycarbonylpiperidin-4-yl)methylphenylamine instead of (4-aminophenyi)methanoi, the desired compound was obtained and used in the next step without further purification. b) (/?}-4-[3-(/V,W-Dimethylamino)pyrrofidin-1-y[3-2-[4-{1-te/i-butoxycarbonyS- prperidiri-4-yJmethy{}phenyllamino-7H-pyrroio[2,3-cf]pyπmidine Following a procedure similar to that described in section b of example 2, but starting from the compound obtained in the previous section, 135 mg (yield: 72%) of the desired compound were obtained. LC-MS (Method 1 ): tR = 2.71 ; m/z = 520 (MH+). c) Title compound
Following a procedure similar to that described in example 7, section b, but starting from the compound obtained in the previous section, 34 mg (yield: 8%) of the title compound were obtained. LC-MS (Method 1 ): tR = 1.51 ; m/z = 420 (MH+).
The following compound was obtained following a procedure simiiar to that described in example 9, but using the corresponding starting compound:
Figure imgf000126_0001
Figure imgf000127_0001
EXAMPLE 10
(R)-4-[3-{Λf,Λ/-Dimethyiamino}pyrrofidin-1-yl]-2-[4-{2-morpholin-4- ylethyl)phenylJamino-7W-pyrrolo[2,3-cflpyπmidine 0,03 mL of thionyi chloride (0.413 mmol) was added to a soiution of example 1 bd {72 mg, 0.197 mmol) in CHCi3 (6 mL). The reaction mixture was stirred at 6O0C for 1 h. The volatile components were evaporated to dryness, the resulting reaction crude was dissolved in 4 mL of CHCI3 and morphoiine was added (0.086 mL, 0.986 mmot). The reaction was stirred at room temperature for 1 h and the solvent was evaporated to dryness. The crude obtained was dissolved in DMF (1 mL) and K2CO3 (0.026 g, 0.188 mmoi), morphoiine (0.11 mL, 1.26 mmol) and a spatula tip of Kl were added. The resulting mixture was stirred in a tube under pressure at 130 0C for 18 h. The solvent was evaporated to dryness, and the resuiting crude was purified by column chromatography over silica gel using CHCh/MeOH mixtures of increasing polarity as an eiuent, providing 7 mg (yield: 13%) of the title compound were obtained. LC-MS (Method 2): tR = 1.72 min; m/z = 436 (MH+).
EXAMPLE 11 (RJ-Z-^^-Carboxypipeπdin-i-yϊJphenylϊamino^-fS-CΛfjΛf- dimethylamino)pyrrolidin-1-yl]- 7W-pyrrolo[2,3-c/fpyrim!dine
0.257 g of KOH (4.6 mmol) dissolved In H2O (0.8 mL) were added to a solution of example 1 bf (0.22 g, 0.46 mmol) in EtOH (10 mL). The resuiting mixture was heated at 8O0C for 2 h. The EtOH was evaporated and an 1 N HCI solution was added at O0C up to pH = 3. The solid formed was filtered and washed successively with H2O and diethyl ether. 0.145 g (yield: 70%) of the title compound were obtained.
LC-MS (Method 1 ): tR = 1.18; m/z = 450 (MH+).
EXAMPLE 12 (R)-4-[3-(W,Λ/-Dimethylamino)pyrrolrdin-1-ylI-2-[4-(4- methylaminocarbonySpiperidiπ-1-yl)phenyfJamino-7H-pyrrofo[2,3- djpyrimidfne
0.014 g of EDC (0.073 mmol), HOBT (0.009 g, 0.067 mmol), and N- methylmorpholsne (0.02 g, 0.2 mmol) were added to a solution of example 11 (0.03 g, 0.067 mmol) in DMF (1 ml_). The resulting mixture was stirred at room temperature for 1 h. A solution of N-Methylamine in 2 M THF (0.033 mL, 0.067 mmol) was added and the mixture was stirred at room temperature for 18 h. The crude product obtained was diluted with an saturated aqueous solution of NaHCOs was extracted thrice with EtOAc. The combined organic phases were separated, dried with Na2SO4, and the solvent was evaporated to dryness. 9 mg of the title compound were obtained (yield 27%). LC-MS (Method 1 ): tR = 1.50; m/z = 463 (MH+).
EXAMPLE 13 (l?)-4-[3-(W,W-Dϊrτtethylamiπo)pyrroiidin-1-yl}-2-[4-(1-methyϊpsperidin~4- ylmethyl)pheπyi3amino-7W-pyrrolo[2,3-d]pyrimidine a) (/?)-4-[3-(Λf,Λf-Dimethylamino)pyrrolidin-1-ylϊ-2-[4-(pipeπdin-4- ylmethy!)phenyJjamino-7-[(4-to[uyf)sulfony!]pyrroio[2,3-ofjpyrimidine The desired compound was obtained (1.224 g, 2.13 mmoi) following a procedure that was similar to that described in example 7, section b, but starting from the compound obtained in example 9, section a, (1.71 g, 2.52 mmol) but the crude mixture was basified with NaHCO3 saturated solution instead of NaOH 0.5 N (yield: 84 %). LC-MS (Method 1 ): tR = 2.19 min; m/z = 574 (MH+). b) (/?)-4-[3-{Λ/,Λ/-Diιmethyiamino)pyrroHd!π-1-yI3-2-[4-{1-niethy!pipeπdiπ-4- y!methyl)phenyl]amino-7-[{4»to!uyl)sulfonyl]pyrrolo[2,3-d]pyrimidine 177 mg (0.84 mmol) of Na(BH)(OAc)3 and 0.19 mL (2.61 mmoS) of 37% aqueous formaldehyde were added to a solution of the compound obtained in the previous section (300 mg, 0.523 mmol) in ACN (82 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated to dryness, the desired product was obtained and used in the next step without further purification. c) Title compound Following a procedure simitar to that described in section b of example 2, but starting from the product obtained in the previous section and eluting the column chromatography with mixtures of CH2CI2ZMeOHZN H3 of increasing polarity, 141 mg of the title compound were obtained (0.32 mmol) (yield: 62 %). LC-MS (Method 1 ): tR - 1.66 min; mZz = 434 (MH+).
EXAMPLE 14 (R)-4-[3-(Λf,/V-Dimethylamino)pyrroiidin-1-yl]-2-[4-(1-methytsulfonylpiperidin-
4-yimethy!)phenyl]amϊπo-7H-pyrro[o[2,3-c/]pyπmidine a) (/?)-4-[3-(W,W-Dimethyiamino)pyrrolidiπ-1-y!]-2-[4-(1- methyisulfonylptperidϊn-4-ylmethyf)phenyl]amino-7-[{4- toluy[)suifonyl]pyrrolo[2,3-d]pynmidine
10 mg of DMAP (0.08 mmol) and methanesulfonyl chloride (0.025 mL, 0.57 mmol) were added to a solution of the compound obtained in example 13, section a, (300 mg, 0.52 mmol} in CH2CI2 (2 mL). The mixture was stirred overnight at room temperature. The crude was diluted with NaHCCb saturated aqueous solution and was extracted thrice with CH2Cl2 The combined organic phases were separated, dried over Na2SO4, and the solvent was evaporated to dryness. The desired product was obtained and used in the next step without further purification. b) Title compound Following a procedure similar to that described in section b of example 2, but starting from the product obtained in the previous section, 168 mg (yield: 63%) of the title compound were obtained. LC-MS (Method 1 ): tR = 2.05 min; mZz = 498 (MH+). The following compound was obtained foilowing a procedure similar to that described in example 14, but using the corresponding starting compound:
Figure imgf000129_0001
EXAMPLE 15
(R}-4-[3-(Λf,Λ/-DirnethyIamino)pyrro!idin-1-yl]-2-[1-methyl-(2- methylaminocarbonyl)pyrrolo-4-yI]amino-7H-pyrrolo[2,3-cf|pyrimidine a} (R)-4-[3-(ΛfJΛ/-Dimethylamiπo)pyrrolidin-1-yl]-2-[(2-methoxycarbonyl)-1- methyl-pyrroio-4-yl3amsno-7-[(4-to!uyl)su[fonyf3-pyrroio[2,3-cf3pyrimidine Following a similar procedure to that described in reference example 3, but starting from methyl 4-amino-1-methyl-1H-pyrrolo-2-carboxy!ate hydrochloride instead of 4-(aminophenyl)methanoi, and adding one equivalent of triethylamine, 550 mg (yield: 86%) of the desired compound were obtained. LC-MS (Method 1 ): tR = 2.51 min; m/z = 538 (MH+). b) (R)-2-{2-Carboxy-1 -meihyϊpyrro\-4-yϊ)am"mo-4-lZ-(N,N- dimethylamino)pyrro!idin-1-yl]-7H-pyrroioE2,3-cf|pyrimidine
Following a similar procedure to that described in example 11 , but starting from the product obtained in the previous section, and adding 1 N HCI solution up to pH = 6, 298 mg (yield: 82%) of the desired compound were obtained. LC-MS (Method 1 ): tR = 1.07 min; m/z = 370 (MH+). c) Title compound
1.7 mg (0.014 mmol) of DMAP (0.08 mmol), and 20 mg (0.108 mmoi) of EDC were added to a solution of the compound obtained in the previous section (26.5 mg, 0.072 mmol) in DMF (1 mL). A solution of 2 M N-methyiamine in THF (0.061 mL, 0.122 mmo!) was added and the reaction mixture was stirred at room temperature for 72 h. The solvent was evaporated to dryness, and 2 mg of the title compound were obtained (yield 7%) after HPLC preparative purification. LC-MS (Method 1 ): tR - 1.38 min; m/z = 383 (MH+).
The following compound was obtained by following a similar procedure to that described in example 15, but using the corresponding starting compound:
Starting HPLC
Example Compound name tR (min) m/z compound Method
Figure imgf000131_0001
EXAMPLE 16
(RH-fS-CWjW-DiniethyiaminoΪpyrroIϊdin-i-yl^a-li-methyl^-fi- propy[aminocarbonyl)pyrrolo-4-yS]amino~7W-pyrrolo[2,3-d]pyrimidine
Following a similar procedure to that described in example 12, but starting from the product obtained in example 15, section b, instead of the solution of example 11 , and n-propylamine instead of 2.0M N-methylamine solution in THF. 36 mg (yield: 44%) of the title compound were obtained. LC-MS (Method 1 ): tR = 1.63 min; m/z = 411 (MH+).
The following compounds were obtained by following a similar procedure to that described in example 15a-b and example 16, but using in each case the corresponding starting materials:
Figure imgf000131_0002
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
EXAMPLE 17
{/?)-4.[3_{Af,W-Dimethyiamino)pyrroiidin-1-yil-2-[1-methyl-2-{tetrahydro-2H- pyran-4-yl-amϊnocarbonyl)pyrrolo-4-yi]arπino-7H-pyrrolo[2,3-cfjpyrimidϊπe
124 mg (0.325 mmol) mg of HATU (0.08 mmol), and 42 mg (0.325 mmol) of DlPEA were added to a solution of the compound obtained in example 15, section b (100 mg, 0.271 mmoi) in DMF (2 mL). Tetrahydro-2H-pyran-4-amine (55 mg, 0.541 mmoi) was added and the reaction mixture was stirred at room temperature for 18 h. The resulting crude product was purified by column chromatography over silica ge! using CH2CbZMeOH mixtures of increasing polarity as eiuent. 73 mg (yield: 51 %) of the title compound were obtained. LC-MS (Method 2): tR = 1.98 min; m/z = 453 (MH+).
The following compounds were obtained by following a similar procedure to that described in example 17, but using in each case the corresponding starting materials:
Starting HPLC
Example Compound name tR (min) m/z compound Method
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
(a) 3.2 equivalents of DIPEA were added
EXAMPLE 18
(/?)-4-[3-(Λf,Λ/-Dimethy[amino)pyrro!idin-1-y!|-2-[2-(morphoiin-4- yfmethyi)thiophen-4-yi]amino-7H-pyrro!o[2,3-d]pyrimidine 16 ml_ of 1.0 M LiAIH4 solution in THF (16 mmol) was added to a solution of (/?)- 4-[3-(Λ/,Λ/-dimethyiamino)pyrrolidin-1-yl]-2-[2-(morphoiin-4-yicarbonyl)thiophen-4- yl3amino-7H-pyrrolo[2,3-d]pyrimidine (obtained following a similar procedure to that described in example 15, section a and b, and example 16, but starting from 4-amino-thiophen-2-carboκylic acid methyi ester and morphoiine instead of the corresponding starting compounds) (1.425 g, 3.23 mmol) in THF:CH2Cl2 1 :1 (110 ml_). The resulting mixture was stirred at 60 0C for 18 h. An aqueous saturated solution of sodium potassium tartrate was added and the aqueous phase was extracted thrice with CH2CI2. The combined organic phases were dried with Na2SO4, filtered and the solvent was evaporated to dryness. The resulting crude poduct was purified by column chromatography over siiica gel using CHC!3/lvleOH mixtures of increasing polarity as eluent 605 mg of the title compound were obtained (yield 44%).
LC-MS (Method 1 ): tR - 1.70; m/z - 428 (MH+).
The following compounds were obtained by following a similar procedure to that described in example 15, (section a and b) example 16 and example 18. But using 4-amino-thiophen-2-carboxy!ic acid methyi ester in example 15, section a, and the corresponding starting compound in example 16 and example 18.
Reagent for HPLG
Example Compound name tR (mtn) m/z Example 16 Method
(R)-4-[3-(N,N- dsmethylarmno)pyrrolfdιn-1 -yl]-
2,2,2-
18a 2-[2-(2,2,2- tπftuoroethyla 2.07 440 tπflυoroethylamιnomethyl)thιo mine phen-4-yl]amino-7H- pyrrolo[2,3-c/]pyrimιdine
(R)-4-[3-{N,N- dimethylamiπo)pyrrolιdin-1 -yl]-
1 , 1 -
18b 2-[2-((1 ,1 -dioxothιomorphoiiπ- dioxothiomorp 1.67 476
4-yl)methyl)thiophen-4- hoiine yi]amino~7/τ'-pyrrolo[2,3- cGpyπmidsne
Figure imgf000141_0001
EXAMPLE 19 {!?}-4-[3-(W,/V-Dimethyfamino)pyrrolidin-1-yl3-2-[2-methySsulfonylisoindoHne-
S-ylJamino-TH-pyrroio^jS-djpyrimidsne a) (R}-4-[3-(A/,Λf-Dimethylammo)pyrroIidin-1-yl]-2-t2-teft- butoxycarbonylisoindoiine-5-ytϊamino-7W-pyrrolo[2,3-d]pyrtmidine Following a similar procedure to that described in example 1 , but starting from 5- amino-2-fe/t-butoxycarbonylisoindoline instead of 4-{morpholin-4- ylmethyl)phenyiamine, 54 mg (yieid: 66%) of the title compound were obtained. b) (/?)-4-[3-(Λf,W-Dimethy[amϊno)pyrrolϊdin-1-y[]-2-[isoiπdoline-5-yI]amino-7H- pyrroio[2,3-d]pyπmϊdine trifluoroacetate
0.43 ml_ of trifluoroacetic acid (5.62 mmol) were added to a solution of the compound obtained in the previous section (43 mg, 0.093 mrnol), and the reaction mixture was left to stir at room temperature for 2 h. The solvent was evaporated to dryness, The desired compound was obtained and was used in the next step without further purification. c) Title compound
0.010 mL (0.131 mmol) of methansulfonyl chloride, and 0.031 mL (0.272 mmol) of TEA were added to a solution of the compound obtained in the previous section (52 mg, 0.109 mmol) in CH2CS2 (2 mL), The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated to dryness, and the resulting crude poduct was purified by column chromatography over silica gel using AcOEt/MeOH mixtures of increasing polarity as eiuent. 15 mg of the title compound were obtained (yield 37%). LC-MS (Method 1): tR = 1.71 ; m/z = 442 (MH+). EXAMPLE 20
{R)»2-[2-Azetidin-3-y!isoindolinone-5-yl]amino-4-[3-(W,W- dimethylamiπo)pyrrolidin-1-yl3-7H-pyrroio[2,3-cf|pyπmidine
53 mg (0.10 mmo!) of the compound obtained in example 1 bt were added to 1.5 mL (6 mmo!) of HCI in dioxane solution 4.0M. The reaction mixture was left to stir at room temperature for 1 h. The solvent was evaporated to dryness, and the resulting crude poduct was filtered through a SCX-2 cartridge (2 g), 42 mg of the titie compound were obtained (yield 98%). LC-MS (Method 2): tR = 0.83; m/z = 433 (MH+). EXAMPLE 21
(R)-2-[2-(2J2,2-TrifiuoroethyS)isoindoSin-5-yl]amino-4-[3-{WJΛ/- dimethyiamϊno)pyrroSidin-1-yI]-7H-pyrrolo[2,3-cf]pyrimidine 0.17 mL of 1.0M LiA!H4 solution in THF (0.165 mmol) was added to a solution of the compound obtained in example 1 bw (15 mg, 0.033 mmol) in THFiCH2CI2 1 :1 (1 mL). The reaction mixture was stirred at room temperature for 72 h. 0.5 mL of Water and 0.5 M NaOH solution were added, filtered through a plug of Celtte® and and the solvent was evaporated to dryness. 5.4 mg of the title compound were obtained after preparative HPLC purification (yield 3%). LC-MS (Method 1 ): tR = 2.19; m/z = 446 (MH+). EXAMPLE 22
(RJ-a-^-fAminoethylsuifonylmethylJphenyllamino^-fS^WjΛ/- dimethy[amino)pyrroiidsn-1-y[]-7H-pyrro(o[2,3-d]pyπmidine a) (/?)-2-[3-(TriffuoromethylcarbonySaminoethylsulfonylmethyI)phenyl}- amino-4"[3-(Λ/,W-dimethy[amino)pyrroSidm-1-yS]-7W-pyrroio[2,3-d|pyπmidine Following a similar procedure to that described in reference example 3, but starting from (3-triftuoromethylcarbonylaminoethylsulfonylmethyl)phenylamine (98 mg, 0.452 mmol) instead of 4-(aminophenyl)methano), the title compound was obtained, which was used in the following step without prior purification. b) Title compound 5 mL of saturated aqueous solution were added to a solution of the product obtained in the previous section (0.376 mmo!) in THF (5 mL). The reaction mixture was stirred at room temperature for 48h. The crude product was diluted with H2O and extract thrice with CHCI3. The combined organic phases were washed with NaCI saturated aqueous solution and dried over Na2SO4. The solvent was evaporated to dryness, and the crude poduct thus obtained was purified by preparative HPLC providing 6.5 mg of the title compound (yield: 4%). LC-MS (Method 1 ): tR = 1.42 min; m/z = 444 (MH+). EXAMPLE 23
{/?)-4-[3-(Λ/,W-Dimethy[amino)pyrroHdin-1-ylJ-2-[3-{3-methylarninoazetidin-1- yl)su[fonyimethySphenyl]amino-7H-pyrrolo|;2,3-cf]pyrimidϊne a) (R)-4-t3-(/V,W-Dimβthylamino)pyrrolidin-1-y1]-2-[3-(3-(teιt- biitoxycarbonyl)methylaminoazetidin-1-y!)sulfonylmethylphenyl]amino- 7H- pyπrofo[2,3-d!ρyrimidine
Following a similar procedure to that described in reference exampie 3, but starting from reference example 23b (750 mg, 2.11 mmol) instead of (4- aminophenyl)methanol, the desired compound was obtained and used in the next step without further purification. b) Title compound
45 mL of 2.5 N HCΪ solution was added in several times to a solution of the product obtained in the previous section (1.12 g, 1.92 mmoi) in MeOH (37 mL). The reaction mixture was stirred overnight at room temperature. The crude product was concentrated and 2N NaOH aqueous solution was siowly added up to pH = 8. The aqueous phase was extracted thrice with CH2CI2 and the combined organic phases were washed with brine and dried over Na2SO4 The solvent was evaporated to dryness, and the crude product purified by column chromatography over silica gel using CH2CyMeOHZNH3 mixtures of increasing polarity as eSuent, providing 342 mg of the title compound (yield: 37%). LC-MS (Method 1 ): tR = 1.63; m/z = 485 (MH+).
The following compounds were obtained by following a similar procedure to that described in example 23, but using in each case the corresponding starting compounds:
Starting HPLC
Example Compound name tR {min) m/z compound Method
Figure imgf000144_0001
EXAMPLE 24
(/?)-4-[3-(WfW-Dimethylamino)pyrro[idin-1-yf]-2-[3-methy!-4- dimethyfaminocarbonyiphenyi]amino-7H-pyrroIo[2,3-orSpyrimidine a) fRH-IS-fW^W-DsmethyϊaminoJpyrroiidin-i-ylj^-^-methyf^- methoxycarbonySphenyl]amino-7H-pyrrolo[2,3-d]pyrimidine Following a similar procedure to that described in reference example 3, but starting from 3~methyl-4-methoxycarbonylphenylarnine (500 mg, 3.03 mmol) instead of 4-{aminophenyl)methanol, and using reference example 1 instead of reference exampie 2, 361 mg of the desired compound (yield: 45%) were obtained. b) ^/?)-4-[3-(W,W-Dimethylamino)pyrrol(din-1-y!]-2-[3-methyl-4- hydroxycarbonylphenyl]amino-7H-pyrroIo[2,3-of|pyπmidine
Following a similar procedure to that described in example 11 , but starting from the product obtained in the previous section, the desired compound was obtained (349 mg, 0.917 mmoi) (quantitative yield). c) Title compound
Following a similar procedure to that described in example 12, but starting from the product obtained in the previous section (80 mg, 0.21 mmol) and 2 N N, N,- dimethylamine solution in THF (0.18 mLt 0.357 mmol), 5.4 mg (yield: 6.3%) of the title compound were obtained. LC-MS (Method 2): tR = 2.13 min; m/z = 408 (MH+).
EXAMPLE 25
4-[(/?)-3-(Λ/,W-dimethylamino)pyrro!idin-1-ySΪ-2-[4- (methylaminocarbony!(morphoiin-4-yf)methyf)pheny!]am!no-7W-pyrroSo[2,3- dlpyrimsdϊne a) 4-[(/?)-3-{ N, tø-dimethy!ammo)pyrrolidin-1 -yf]-2-[4- {hydroxycarbonyi(morphoIiπ-4-yl)methyE)phenylJamiπo-7W-pyrroio[2,3- cdpyrimidsne The title compound was obtained by following a similar procedure to that described in example 2, section b, but using the product obtained in example 1di (400 mg, 0.83 mmol). b) Title compound The title compound was obtained in 55% yield by following a similar procedure to that described in exampSe 6, but starting from the product obtained in the previous section and 2.0 M methyiamine solution in THF instead of morphoiine. LC-MS (Method 3): tR = 2.75 min; m/z = 479 (MH+).
EXAMPLE 26 Inhibition of JAK3 activity
The inhibition of 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.
In a final volume of 10 μL per well, 2.5 μL of the product to be tested dissolved in 4% DMSO (final concentration of the product to be tested, 0.1 -10000 nM) was incubated with 0.3 μg/mL of the catalytic domain of human JAK3 (amino acid sequence 281 -1124), 2 μM of the substrate peptide Z'-Lyte® Tyr 6 and 4 μM of ATP; all components were dissolved in 50 mM pH 7.5 Hepes buffer, 10 mM
Magnesium chloride (N), 1 mM EGTA and 0.01 % Brij® 35. The reaction was started by the addition of said 4 μM ATP; after incubation for 1 hour at 250C, 5 μL of A Z'-Lyte® Tyr 6 development reagent was added and the mixture was incubated for 1 hour at 250C. Phosphorylation was then quantified in each well using a Safire2® fluorescence micropiate reader from Tecan.
The compounds of all examples showed more than 50% inhibition of JAK3 activity at 1 μM in this assay.
EXAMPLE 27
In vivo test: Coliagen-induced arthritis in mice
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 μg of type Il chicken collagen in complete Freund's adjuvant (CFA) (100 μg M. Tuberculosis). On day 21 , the animals received an injection booster consisting in 0.1 mL of an emulsion containing 100 μg of type Ii chicken collagen in incomplete Freund's adjuvant (IFA). Approximately 30 days after the primary immunisation, the animals that developed the arthritic process were selected and distributed into a control group and a group that received the product to be tested, so that the mean of the arthritic index were similar between groups. 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:
0 norma!
1 mild but defined redness and sweliing of the tarsus or carpus joints or of individual fingers
2 moderate redness and swelling of the tarsus or carpus joints
3 serious redness and swelling of the tarsus or carpus joints
4 maximally inflamed joint with involvement of multiple joints
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).
The compounds of examples 1 , I b1 1bq, 1 e, 1 n, 17c and 18 showed more than 40% of inhibition in this test when administered at the dose mentioned above.

Claims

1.- A compound of formula I:
Figure imgf000147_0001
or a salt thereof, wherein:
Cyi represents phenyl or a 5- or 6-membered aromatic heterocycle bonded to the NH group through a C atom, each of which can be optionally fused to a 5- or 6-membered saturated, partiaϋy unsaturated or aromatic carbocyciic or heterocyclic ring, wherein Cy1 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 SO2 groups, and wherein Cyi can be optionally substituted with one or more R1; each Ri independently represents Chalky!, C2-4alkenyl, C2-4alkynyl, halogen, -CN, -NO2, -COR2, -CO2R2, -CONR2R2, -COCONR2R2, -OR2, -OCOR3, -OCONR3R3, -OCO2R3, -SR2, -SOR3, -SO2R3, -SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CONR2R2, -NR4CO2R3, -C(=N-OH)R3 or Cy2, wherein Ci-4alkyS, C2-4alkenyl and C2-4alkynyl can be optionally substituted with one or more Rg and Cy2 can be optionally substituted with one or more Re; each R2 independently represents hydrogen or R3; each R3 independently represents Ci-4alkyS, C2-4alkenyi, C2.4alkynyi, or Cy3, wherein Ci-4aikyl, C2-4alkenyi and C2-4alkynyl can be optionally substituted with one or more R5 and Cy3 can be optionally substituted with one or more R7; each R4 independently represents hydrogen or C-Malkyl; each R5 independeπtiy represents halogen, -CN, -NO2, -CORs, -CO2Rs,
-CONR8Rs, -OR8, -OCOR9, -OCONR9R9, -OCO2R9, -SR8, -SOR9, -SO2Rg,
-SO2NR8R8, -SO2NR4COR9, -NR8R8, -NR4COR8, -NR4CONR8R8, -NR4CO2R9,
-NR4SO2R8, -C(=N-OH)R9 or Cy3, wherein Cy3 can be optionally substituted with one or more R7; each Re independently represents Ci-4alkyl that can be optionally substituted with one or more Ri0, or R6 represents any of the meanings described for Rn; each R7 independently represents Chalky!, haioCi-4alkyi, Ci-4aikoxyCi, 4alkyl, hydroxyCi-4alkyi, cyanoCi-4alkyi or any of the meanings described for Rn; each Rg independently represents hydrogen or R9; each Rg independently represents Chalky!, haloC1-4aikyl, Ci-4alkoxyCi. 4alkyl, hydroxyCi.4alkyl, cyanoCi-4alkyl, Cy4-Ci-4aIkyl or Cy3, wherein Cy3 can be optionally substituted with one or more R7; each R^o independently represents halogen, -CN, -NO2, -CORs, -CO2Ra,
-CONR8R8, -OR8, -OCOR9, -OCONR9R9, -OCO2R9, -SR8, -SOR9, -SO2R9, -SO2NR8R8, -SO2NR4CORs, -NR8R81 -NR4COR8, -NR4CONR8R8, -NR4CO2R9, -NR4SO2R9, or -C(=N-OH)R9; each Rn independently represents halogen, -CN, -NO2, -CORi2, -CO2Ri2, -CONR12Ri2, -OR12, -OCORi3, -OCONR13Ri3, -OCO2Ri3, -SRi2, -SORi3, -SO2R13, -SO2NR12R12, -SO2NR4COR12, -NR12R12, -NR4COR12, -NR4CONR12R12, -NR4CO2R13, -NR4SO2R13 or -C(=N-0H)R13; each Ri2 independently represents hydrogen or R13; each R13 independently represents Ci-4afkyl,
Figure imgf000148_0001
4aikyl or
Figure imgf000148_0002
or two R12 groups or two Ri3 groups on the same N atom can be bonded completing, together with the N atom, a 5- or δ-membered saturated ring, which can additionally contain one or two heteroatoms selected from N, S and O, and which can be optionally substituted with one or more
Figure imgf000148_0003
groups; each Cy2 and Cy3 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, wherein each Cy2 and Cy3 can be saturated, partially unsaturated or aromatic, and can be bonded to the rest of the molecuie 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; each Cy4 independently represents a ring selected from (a)-(c):
Figure imgf000149_0001
(a) (b) (C) ; and
each Ri4 independently represents hydrogen or C1-4aikyS; with the proviso that the following compounds are excluded: (f?)-2-(3-acetyiaminophenyl)amino-4-[3-(Λ/JΛ/-dimethyiamino)pyrro!idin-1-y!]-
7H-pyrroio[2,3-c/]pyrimidineI
(R)-4-i>(Λ/,/V-dimethylarnino)pyrro!idin-1-yl]-2-[3~ (phenylamino)phenyi]amino~7H-pyrrolo[2,3-d]pyrimidinet
(/?)-4-[3-(W,A/-dimethylamino)pyrroiidin-1-yl]-2-[4-(morphoiin-4- yl)phenyl]amino-7H-pyrrolo-[2,3-d]pyrimidineI
(R)-4-[3-fΛ/τΛ/-dimethylamino)pyrro!idin-1-yl]-2-(3-fiuoro-4- methoxyphenyl)amino-7H-pyrrolo-[2,3-of]pyrimidinef
(R)-4-[3-(/V,Λ/-dimethylamino)pyrrolidin-1-yl]-2-(3- methy[aminosulfonySphenyl)amino-7H-pyrro!o[2,3-c/]pyrimidine, (R)-2-(3-aminosulfonylpheny[)amino-4-[3-(A/,Λ/-dimethylamino)pyrroiidin-1 - yl]~7f7-pyrrofo[2,3-c/]pyrimidine.
2.- A compound according to claim 1 wherein Cy1 represents: a) phenyl; b) a 5-membered aromatic heterocycle bonded to the NH group through a C atom, which contains from 1 to 3 heteroatoms selected from N, O and S; or c) a ring of formula Cy-|b
Figure imgf000150_0001
Figure imgf000150_0002
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 Cyi can be optionally substituted with one or more R-i.
3,- A compound according to claim 1 wherein Cyi represents: a) phenyl substituted at one or two of positions 3, 4 and 5 with an R1; b) a ring of formula Cyid
Figure imgf000150_0003
c) a ring of formula Cy<jθ
Figure imgf000150_0004
wherein Cyie can be optionally substituted with one Ri at the NH group.
4.- A compound according to claim 1 wherein Cy1 represents phenyl or a ring of formula Cyib wherein ring A represents a saturated 5- or 6-membered carbocycSic 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 optionaiiy oxidized forming CO1 SO or SO2 groups, and wherein the phenyl and Cy1 b groups can be optionaiiy substituted with one or more Ri.
5.- A compound according to claim 1 wherein Cyi represents phenyl substituted with one or more R1.
6.- A compound according to claim 1 wherein Cyi represents phenyi substituted at one or two of positions 3, 4 and 5 with an R1.
7.- A compound according to claim 1 wherein Cyi represents phenyl substituted with one R1, which is placed at position 3 of the phenyl ring.
8,- A compound according to claim 1 wherein Cy1 represents phenyl substituted with one R1, which is placed at position 4 of the phenyl ring.
9,- A compound according to claim 1 wherein Cy-i represents a 5- or 6-membered aromatic heterocycle bonded to the NH group through a C atom, which can be optionaiiy fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein Cy1 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 Cy1 can be optionally substituted with one or more R1.
10.- A compound according to claim 1 wherein Cy1 represents a 5-membered aromatic heterocycie bonded to the NH group through a C atom, wherein Cy1 contains from 1 to 2 heteroatoms selected from N and S, and wherein Cy1 can be optionally substituted with one or more R1.
11.- A compound according to claim 1 wherein Cy1 represents a ring of formula
Cy1d
Figure imgf000152_0001
Cy id
12.- A compound according to claim 1 wherein Cyi represents a ring of formula Cyib
Figure imgf000152_0002
wherein ring A represents a saturated 5- or 6-membered ring which can be carbocyclic 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 SO2 groups, and wherein the Cy-jb group can be optionally substituted with one or more R^.
13.- A compound according to ciaim 1 wherein Cyi represents a ring of formula
Figure imgf000152_0003
Cy1b 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 Cyib group can be optionally substituted with one or more R1.
14.- A compound according to claim 1 wherein Cy1 represents a ring of formula Cy1 e
Figure imgf000153_0001
wherein Cyie can be optionally substituted with one Ri at the NH group.
15,- A compound according to any of claims 1 to 14 wherein each R-i independently represents Chalky!, halogen, -CN, -COR2, -CO2R2, -CONR2R2, -OR2, -OCOR3, -OCONR3R3, -SR2, -SOR3, -SO2R3, SO2NR2R2, -SO2NR4COR3, -NR2R2, -NR4COR2, -NR4CO2R3 or Cy2, wherein Ci-4alkyl can be optionally substituted with one or more R5 and Cy2 can be optionally substituted with one or more R6.
16,- A compound according to any of claims 1 to 14 wherein each R1 independently represents C1-4alkyl, -CN, -COR2, -CO2R21 -CONR2R2, -OCOR3, -OCONR3R31 -SR2, -SOR3, -SO2R3, -SO2NR4COR3 or -NR4CO2R3, wherein Ci_4alkyl can be optionally substituted with one or more R5.
17,- A compound according to any of claims 1 to 14 wherein each Ri independently represents C-ι_4alkyl, -CN or -CONR2R2, wherein Ci-4aikyl can be optionally substituted with one or more R5.
18.- A compound according to any of claims 1 to 14 wherein each R1 independently represents Chalky! (preferably methyl) optionally substituted with one R5.
19,- A compound according to any of claims 1 to 14 wherein each R1 independently represents
Figure imgf000153_0002
(preferably methyl) substituted with one R5.
20.- A compound according to any of claims 1 to 15 wherein Cy2 represents Cy2a, and Cy2a 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, with the proviso that Cy2a is not morpholine, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO2 groups, and wherein said Cy2a can be optionally substituted with one or more R6.
21.- A compound according to any of claims 1 to 15 wherein Cy2 represents Cy2b, and Cy2b represents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N and S1 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 SO2 groups, wherein said Cy2b can be optionally substituted with one or more R6.
22.- A compound according to any of claims 1 to 21 wherein each R5 independently represents halogen, -CN, -COR8, -CONR8Rs, -OR8, -SR8, -SOR9, - SO2R9, -SO2NR8R8, -SO2NR4COR9, -NR8Rs, -NR4COR8, -NR4SO2R9 or Cy3, wherein Cy3 can be optionally substituted with one or more R7.
23.- A compound according to any of claims 1 to 21 wherein each R5 independently represents halogen, -CONR8Rs, -OR8, -SO2R9, -SO2NR8R8, -NR8R8, -NR4COR8, -NR4SO2R9 or Cy3, wherein Cy3 can be optionally substituted with one or more R7.
24.- A compound according to any of claims 1 to 21 wherein R5 represents Cy3.
25,- A compound according to any of claims 1 to 24 wherein Cy3 represents Cy3Gl and Cy30 represents a saturated 5- or 6-membered monocyclic 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 Cy3c can be optionally substituted with one or more R7.
26.- A compound according to claim 1 selected from: (R)-4-[3-(Λ/,N-dimethylamino)pyrrolidin-1 -yl]-2-[(4-morpholin-4- yimethyl)phenyl]amino-7H-pyrroio[2,3-αf]pyrimidine; (R)-4-[3-(Λ/,Λ/-dimethylamino)pyrrolidin-1-yi]-2-[4-(1 ,1-dioxothiomorpholin-4- yl)phenyl]amino-7H-pyrrolo[2,3-c/]pyπmidine;
(/?)-4-[3-(Λ/JW-dimethy!amino)pyrroJidin-1-yl]-2-{4-methylsuifonyiphenyl)amino-7H- pyrrolo[2,3-c/jpyπmidine; (R)-4~[3-(Λ/,Λ/-dimethyiamino)pyrrolidin-1-yl]-2-[3-fiuoro-4-(morpho!in-4- yl)pheny!]amino-7H-pyrrolo[2,3-c/jpyπmidine;
(R)-4-[3-{WJW-dimethylamino)pyrrolidin~1-yi]-2-(2-isopropyNso!ndolinone-5- yi)amino-7H-pyrrolo[2,3-d]pyrimidine; (R)-2-[2-(S)-sec>butylaminocarbonyl)-1-methylpyrrole-4~yl]arnjno-4-[3-(Λ/,Λ/- dimethylamino)pyrro!idin-1-yl]-7H-pyrrolo[2,3-c/jpyrimidine; (R)-4-[3-(W,W-Dimethylamino)pyrrolidin-1-yt]-2-[2-(morpholin-4-ylmethyl)thiophen- 4-yl]amino-7/-/~pyrrolo[2,3-cflpyπmidine; (RH-fS-fW^-dimethylaminoJpyrrolidin-i-yl^-KS-dimethylaminosulfonylmethyl)- (4-moφho!in-4-yl)phenyl]amino-7H-pyrrolo[2,3-d]pyrimidine; (R)-2-[3-(azetidin-1-yl)suifonyimethyiphenyl]amino-4-j;3-(/V;N- dimethylamiπo)pyrrolidin-1-yl]- 7H-pyrrolo[2,3-d]pyrimidine; and (R)-4-[3-(W,/V-dimethy!amino)pyrro!idtn-1-yl]-2-(3--methylisothiazole-5-yl)amino-7/-/- ρyrrolo[2,3-c(3pyrimidine; or a salt thereof.
27,- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 26 or a pharmaceuticaliy acceptable salt thereof and one or more pharmaceutically acceptable excipients.
28.- A compound according to any of claims 1 to 26 for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3.
29.- A compound according to any of claims 1 to 26 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.
30.- A compound according to any of claims 1 to 26 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 scierosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
31.- A process for the preparation of a compound of formula ! according to claim 1 , which comprises: (a) reacting a compound of formula IV (or a protected form thereof) with a compound of formula V (or a protected form thereof)
Figure imgf000156_0001
IV V wherein Cyi has the meaning described in claim 1 , followed if necessary by the removal of any protecting group that may be present; or
(b) converting, in one or a plurality of steps, a compound of formula I into another compound of formuia I.
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