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WO2023110843A1 - Dérivés hétérobicycliques utilisés comme inhibiteurs de l'itk - Google Patents

Dérivés hétérobicycliques utilisés comme inhibiteurs de l'itk Download PDF

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Publication number
WO2023110843A1
WO2023110843A1 PCT/EP2022/085575 EP2022085575W WO2023110843A1 WO 2023110843 A1 WO2023110843 A1 WO 2023110843A1 EP 2022085575 W EP2022085575 W EP 2022085575W WO 2023110843 A1 WO2023110843 A1 WO 2023110843A1
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Prior art keywords
pyridin
pyrrolo
methyl
group
pyrimidin
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Inventor
Joan Taltavull Moll
Montserrat Erra Sola
Cristina Esteve Trias
Lluis Miquel Pages Santacana
Jordi Bach Taña
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Almirall SA
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Almirall SA
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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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • ITK interleukin-2-inducible T-cell kinase
  • EMT EMT
  • TSK nonreceptor tyrosine kinases
  • the TEC-family kinases are characterized by a common domain organization consisting of an N-terminal pleckstrin-homology domain (PH) important for recruitment to the plasma membrane. Following the PH domain there is a proline-rich Tec homology region (TH) relevant for the protein activation state and the Src homology 2 (SH2) and 3 (SH3) domains that regulate protein-protein interactions. On the carboxy-terminal end lies the specific kinase catalytic domain. (Schwartzberg, et al., 2005; Lechner et al, 2020). ITK is specially expressed in T lymphocytes, natural killer cells and mast cells.
  • ITK is considered to be the predominant Tec kinase in T cells being a critical contributor to the strength of signal delivered by the T cell receptor (TCR) (Elmore et al., 2020).
  • TCR stimulation leads to phosphorylation of associated cytoplasmic proteins, and accumulation of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in the plasma membrane, leading to recruitment of ITK to the TCR signaling complex.
  • PIP3 Phosphatidylinositol
  • ITK phospholipase C gamma 1
  • PLC- ⁇ 1 phospholipase C gamma 1
  • PIP2 phosphatidylinositol 4,5-bisphosphate
  • DAG diacylglycerol
  • ITK regulates multiple outcomes including cell activation, differentiation, proliferation, and function such as cytokine production in different subsets of T lymphocytes including Th1, Th2, Th17, T regulatory cells and CD8+Tcells (Fowell et al., 1999; Gomez-Rodriguez et al, 2009; Nadeem et al., 2020; Gomez-Rodriguez et al, 2014; Mamontov et al., 2019; Xu et al, 2019)
  • ITK could be involved in various inflammatory diseases and cancer.
  • ITK inflammatory diseases
  • ITK -/- mice show reduced inflammation in models of acute contact hypersensitivity reactions and treatment with ITK inhibitor or using siRNA against ITK could also reduce inflammatory symptoms in mice (Matsumoto et al., 2002; von Bonin et al, 2011).
  • Evidences in allergic asthma show a contradictory role, as there are studies showing that ITK deficiency leads to less cell infiltration and less mucous production whereas other studies demonstrated that the loss has no beneficial effect and instead leading to T cell hyperplasia (Mueller and August, 2003; Sun et al., 2015).
  • ITK Inhibition of ITK may be beneficial for treatment of T-cell lymphoma.
  • ITK is highly expressed and phosphorylated in in angioimmunoblastic T cell lymphoma and is a potential anti-cancer drug target (Liu et al., 2019; Lechner et al., 2020).
  • the ITK inhibitor CPI-818 shows preclinical anti-tumour activity and is currently in clinical trials in patients with relapsed/refractory T cell lymphoma.
  • novel heterobicyclic derivatives for use in the treatment of conditions in which targeting of the ITK pathway or inhibition of ITK kinase can be therapeutically useful. It has now been found that certain heterobicyclic derivatives are novel and potent ITK inhibitors and can therefore be used in the treatment or prevention of these diseases.
  • heterobicyclic derivative which heterobicyclic derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
  • Formula (I) wherein: • A represents a C3-7 cycloalkyl group, a C6-14 aryl group, a 4- to 10-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, a 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S, or a linear or branched C 1-4 haloalkyl group, wherein the C 3-7 cycloalkyl group, the C 6-14 aryl group, the 4- to 10-membered heterocyclyl group and the 5- to 14-member
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing said heterobicyclic derivatives.
  • the invention is also directed to a heterobicyclic derivative of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention is also directed to the heterobicyclic derivatives of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leuk
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • the invention also provides a pharmaceutical composition comprising the heterobicyclic derivatives of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention is also directed to use of the heterobicyclic derivatives of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • ITK Interleukin-2-induc
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • the invention also provides a method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • ITK Interleukin-2-inducible T-cell kinase
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • the invention also provides a combination product comprising (i) the heterobicyclic derivatives of the invention as described herein; and (ii) one or more additional active susbtances.
  • the invention also provides a combination product comprising (i) the heterobicyclic derivatives of the invention as described herein; and (ii) one or more active ingredients selected from: a) Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone; b) Dyhydrofolate reductase inhibitors, such as methotrexate or pralatrexate; c) Dihydroorotate dehydrogenase (DHODH) inhibitors such as
  • Cysteinyl leukotriene (CysLT) receptor antagonists such as montelukast, zafirlukast, tipelukast, masilukast
  • CysLT Cysteinyl leukotriene
  • Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant
  • Topical anti-septics such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.
  • C 1-4 alkyl embraces unsubstituted or substituted, linear or branched radicals having 1 to 4 carbon atoms.
  • Examples of C 1-4 alkyl include methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl or t-butyl.
  • Such alkyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • C 1-4 alkyl is typically unsubstituted.
  • C 1-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1, 2 or 3 halogen atoms. Examples of haloalkyl groups include CCl 3 , CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 and CH 2 CHF 2 .
  • C 3-7 cycloalkyl embraces non-aromatic, saturated or insaturated monocyclic or bicyclic carbocyclic radicals having from 3 to 7 carbon atoms.
  • Examples of monocyclic or bicyclic C 3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, spiro[2.2]pentyl and spiro[3.3]heptyl.
  • Such C 3-7 cycloalkyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • C 3-6 cycloalkyl embraces non-aromatic, saturated or insaturated monocyclic or bicyclic carbocyclic radicals having from 3 to 6 carbon atoms.
  • Examples of C 3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl and spiro[2.2]pentyl.
  • Such C 3-6 cycloalkyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • C 6-14 aryl radical embraces typically a monocyclic or bicyclic C 6-14 aryl radical, more preferably monocyclic or bicyclic C 6-10 aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred. Such C 6-14 aryl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • 4- to 10-membered heterocyclyl radical embraces typically a non- aromatic, saturated or unsaturated C 4-10 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms, preferably 1 or 2 of the carbon atoms, are replaced by a heteroatom selected from N, O and S.
  • a 4- to 10-membered heterocyclyl radical may be a monocyclic heteroring, bicyclic heteroring and spiro-heteroring, wherein at least one ring contains a heteroatom. In bicyclic heteroring two rings are linked together so that they have at least two atoms in common. In spiro-heteroring one atom (spiroatom) belongs to two rings together.
  • 4- to 10-membered heterocyclyl radicals include oxetanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pirazolidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1,3-dioxol-2-one, tetrahydrofuranyl, 2,3- dihydrofuranyl, 2,5-dihydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, 2,5-dio
  • Such heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • 4- to 9-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C 4-9 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms, preferably 1 or 2 of the carbon atoms, are replaced by a heteroatom selected from N, O and S.
  • a 4- to 9-membered heterocyclyl radical may be a monocyclic heterorings, bicyclic heterorings and spiro-heterorings, wherein at least one ring contains a heteroatom.
  • Examples of 4- to 9-membered heterocyclyl radicals include oxetanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pirazolidinyl, triazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1,3-dioxol-2-one, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, 2,5-dioxopyr
  • heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • 4- to 7-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C 4-7 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms, preferably 1 or 2 of the carbon atoms, are replaced by a heteroatom selected from N, O and S.
  • a 4- to 7-membered heterocyclyl radical may be a monocyclic heterorings, bicyclic heterorings and spiro-heterorings, wherein at least one ring contains a heteroatom.
  • Examples of 4- to 7-membered heterocyclyl radicals include oxetanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pirazolidinyl, triazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1,3-dioxol-2-one, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, 2,5-dioxopyr
  • heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • term 5- to 6-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C 5-6 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms, preferably 1 or 2 of the carbon atoms, are replaced by a heteroatom selected from N, O and S.
  • a 5- to 6-membered heterocyclyl radical may be a monocyclic heterorings, bicyclic heterorings and spiro-heterorings, wherein at least one ring contains a heteroatom.
  • Examples of 5- to 6-membered heterocyclyl radicals include pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pirazolidinyl, triazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1,3-dioxazolyl-2-one, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2,5- dihydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 3,4- dihydropyranyl, 3,6-dihydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, 2,5-dioxopyrrolidinyl, 2-oxopyrrolidinyl), 1,3
  • heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different.
  • the term 5- to 14-membered heteroaryl radical embraces typically a monocyclic or bicyclic 5- to 14- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, preferably a N.
  • a 5- to 14-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzo[b]thienyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thiant
  • 5- to 9-membered heteroaryl radical embraces typically a monocyclic or bicyclic 5- to 9- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, preferably a N.
  • a 5- to 9-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzo[b]thienyl, benzothiazolyl, indolyl, indazolyl, purinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H- pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridyl, benzo[b]thi
  • 5- to 6-membered heteroaryl radical embraces typically a monocyclic or bicyclic 5- to 6- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, preferably a N.
  • a 5- to 6-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, triazolyl, imidazolidinyl and pyrazolyl.
  • monocyclic 5- to 7-membered heteroaryl radical embraces typically a 5- to 7- membered ring system, comprising at least one heteroatom selected from O, S and N, preferably a N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, triazolyl, imidazolidinyl and pyrazolyl.
  • monocyclic 5- to 6-membered heteroaryl radical embraces typically a 5- to 6- membered ring system, comprising at least one heteroatom selected from O, S and N, preferably a N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, triazolyl, imidazolidinyl and pyrazolyl.
  • monocyclic 6-membered heteroaryl radical embraces typically a 6- membered ring system, comprising at least one heteroatom selected from O, S and N, preferably a N. Examples include pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
  • halogen atom embraces chlorine, fluorine, bromine and iodine atoms.
  • a halogen atom is typically a fluorine, chlorine or bromine atom.
  • the term halo when used as a prefix has the same meaning.
  • carbonyl group refers to a -C(O)- moiety [i.e. a bivalent moiety comprising a carbon atom attached to an oygen atom via a double bond].
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are “unsubstituted or substituted”. This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • unknown configurations of a chiral center are denoted by the configurational descriptors R* or S*.
  • R* -5-(2,2-difluorocyclopropyl)-N- ((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • R* means that the configuration at that quiral center is unknown, being R or S, for convenience denoted as R.
  • R means that the configuration at that quiral center is unknown, being R or S, for convenience denoted as R.
  • R* configuration for the first eluting peak isolated in the enantiomeric separation and the S* configuration for the second eluting peak, unless otherwise indicated.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. ElieI (Wiley, New York, 1994).
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient; (b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient.
  • pathological condition or disease susceptible to amelioration by inhibiton ITK includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased ITK activity.
  • Such disease states include, but are not limited to, a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • a dermatological disease a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically- acceptable inorganic or organic acids.
  • a N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • the heterobicyclic derivatives of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules.
  • the term hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • the invention also includes isotopically-labelled heterobicyclic derivatives of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention.
  • the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Isotopically-labelled heterobicyclic derivatives of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.
  • tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • tautomerism The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.
  • Prodrugs of the heterobicyclic derivatives described herein are also within the scope of the invention. Thus certain derivatives of the heterobicyclic derivatives of the present invention, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • the compound of Formula (I) is a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV) or a compound of Formula (V),
  • the compound of Formula (I) is a compound of Formula (II).
  • Formula (II) It is also particulary preferred that the compound of Formula (I) is a compound of Formula (III).
  • Formula (III) It is also preferred that the compound of Formula (I) is a compound of Formula (IV).
  • the compound of Formula (I) is a compound of Formula (V).
  • A represents a C 3-7 cycloalkyl group, a C 6-14 aryl group, a 4- to 10-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-7 cycloalkyl group, the C 6-14 aryl group, the 4- to 10-membered heterocyclyl group and the 5- to 14-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –(CH 2 ) 0-4 -NR’R’’ group, a –(CH 2 ) 0-4 -OR’ group, a
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6-membered heterocyclyl group and the 5- to 9-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –NR’R’’ group, a –(CH 2 ) 0-4 -OR’ group, a halogen atom, and a –CONR’R’’ group.
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one O atom, or a 5- to 6-membered heteroaryl group containing at least one N atom, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6- membered heterocyclyl group and the 5- to 6-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –NR’R’’ group, a –(CH 2 ) 0-4 -OR’ group, a halogen atom, and a –CONR’R’’ group.
  • A represents a cyclopropyl group, a cyclohexanyl group, a phenyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a dihydropyranyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a 1H-pyrrolo[2,3- b]pyridyl group, a imidazo[1,2-a]pyridyl group, a indolyl group, or a -CF3 group, wherein the cyclopropyl group, the cyclohexanyl group, the phenyl group, the tetrahydrofuranyl group, the tetrahydropyranyl group, the dihydropyranyl group, the pyrazolyl group, the pyridy
  • B represents a -NR’- group or -O- atom.
  • B represents a -NR’- group. More preferably, B represents a -NH- group. It is also preferably that B represents a -O- atom.
  • C represents a phenyl group or a monocyclic 5- to 6-membered heteroaryl group containing at least one N atom, wherein the phenyl group and the monocyclic 5- to 6-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a C 3-7 cycloalkyl group, a linear or branched C 1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group.
  • C represents a phenyl group or a monocyclic 6-membered heteroaryl group containing at least one N atom, wherein the phenyl group and the monocyclic 6-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a C 3-7 cycloalkyl group, a linear or branched C 1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group.
  • C represents a phenyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group or a pyrimidinyl group, wherein the phenyl group, the pyrazolyl group, the pyridyl group, the pyrazinyl group and the pyrimidinyl group are unsubstituted or substituted by one or more substituents selected from a fluorine atom, a linear or branched C 1-4 alkyl group, a cyclopropyl group, a -CF 3 group, a –OCH 3 group, and a -CON(CH 3 ) 2 group.
  • C represents a phenyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group or a pyrimidinyl group, wherein the phenyl group, the pyrazolyl group, the pyridyl group, the pyrazinyl group and the pyrimidinyl group are unsubstituted or substituted by one or more substituents selected from a fluorine atom, a methyl group, a cyclopropyl group, a -CF 3 group, a –OCH 3 group, and a -CON(CH 3 ) 2 group.
  • D represents a -NR a R b group, a -O–(CH 2 ) 1-4 -OH group, a –(CH 2 ) 1-4 -OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH 2 ) 0-4 -NR’R’’ group.
  • D represents a 4- to 9-membered heterocyclyl group containing at least one N atom, wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –(CH 2 ) 0-4 -OR’ group, an oxo group and a –(CH 2 ) 0-4 -NR’R’’ group.
  • D represents a 4- to 9-membered heterocyclyl group containing at least one N atom, wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –OR’ group, an oxo group and a –NR’R’’ group.
  • D represents a 4- to 10-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –(CH 2 ) 0-4 -OR’ group, an oxo group and a –(CH 2 ) 0-4 -NR’R’’.
  • D represents a 4- to 10-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –OR’ group, an oxo group and a -NR’R’’.
  • D represents a -N(CH 3 ) 2 group, a -NH–(CH 2 ) 3 -OH group, a -N(CH 3 )- (CH 2 ) 2 OH group, a -N(CH 2 CH 3 )-(CH 2 ) 2 OH group, a -N(CH 3 )-(CH 2 ) 2 OMe group, a -N(CH 3 )- (CH 2 ) 2 N(CH 3 ) group, a -O–(CH 2 ) 2 -OH group, a –(CH 2 ) 3 -OH group, a azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a 2,5-diazabicyclo[2.2.1]heptanyl group, a 2,5-diazabicyclo[2.2.2]octanyl group, a 3,8-diazabicyclo
  • D represents a azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a 2,5-diazabicyclo[2.2.1]heptanyl group, a 2,5-diazabicyclo[2.2.2]octanyl group, a 3,8-diazabicyclo[3.2.1]octanyl group, a 4,7-diazaspiro[2.5]octanyl group, or a 2-oxa- 5,8-diazaspiro[3.5]nonanyl group, wherein the azetidinyl group, the pyrrolidinyl group, the piperidinyl group, the piperazinyl group, the 2,5-diazabicyclo[2.2.1]heptanyl group, the 2,5- diazabicyclo[2.2.2]octanyl group, the 3,8-diazabicyclo[3.2.1]octanyl group
  • X 1 represents a nitrogen atom or a carbon atom.
  • X 1 represents a carbon atom. It is also preferred that X 1 represents a nitrogen atom.
  • X 2 represents a nitrogen atom or a carbon atom.
  • X 2 represents a carbon atom. It is also preferred that X 2 represents a nitrogen atom.
  • X 3 represents a nitrogen atom or a -CR c - group.
  • X 3 represents a -CR c - group. More preferably, X 3 represents a -CH- group or a - C(CH 3 )- group. Even more preferably, X 3 represents a -CH- group.
  • X 3 represents a nitrogen atom.
  • X 4 represents a nitrogen atom or a carbon atom.
  • X 4 represents a carbon atom.
  • X 4 represents a nitrogen atom.
  • X5 represents a nitrogen atom or a -CR c - group.
  • X 5 represents a -CR c - group. More preferably, X 5 represents a -CH- group, a - C(CH 3 )- group or a -C(CN)- group. Even more preferably, X 5 represents a -CH- group. It is also preferred that X 5 represents a nitrogen atom.
  • Z represents a -NH-group.
  • Z represents a -CH- group.
  • R 1 is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group and a –(CH 2 ) 1-4 -OR’ group.
  • R 1 represents a hydrogen atom, or a linear or branched C 1-4 alkyl group. More preferably, R 1 represents a hydrogen atom, or a methyl group.
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group and a –(CH 2 ) 1-4 -OR’ group.
  • R 2 represents a hydrogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group and a –(CH 2 ) 1-4 -OR’ group.
  • R 2 represents a hydrogen atom, a methyl group, an ethyl group, an isobutyl group, a -CH 2 CF 3 group and a –(CH 2 ) 2 -OH group.
  • R c represents a hydrogen atom, a halogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, or a -CN group.
  • R c represents a hydrogen atom, a linear or branched C 1-4 alkyl group, or a -CN group. More preferably, R c represents a hydrogen atom, a methyl group or a -CN group.
  • R’ and R’’ are independently selected from the group consisting of a hydrogen atom and a linear or branched C 1-4 alkyl group.
  • R’ and R’’ represent independently a hydrogen atom or a methyl group.
  • A represents a C 3-7 cycloalkyl group, a C 6-14 aryl group, a 4- to 10-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, a 5- to 14-membered heteroaryl group containing at least one heteroatom selected from N, O and S, or a linear or branched C1-4 haloalkyl group, wherein the C 3-7 cycloalkyl group, the C 6-14 aryl group, the 4- to 10-membered heterocyclyl group and the 5- to 14-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4
  • A represents a C 3-7 cycloalkyl group, a phenyl group, a 4- to 10-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N, O and S, or a linear or branched C 1-4 haloalkyl group, wherein the C 3-7 cycloalkyl group, the C 6-14 aryl group, the 4- to 10-membered heterocyclyl group and the 5- to 14-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a –(CH 2 ) 0-4 -NR’R’’ group, a –(CH 2 ) 0-4 -OR’ group, a
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6-membered heterocyclyl group and the 5- to 9-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a -NR’R’’ group, a–(CH 2 ) 0-4 - OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group,
  • the compound of Formula (I) is represented by compound of Formula (II): Formula (II) wherein X 3 and X 5 each independently represents a nitrogen atom or a -CR c - group.
  • X3 represents a -CR c - group, preferably X 3 represents a -CH- group.
  • X 3 represents a a nitrogen atom.
  • X 5 represents a nitrogen atom.
  • X 5 represents a -CR c - group, preferably X 5 represents a -CH- group.
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6-membered heterocyclyl group and the 5- to 9-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a -NR’R’’ group, a–(CH 2 )
  • the compound of Formula (I) is represented by compound of Formula (III): wherein X 3 and X 5 each independently represents a nitrogen atom or a -CR c - group.
  • X 3 represents a -CR c - group, preferably X 3 represents a -CH- group.
  • X 3 represents a nitrogen atom.
  • X 5 represents a nitrogen atom.
  • X 5 represents a -CR c - group, preferably X 5 represents a -CH- group.
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6-membered heterocyclyl group and the 5- to 9-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a -NR’R’’ group, a–(CH 2 ) 0-4 - OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B
  • the compound of Formula (I) is represented by compound of Formula (IV): wherein X 3 and X 5 each independently represents a nitrogen atom or a -CR c - group.
  • X 3 represents a -CR c - group, preferably X 3 represents a -CH- group.
  • X 3 represents a nitrogen atom.
  • X 5 represents a nitrogen atom.
  • X5 represents a -CR c - group, preferably X 5 represents a -CH- group.
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6-membered heterocyclyl group and the 5- to 9-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a -NR’R’’ group, a–(CH 2 ) 0-4 - OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably
  • the compound of Formula (I) is represented by compound of Formula (V): wherein X 3 and X 5 each independently represents a nitrogen atom or a -CR c - group.
  • X 3 represents a -CR c - group, preferably X 3 represents a -CH- group.
  • X 3 represents a nitrogen atom.
  • X 5 represents a nitrogen atom.
  • X 5 represents a -CR c - group, preferably X 5 represents a -CH- group.
  • A represents a C 3-6 cycloalkyl group, a phenyl group, a 5- to 6-membered heterocyclyl group containing at least one heteroatom selected from N, O and S, or a 5- to 9- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C 3-6 cycloalkyl group, the phenyl group, the 5- to 6-membered heterocyclyl group and the 5- to 9-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a linear or branched C 1-4 haloalkyl group, a -NR’R’’ group, a–(CH 2 ) 0-4 - OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B
  • A represents a cyclopropyl group, a cyclohexanyl group, a phenyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a dihydropyranyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a 1H- pyrrolo[2,3-b]pyridyl group, a imidazo[1,2-a]pyridyl group, a indolyl group, or a -CF 3 group, wherein the cyclopropyl group, the cyclohexanyl group, the phenyl group, the tetrahydrofuranyl group, the tetrahydropyranyl group, the dihydropyranyl group, the pyrazolyl
  • the compound of Formula (I) is represented by Formula (II). In a particular embodiment, it is preferred that the compound of formula (I) is represented by Formula (III). In a particular embodiment, it is preferred that the compound of Formula (I) is represented by Formula (IV). In a particular embodiment, it is preferred that the compound of formula (I) is represented by Formula (V).
  • Particular individual compounds of the invention include: 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(5-aminopyridin-3-yl)-N-((6-((3R,5S)-3,
  • GENERAL SYNTHETIC PROCEDURES Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their IUPAC name. Ether refers to diethyl ether, unless otherwise specified. Concentration or evaporation refer to evaporation under vacuum using a Büchi rotatory evaporator. Standard synthetic methods are described the first time they are used. Compounds synthesized with similar methods are referred to only by their starting materials, without full experimental detail. Slight modifications to the general experimental methods used are permitted in these cases. Specific synthetic transformations already described in the literature are referred to only by their Bibliographical reference. Other specific methods are also described in full.
  • the compounds of the invention can be prepared using the methods and procedures described herein or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below. Specific synthetic processes not covered by Schemes 1-6 are described in detail in the experimental section.
  • Compounds of Formula (I) may be prepared, as illustrated in Scheme 1, directly from compounds of Formula (X) by reaction with boronic acids or boronic esters of Formula (XI) under Suzuki– Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457).
  • the B’ group represents a boronic acid or a boronic ester.
  • Such reactions may be catalyzed by a suitable palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) or tris(dibencylidenoacetone)dipalladium (0) in a solvent such as dioxane or dimethoxyethane or toluene or N,N’-dimethylformamide with or without water as a cosolvent, in the presence of a base such as cesium carbonate or sodium carbonate potassium phosphate, at temperatures ranging from 80-120 oC with or without the use of microwave irradiation.
  • a suitable palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) or tris(dibencylidenoacetone)dipalladium (0) in a solvent such as dioxane or dimethoxyethane or toluene or N
  • compounds of formula (I) may also be prepared from compounds of Formula (X) in a two step synthesis, as illustrated in Scheme 2.
  • compounds of Formula (X) may be treated with an appropriate boron reagent such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane with a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (0) or palladium (II) acetate, in the presence of a ligand such as X-Phos or tricyclohexylphosphine, in a solvent such as dioxane or diglyme or water, in the presence of a base such as triethylamine or potassium carbonate, at temperatures ranging from 80-120 oC with or without the use of microwave irradiation to give boronic acids or boronic esters of Formula (XII).
  • an appropriate boron reagent such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • the B’ group represents a boronic acid or a boronic ester.
  • Compounds of formula (XII) may then give compounds of Formula (I) by reaction with haloderivatives of Formula (XIII) under Suzuki–Miyaura reaction conditions, catalyzed by a suitable palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) or tris(dibencylidenoacetone)dipalladium (0) in a solvent such as dioxane or dimethoxyethane or toluene or N,N’-dimethylformamide with or without water as a cosolvent, in the presence of a base such as cesium carbonate or sodium carbonate potassium phosphate, at temperatures ranging from 80-120 oC with or without the use of microwave irradiation.
  • a suitable palladium catalyst such as [1,1′- bis(diphenylphosphino)
  • Compounds of Formula (X) may be obtained by reaction of compounds of Formula (XIV) with nucleophiles of formula (XV) such as an amine or an alcohol or a thioalcohol in the presence of a suitable base and in a suitable solvent as illustrated in Scheme 3.
  • nucleophiles of formula (XV) such as an amine or an alcohol or a thioalcohol
  • compounds of Formula (XIV) may be treated with amines of Formula (XV-a) in the presence of a suitable base such as cesium carbonate or diisopropylethylamine in a suitable solvent such as acetonitrile or dimethylsulfoxide or ethanol or N-N-dimethylacetamide at a temperature ranging from 60-180 oC.
  • compounds of Formula (XIV) may be treated with amines of Formula (XV-a) under Buchwald-Hartwig amination conditions, in the presence of a suitable catalyst such as palladium (II) acetate or tetrakis(triphenylphosphine) palladium (0) in the presence of a ligand such as XantPhos or XPhos and a suitable base such as cesium carbonate in a suitable solvent such as dioxane.
  • a suitable catalyst such as palladium (II) acetate or tetrakis(triphenylphosphine) palladium (0)
  • a ligand such as XantPhos or XPhos
  • a suitable base such as cesium carbonate
  • compounds of Formula (XIV) may be treated with alcohols of Formula (XV-b) in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in an appropriate solvent such as tetrahydrofurane or dimethylsulfoxide.
  • a suitable base such as sodium hydride or potassium tert-butoxide
  • compounds of Formula (I) may be obtained from compounds of Formula (XIV) as illustrated in Scheme 4.
  • Compounds of Formula (XIV) may be treated in a first step with boronic acids or boronic esters of Formula (XI) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • the B’ group represents a boronic acid or a boronic ester.
  • a suitable palladium catalyst such as [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) or tris(dibencylidenoacetone)dipalladium (0) in a solvent such as dioxane or dimethoxyethane or toluene or N,N’-dimethylformamide with or without water as a cosolvent, in the presence of a base such as cesium carbonate or sodium carbonate potassium phosphate, at temperatures ranging from 80-120 oC with or without the use of microwave irradiation to give compounds of Formula (XVI).
  • a base such as cesium carbonate or sodium carbonate potassium phosphate
  • compounds of Formula (XVI) may be treated with nucleophiles of Formula (XV) such as an amine or an alcohol or a thioalcohol in the presence of a suitable base and in a suitable solvent to give compounds of Formula (I).
  • nucleophiles of Formula (XV) such as an amine or an alcohol or a thioalcohol
  • compounds of Formula (XVI) may be treated with amines of Formula (XV-a) in the presence of a suitable base such as cesium carbonate or diisopropylethylamine in a suitable solvent such as acetonitrile or dimethylsulfoxide or ethanol or N-N-dimethylacetamide at a temperature ranging from 60-180 oC.
  • compounds of Formula (XVI) may be treated with amines of Formula (XV-a) under Buchwald-Hartwig amination conditions, in the presence of a suitable catalyst such as palladium (II) acetate or tetrakis(triphenylphosphine) palladium (0) in the presence of a ligand such as XantPhos or XPhos and a suitable base such as cesium carbonate in a suitable solvent such as dioxane.
  • a suitable catalyst such as palladium (II) acetate or tetrakis(triphenylphosphine) palladium (0)
  • a ligand such as XantPhos or XPhos
  • a suitable base such as cesium carbonate
  • compounds of Formula (XVI) may be treated with alcohols of Formula (XV-b) in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in an appropriate solvent such as tetrahydrofurane or dimethylsulfoxide.
  • a suitable base such as sodium hydride or potassium tert-butoxide
  • an appropriate solvent such as tetrahydrofurane or dimethylsulfoxide.
  • amines of Formula (XV-aa) may be obtained from nitriles of Formula (XVII) as illustrated in Scheme 5 by reduction of nitriles of Formula (XVII) with hydrogen at a pressure between atmospheric pressure and 60 psi in the present of a suitable catalyst such as palladium on carbon or Niquel-Raney in a suitable solvent such as methanol at a temperature between room temperature and 50 oC.
  • a suitable catalyst such as palladium on carbon or Niquel-Raney
  • a suitable solvent such as methanol
  • alcohols of Formula (XV-ba) may be obtained from esters of Formula (XVIII) as illustrated in Scheme 6 by reduction with a suitable reductive agent such as lithium alluminium hydride in a suitable solvent such as tetrahydrofurane at a temperature between -20 oC and 80 oC.
  • a suitable reductive agent such as lithium alluminium hydride in a suitable solvent such as tetrahydrofurane at a temperature between -20 oC and 80 oC.
  • any reactant and intermediate can be used in a protected form to prevent certain functional groups from undergoing undesired reactions.
  • standard methods for the introduction and subsequent removal of these protecting groups can be used at any suitable step of the synthesis. Numerous protecting groups, their introduction and their removal are described in T. W. Greene and G. M.
  • this stereoisomers may be separated at any convenient step of the synthetic route.
  • the single enantiomers of racemic mixtures obtained during the synthesis may be separated by conventional techniques such as chiral chromatography, in particular, chiral HPLC and superfluid chromatography (SFC). This separation may take place at the final step of the synthetic sequence or at any intermediate stage of the synthesis, yielding enantiomerically pure intermediates that may be further transformed into the final products of the synthetic route.
  • BSM SM with SO
  • PDA PDA
  • TQD ESI
  • column Waters Acquity UPLC BEH C-18, 50x2.1mm, 1.7 ⁇ m, Temp: 50oC, Flow rate: 0.65 mL/min, Gradient: from 5% B to 95% B, Run time: 5 min, Eluent A: 0.05% formic acid + 0.0125% ammonia in water, Eluent B: 0.04% formic acid + 0.01% ammonia in acetonitrile/methanol (1/1). Sample concentration: 1 mM in dimethyl sulfoxide. Injection volume: 0.5 ⁇ L. Chromatograms were processed at 210 nm.
  • LCMS method 2 LCMS 2 Apparatus: Waters Alliance 2795 system; Waters 2996 PDA; Waters ZQ; ESI, pos/neg 160-900; column: Waters Symmetry C-18, 50x2.1mm, 3.5 ⁇ m, Temp: 25oC, Flow rate: 0.8 mL/min, Gradient: from 5% B to 95% B, Run time: 5 min, Eluent A: 0.05% formic acid + 0.0125% ammonia in water, Eluent B: 0.04% formic acid + 0.01% ammonia in acetonitrile/methanol (1/1).
  • LC-MS method 3 LCMS 3 Apparatus: Waters Acquity UPLC; Bin.
  • BSM SM with SO
  • PDA PDA
  • SQD SQD
  • ESI pos/neg 160- 900
  • column Waters Acquity UPLC BEH C-18, 50x2.1mm, 1.7 ⁇ m, Temp: 50oC, Flow rate: 0.65 mL/min, Gradient: from 5% B to 95% B, Run time: 3 min, Eluent A: 0.05% formic acid + 0.0125% ammonia in water, Eluent B: 0.04% formic acid + 0.01% ammonia in acetonitrile/methanol (1/1).
  • LC-MS method 4 LCMS 4 Apparatus: Waters Acquity UPLC; Bin.
  • BSM SM with SO
  • PDA PDA
  • SQD SQD
  • ESI pos/neg 160- 900
  • column Waters Acquity UPLC BEH C-18, 50x2.1mm, 1.7 ⁇ m, Temp: 50oC, Flow rate: 0.65 mL/min, Gradient: from 5% B to 95% B, Run time: 5 min, Eluent A: 0.05% formic acid + 0.0125% ammonia in water, Eluent B: 0.04% formic acid + 0.01% ammonia in acetonitrile/methanol (1/1).
  • NMR 1 H Nuclear Magnetic Resonance Spectra were recorded using the following instruments: Varian Mercury plus 400MHz Bruker Avance III HD 400 MHz Agilent VNMRS DD2600 MHz equipped with a cold probe Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference. Preparative methods Reaction products were purified, when necessary, by one or several of the following methods, as indicated in the examples: Flash chromatography Instrument type: Grace Reveleris X2 ® C-815 Flash; Detection: UV 200-400nm, combination of up to 4 UV signals and scan of entire UV range, ELSD; Column sizes: 4-330 g on instrument.
  • reaction mixture was directly purified by reverse phase chromatography eluting water to ACN/MeOH (50:50) to give the title compound (900 mg, 77% yield) as a yellow oil. Purity based on LC-MS 90%. LRMS (m/z): 411 [M+1] + LCMS 2 r.t.
  • reaction mixture was filtered through Celite ® washing with AcOEt and water. Phases were separated and the aqueous phase was further extracted with more AcOEt. The combined organic phases were dried over magnesium sulphate, filtered and the solvent was evaporated to give a reaction intermediate (1.96 g). This intermediate was solved in 40 mL of THF, HCl 5N (40 mL) was added and stirred and heated at 30 oC for 2h. The reaction mixture was poured slowly to a aqueous sodium carbonate and extracted twice with AcOEt. The combined organic phases were dried over magnesium sulphate, filtered and the solvent was evaporated.
  • EXAMPLE 7 4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)pyridin-2-ol N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methoxypyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (32 mg, 0.072 mmol) was heated in concentrated hydrochloric acid (0.7 mL) at 120 oC for 3 hours.
  • EXAMPLE 8 1-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-3-ol
  • the title compound was prepared from 1-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)piperidin-3-ol and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 1. Purity based on LC-MS 99%.
  • EXAMPLE 15 and EXAMPLE 16 5-(2-Aminopyridin-4-yl)-N-((R*)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, first eluting peak 5-(2-Aminopyridin-4-yl)-N-((S*)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, second eluting peak The title compounds were separated from a racemic mixture of 5-(2-aminopyridin-4-yl)-N-(1-(6- ((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl
  • EXAMPLE 18 and EXAMPLE 19 N-((R*)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(1-methyl-1H-pyrazol- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, first eluting peak N-((S*)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(1-methyl-1H-pyrazol- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, second eluting peak
  • the title compounds were separated from a racemic mixture of N-(1-(6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(1-methyl
  • Example 43 Purity by LC-MS 98%.
  • Second eluting peak Example 44: Purity by LC-MS 92%.
  • EXAMPLE 64 5-(2,4-Difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate and (2,4- difluorophenyl)boronic acid following the experimental procedure described in Example 61.
  • the purification of the title compound was done by preparative LC-MS under buffered conditions.
  • EXAMPLE 65 5-(3-Fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine
  • the title compound was prepared from tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate (3-fluorophenyl)boronic acid following the experimental procedure described in Example 61.
  • the purification of the title compound was done by preparative LC-MS under buffered conditions.
  • EXAMPLE 66 5-(3,5-Difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate (3,5-difluorophenyl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 96%.
  • EXAMPLE 89 and EXAMPLE 90 (R*)-5-(3,4-Difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, first eluting peak (S*)-5-(3,4-Difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, second eluting peak
  • the title compounds were separated from a racemic mixture of 5-(3,4-difluorophenyl)-N-(1-(6- (piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg), prepared as described in Example 88.
  • EXAMPLE 110 5-(2-Aminopyridin-4-yl)-N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl 4-(4-(((5-iodo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2- yl)piperazine-1-carboxylate and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 105.
  • EXAMPLE 138 5-(4,4-Difluorocyclohexyl)-N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl (2R,6S)-4-(4-(((5-(4,4-difluorocyclohex-1-en-1- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2- yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127.
  • EXAMPLE 160 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(4- fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine
  • the title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and (4-fluorophenyl)boronic acid following the experimental procedure described in Example 157.
  • the purification of the title compound was done by preparative LC-MS under buffered conditions.
  • EXAMPLE 164 and EXAMPLE 165 (R*)-5-(2,2-Difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, first eluting peak (S*)-5-(2,2-Difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, second eluting peak
  • the title compounds were separated from a racemic mixture of 5-(2,2-Difluorocyclopropyl)-N-((6- (piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (86 mg), prepared according to the experimental procedure described in Example 163.
  • EXAMPLE 238 4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 99% LRMS (m/z): 514 [M+1] + LCMS 1 r.t.
  • ITK kinase Assays Compounds were screened for their ability to inhibit ITK using the assays as indicated below.
  • the full-length recombinant human ITK was expressed as N-terminal GST-fusion proteins using a baculovirus expression system and was purchased from SignalChem, The enzymatic activity was assayed using as substrate MBP (Sigma) and using as a co- substrate ATP.
  • the MPB concentration in the reaction was 5.4 ⁇ M.
  • the degree of ADP formation was detected by luminescence (ADP-Glo Kinase Assay from Promega).
  • IC50s of compounds were measured in a reaction mixture containing the enzyme, ATP and MBP in Kinase Assay Buffer III + 50 ⁇ M DTT.
  • the ATP concentration in the reaction was 25 ⁇ M and the final concentration of DMSO was 4%.
  • the enzymatic reaction took place for 60 minutes at room temperature. Then, the 5 ⁇ l reaction were stopped with 5 ⁇ L of ADP-Glo, incubated for 40 minutes and finally added 10 ⁇ l of Kinase Detection Reagent.
  • Luminoskan Incubate for 30 minutes and read luminescence on Luminoskan (Thermo Fisher Luminescence reader)
  • AA aminoacids
  • MBP Myelin Basic Protein GST: glutathione-S-transferase His: Histidine ATP: adenosine tri-phosphate
  • ADP adenosine bi-phosphate Kinase Buffer III (from SignalChem): 20 mM Tris-HCl, pH 7.4, 10 mM MgCl2 and 0.5 mg/ml BSA.
  • IC 50 values are represented by letters according to the value: A: ⁇ 100 nM B: 100 – ⁇ 500 nM C: 500- ⁇ 1000 nM D: ⁇ 1000 nM
  • Preferred heterobicyclic derivatives of the invention possess an IC 50 value for the inhibition of ITK kinase (determined as defined above) of less than 1 ⁇ M (1000 nM), preferably of less than 0.5 ⁇ M (500 nM), more preferably of less than 0.1 ⁇ M (100 nM).
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying.
  • the heterobicyclic derivatives of the present invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of ITK.
  • the heterobicyclic derivatives of the present invention may be used in the treatment of a pathological condition or disease selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, a myelo- dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor; more in particular wherein the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidra
  • the heterobicyclic derivatives of the present invention may be used in the treatment of dermatological diseases.
  • the heterobicyclic derivatives of the present invention may be used in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo.
  • the patient or subject treated in the present invention is an animal, preferably a human.
  • COMBINATIONS The heterobicyclic derivatives of the present invention may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK).
  • the combinations of the invention comprise the heterobicyclic derivatives of the invention and one or more additional active substances, such as, a) Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone; b) Dyhydrofolate reductase inhibitors, such as methotrexate or pralatrexate; c) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or farudodstat; d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; e) Antimalarials, such
  • Cysteinyl leukotriene (CysLT) receptor antagonists such as montelukast, zafirlukast, tipelukast, masilukast
  • CysLT Cysteinyl leukotriene
  • Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant
  • Topical anti-septics such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.
  • the active compounds in the combination product i.e the heterobicyclic derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • the heterobicyclic derivatives of the present invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of ITK.
  • the combinations of the invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of ITK, which is typically selected from of a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor; more in particular wherein the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous
  • the combinations of the invention may be used in the treatment of dermatological diseases.
  • the combinations of the invention may be used in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. It is contemplated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other(s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other(s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
  • the invention is also directed to a combination product of the heterobicyclic derivatives of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • the invention also encompasses the use of a combination of the heterobicyclic derivatives of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • ITK Interleukin-2-inducible T-cell kinase
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • the active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc) or by injection (subcutaneous, intradermic, intramuscular, intravenous, etc).
  • One execution of the present invention consists of a kit of parts comprising a heterobicyclic derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pust
  • Another execution of the present invention consists of a package comprising a heterobicyclic derivative of the invention and another active compound useful in the treatment of atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulo
  • compositions according to the present invention comprise the heterobicyclic derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition refers to a mixture of one or more of the heterobicyclic derivatives of the invention or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • the invention further provides pharmaceutical compositions comprising the heterobicyclic derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described.
  • ITK Interleukin-2-inducible T-cell kinase
  • the invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • ITK Interleukin-2-inducible T-cell kinase
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • the invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating a pathological condition or disease susceptible to amelioration by inhibition of ITK, such as the ones previously described.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Interleukin-2-inducible T-cell kinase (ITK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
  • ITK Inter
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, hidradenitis suppurativa, dyshidrosis, nummular eczema, chronic actinic dermatitis, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitis, dermatomyositis, acne, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, discoid lupus, pityriasis, generalized pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus
  • compositions according to the present invention comprise the heterobicyclic derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition refers to a mixture of one or more of the heterobicyclic derivatives of the invention or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • the invention further provides pharmaceutical compositions comprising the heterobicyclic derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of ITK, such as the ones previously described.
  • the invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating a pathological condition or disease susceptible to amelioration by inhibiton of ITK, such as the ones previously described.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of ITK, such as the ones previously described, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
  • compositions which comprise, as an active ingredient, at least a heterobicyclic derivative of the invention in association with a pharmaceutically acceptable excipient such as a carrier or diluent.
  • a pharmaceutically acceptable excipient such as a carrier or diluent.
  • the compositions are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.
  • the compositions are made up in a form suitable for oral administration.
  • the compositions are made up in a form suitable for topical administration.
  • Pharmaceutical compositions suitable for the delivery of heterobicyclic derivatives of the invention and methods for their preparation will be readily apparent to those skilled in the art.
  • compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.
  • Topical Administration The heterobicyclic derivatives of the invention may be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions.
  • Topical administration examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Oral Administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Oral mucosal administration The heterobicyclic derivatives of the invention can also be administered via the oral mucosal.
  • sublingual delivery which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth
  • buccal delivery which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa)
  • local delivery which is drug delivery into the oral cavity.
  • Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers and/or oral mucosal permeation enhancers.
  • the heterobicyclic derivatives of the invention can also be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant.
  • atomizer preferably an atomizer using electrohydrodynamics to produce a fine mist
  • nebulizer preferably an atomizer using electrohydrodynamics to produce a fine mist
  • Nasal mucosal administration The heterobicyclic derivatives of the invention may also be administered via the nasal mucosal.
  • compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents vi) Parenteral Administration
  • the heterobicyclic derivatives of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Rectal/lntravaginal Administration The heterobicyclic derivatives of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the heterobicyclic derivatives of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable ⁇ e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the amount of the heterobicyclic derivative of the invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
  • the pharmaceutical compositions of the invention are made up in a form suitable for oral or topical administration, being particularly preferred oral administration.
  • the amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.

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Abstract

L'invention concerne de nouveaux dérivés hétérobicycliques de formule (I) ; ainsi qu'un procédé pour leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation en thérapie comme inhibiteurs de la kinase des lymphocytes T inductible par l'interleukine-2 (ITK).
PCT/EP2022/085575 2021-12-15 2022-12-13 Dérivés hétérobicycliques utilisés comme inhibiteurs de l'itk Ceased WO2023110843A1 (fr)

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WO2023196278A1 (fr) * 2022-04-05 2023-10-12 Corvus Pharmaceuticals, Inc. Inhibiteurs d'itk pour augmenter l'activité de cellules th1
CN120514705A (zh) * 2025-07-28 2025-08-22 华中科技大学同济医学院附属协和医院 Farudodstat在制备预防或治疗脑缺血再灌注损伤药物中的应用
WO2025181247A1 (fr) 2024-02-28 2025-09-04 Almirall, S.A. Dérivés hétérobicycliques utilisés en tant qu'inhibiteurs de l'itk
US12459951B2 (en) 2022-04-08 2025-11-04 Shy Therapeutics, Llc Compounds that interact with RAS superfamily proteins for treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023196278A1 (fr) * 2022-04-05 2023-10-12 Corvus Pharmaceuticals, Inc. Inhibiteurs d'itk pour augmenter l'activité de cellules th1
US12459951B2 (en) 2022-04-08 2025-11-04 Shy Therapeutics, Llc Compounds that interact with RAS superfamily proteins for treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
WO2025181247A1 (fr) 2024-02-28 2025-09-04 Almirall, S.A. Dérivés hétérobicycliques utilisés en tant qu'inhibiteurs de l'itk
CN120514705A (zh) * 2025-07-28 2025-08-22 华中科技大学同济医学院附属协和医院 Farudodstat在制备预防或治疗脑缺血再灌注损伤药物中的应用

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