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WO2023110843A1 - Heterobicyclic derivatives as itk inhibitors - Google Patents

Heterobicyclic derivatives as itk inhibitors 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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French (fr)
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

Novel heterobicyclic derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Interleukin-2-inducible T-cell kinase (ITK).

Description

HETEROBICYCLIC DERIVATIVES AS ITK INHIBITORS FIELD OF THE INVENTION The present invention relates to novel compounds having ITK inhibitory activity. This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders. BACKGROUND OF THE INVENTION ITK (interleukin-2-inducible T-cell kinase; also known as EMT or TSK) is a member of the TEC family of nonreceptor tyrosine kinases together with BTK, TEC, TXK, and BMX. 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. ITK is then phosphorylated by LCK, triggering its autophosphorylation and full activation. Activated ITK subsequently phosphorylates and activates phospholipase C gamma 1 (PLC-γ1), leading to the generation of phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) that serve as second messengers. These phospholipid metabolites stimulate signaling via calcium mobilization, activation and translocation of transcription factors like AP-1, IRF4 and NFAT into the nucleus, induction of transcription and the production and release of relevant cytokines like IL-2, IL-4 and IL-17A among others. By modulating TCR signaling, 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) Considering the potential of ITK to modulate T cell function, numerous studies suggest that ITK could be involved in various inflammatory diseases and cancer. Regarding inflammatory diseases, ITK is increased in the skin of patients suffering from atopic dermatitis and also elevated levels of ITK were found in peripheral blood T cells. 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). In models of experimental autoimmune encephalomyelitis, which serves as a model for multiple sclerosis, depletion of ITK results in a diminished disease severity in mice with less transmigration of CD4+ cells into the central nervous system and across the brain endothelial barrier as well as reduced secretion of Th1 and Th17 effector cytokines (Kannan et al., 2015). Potential involvement of ITK in oncogenesis has also been described. 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. In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of the ITK pathway or of the ITK kinase it is immediately apparent that new compounds that modulate ITK pathways and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients. Provided herein are 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. SUMMARY OF THE INVENTION The present invention is directed to new compounds that possess ITK inhibitory activity. Accordingly there is provided a 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:
Figure imgf000004_0001
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 C1-4 haloalkyl group, wherein the C3-7 cycloalkyl group, the C6-14 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a –(CH2)0-4-CONR’R’’ group; • B represents a -NR’- group, a -S- atom or -O- atom, • C represents a C6-14 aryl group or a monocyclic 5- to 7-membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C6-14 aryl group and the monocyclic 5- to 7-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, and a –(CH2)0-4-CONR’R’’ group; • D represents a -(CH2)0-4-NRaRb- group, a -O–(CH2)1-4-NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’; • X1, X2, X3, X4 and X5 each independently represent a nitrogen atom, a carbon atom or a - CRc- group; • Z represents a -CH- group or a -NH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group. 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, 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. 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. 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. 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. 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. 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 leflunomide, teriflunomide or farudodstat; d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; e) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; f) Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; g) JAK inhibitors, such as baricitinib, upadacitinib or abrocitinib h) TYK2 inhibitors such as deucravacitinib i) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine; j) Fumaric acid esters, such as dimethyl fumarate; k) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; l) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; m) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; n) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC- 11050; o) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061; p) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; q) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab; r) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; s) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab; t) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab; u) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; v) Anti-Interleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab; w) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab; x) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab; y) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept; z) Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI- 551 or MOR-208; aa) Anti-IL-1b antibodies such as canakinumab; bb) Anti-IL-alpha antibodies such as bermekimab; cc) Anti-Interleukin 1 Receptor (IL-1R) antibody dd) Anti-CD6 antibodies such as itolizumab; ee) Anti-IL-36/ IL-36R antibodies such as BI-655130 or ANB019; ff) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR-845; gg) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; hh) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; ii) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine; jj) Histamine 4 (H4) receptor antagonists. kk) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast; ll) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant; or mm) Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths. DETAILED DESCRIPTION OF THE INVENTION When describing the heterobicyclic derivatives, compositions, combinations and methods of the invention, the following terms have the following meanings, unless otherwise indicated. As used herein the term C1-4 alkyl embraces unsubstituted or substituted, linear or branched radicals having 1 to 4 carbon atoms. Examples of C1-4 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. Unless otherwise specified, the C1-4 alkyl is typically unsubstituted. As used herein, the term C1-4 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 CCl3, CF3, CHF2, CH2F, CH2CF3 and CH2CHF2. As used herein, the term C3-7 cycloalkyl embraces non-aromatic, saturated or insaturated monocyclic or bicyclic carbocyclic radicals having from 3 to 7 carbon atoms. Examples of monocyclic or bicyclic C3-7 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 C3-7 cycloalkyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Analogously, the term C3-6 cycloalkyl embraces non-aromatic, saturated or insaturated monocyclic or bicyclic carbocyclic radicals having from 3 to 6 carbon atoms. Examples of C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl and spiro[2.2]pentyl. Such C3-6 cycloalkyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. As used herein, the term C6-14 aryl radical embraces typically a monocyclic or bicyclic C6-14 aryl radical, more preferably monocyclic or bicyclic C6-10 aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred. Such C6-14 aryl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. As used herein, the term 4- to 10-membered heterocyclyl radical embraces typically a non- aromatic, saturated or unsaturated C4-10 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. Examples of 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-dioxopyrrolidinyl, 2-oxopyrrolidinyl), 1,3-dioxol-4-yl, 1,3-dioxolyl, azepanyl, 1,4-diazepanyl, 2,5-diazabicyclo[2.2.1]-heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 4,7-diazaspiro[2.5]octanyl, quinuclidinyl, pyrrolizidinyl, 1-azaadamantanyl, 2-azaadamantanyl, indolinyl, 3H-indolinyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7- azaspiro[3.5]nonanyl, decahydroquinolinyl, decahydroisoquinolinyl or 1-oxaspiro[4.5]decanyl. Such heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Analogously, the term 4- to 9-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C4-9 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-dioxopyrrolidinyl, 2-oxopyrrolidinyl, 1,3-dioxol-4-yl, 1,3- dioxolyl, azepanyl, 1,4-diazepanyl, 2,5-diazabicyclo[2.2.1]-heptanyl, 2,5- diazabicyclo[2.2.2]octanyl, 4,7-diazaspiro[2.5]octanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, quinuclidinyl or pyrrolizidinyl. Such heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Analogously, the term 4- to 7-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C4-7 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-dioxopyrrolidinyl, 2-oxopyrrolidinyl), 1,3-dioxol-4-yl, 1,3- dioxolyl, azepanyl, 1,4-diazepanyl or 2,5-diazabicyclo[2.2.1]-heptyl. Such heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Analogously, term 5- to 6-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-6 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-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-dioxopyrrolidinyl, 2-oxopyrrolidinyl), 1,3-dioxol-4-yl or 1,3-dioxolyl. Such heterocyclyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. As used herein, 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, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4- d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridyl, benzo[b]thienyl, thieno[2,3- d] pyrimidinyl, thieno[3,2-d]pyrimidinyl and the various pyrrolopyridyl, pyridopyrimidinyl, pyrimidopyridazinyl, pyrazinopyrimidinyl, imidazopyridyl, imidazotriazinyl, pyridotriazinyl and triazolopyrimidinyl radicals. Analogously, the term 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]thienyl, thieno[2,3-d] pyrimidinyl, thieno[3,2-d]pyrimidinyl and the various pyrrolopyridyl, imidazopyridyl, imidazotriazinyl, and triazolopyrimidinyl radicals. Analogously, the term 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. As used herein, the term 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. Analogously, the term 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. Analogously, the term 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. As used herein, the term 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. As used herein, the term 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]. As used herein, the term oxo group refers to a =O moiety [i.e. a substituent oxygen atom connected to another atom via a double bond]. As used herein, some of the 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. As used herein, unknown configurations of a chiral center are denoted by the configurational descriptors R* or S*. An example of such notation would be (R*)-5-(2,2-difluorocyclopropyl)-N- ((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, wherein R* means that the configuration at that quiral center is unknown, being R or S, for convenience denoted as R. In general, it has been used the R* configuration for the first eluting peak isolated in the enantiomeric separation, and the S* configuration for the second eluting peak, unless otherwise indicated. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, 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. 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 (and chiral precursors thereof) 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). Whenever a chemical name or structure has been given it has been generated by conventional means or by means of a suitable software. Names for the compounds were generated with ChemDraw Professional, version 18.2. The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment. The term "treatment" as used herein 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. The phrase “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. As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically- acceptable inorganic or organic acids. As used herein, 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. The term 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. Examples of 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. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) 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. As used in the present invention, the term 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. 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'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). 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). In the case of heterobicyclic derivatives that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of the present invention. Typically, 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),
It is particulary preferred that 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).
Formula (IV) It is also preferred that the compound of Formula (I) is a compound of Formula (V). Formula (V) Typically, 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, or a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C3-7 cycloalkyl group, the C6-14 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a – (CH2)0-4-CONR’R’’ group. Preferably, A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a –NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a –CONR’R’’ group. More preferably, A represents a C3-6 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 C3-6 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a –CONR’R’’ group. It is also preferred that 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 pyridyl group, the pyrazinyl group, the pyrimidinyl group, the pyridazinyl group, the pyrrolopyridyl group, the imidazopyridyl group and the indolyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CF3 group, a -NH2 group, a - NHCH3 group, a –OH group, a –(CH2)0-1-OCH3 group, a fluorine atom, a chlorine atom, and a – CONH2 group. Typically, B represents a -NR’- group or -O- atom. Preferably, B represents a -NR’- group. More preferably, B represents a -NH- group. It is also preferably that B represents a -O- atom. Typically, 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group. Preferably, 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group. It is also preferred that 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 C1-4 alkyl group, a cyclopropyl group, a -CF3 group, a –OCH3 group, and a -CON(CH3)2 group. It is also preferred that 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 -CF3 group, a –OCH3 group, and a -CON(CH3)2 group. Preferably D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)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 –(CH2)0-4-NR’R’’ group. More preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group. More preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –OR’ group, an oxo group and a –NR’R’’ group. It is also preferred that 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’. More preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –OR’ group, an oxo group and a -NR’R’’. It is also preferred that D represents a -N(CH3)2 group, a -NH–(CH2)3-OH group, a -N(CH3)- (CH2)2OH group, a -N(CH2CH3)-(CH2)2OH group, a -N(CH3)-(CH2)2OMe group, a -N(CH3)- (CH2)2N(CH3) group, a -O–(CH2)2-OH group, a –(CH2)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[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, the 4,7-diazaspiro[2.5]octanyl group and the 2-oxa-5,8- diazaspiro[3.5]nonanyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CH2F group, a -CHF2 group, a -CF3 group, a -OH group, an oxo group, a –NH2 group and a –NHCH3 group. More preferably 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, the 4,7- diazaspiro[2.5]octanyl group and the 2-oxa-5,8-diazaspiro[3.5]nonanyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CH2F group, a -CHF2 group, a -CF3 group, a -OH group, an oxo group, a –NH2 group and a – NHCH3 group. Typically, X1 represents a nitrogen atom or a carbon atom. Preferably, X1 represents a carbon atom. It is also preferred that X1 represents a nitrogen atom. Typically, X2 represents a nitrogen atom or a carbon atom. Preferably, X2 represents a carbon atom. It is also preferred that X2 represents a nitrogen atom. Typically, X3 represents a nitrogen atom or a -CRc- group. Preferably, X3 represents a -CRc- group. More preferably, X3 represents a -CH- group or a - C(CH3)- group. Even more preferably, X3 represents a -CH- group. It is also preferred that X3 represents a nitrogen atom. Typically, X4 represents a nitrogen atom or a carbon atom. Preferably, X4 represents a carbon atom. It is also preferred that X4 represents a nitrogen atom. Typically, X5 represents a nitrogen atom or a -CRc- group. Preferably, X5 represents a -CRc- group. More preferably, X5 represents a -CH- group, a - C(CH3)- group or a -C(CN)- group. Even more preferably, X5 represents a -CH- group. It is also preferred that X5 represents a nitrogen atom. Preferably Z represents a -NH-group. It is also preferred that Z represents a -CH- group. Typically, R1 is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group. Preferably, R1 represents a hydrogen atom, or a linear or branched C1-4 alkyl group. More preferably, R1 represents a hydrogen atom, or a methyl group. Typically, R2 is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group. Preferably, R2 represents a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group. More preferably, R2 represents a hydrogen atom, a methyl group, an ethyl group, an isobutyl group, a -CH2CF3 group and a –(CH2)2-OH group. Typically, Rc represents a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, or a -CN group. Preferably, Rc represents a hydrogen atom, a linear or branched C1-4 alkyl group, or a -CN group. More preferably, Rc represents a hydrogen atom, a methyl group or a -CN group. Typically, R’ and R’’ are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group. Preferably, R’ and R’’ represent independently a hydrogen atom or a methyl group. In a particular preferred embodiment, in the compound of Formula (I) • 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 C1-4 haloalkyl group, wherein the C3-7 cycloalkyl group, the C6-14 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a –(CH2)0-4-CONR’R’’ group; • B represents a -NR’- group, • C represents a C6-14 aryl group or a monocyclic 5- to 7-membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C6-14 aryl group and the monocyclic 5- to 7-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, and a –(CH2)0-4-CONR’R’’ group; • D represents a -NRaRb- group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’; • X1 and X2 represent a carbon atom; • X3 and X5 each independently represent a nitrogen atom or a -CRc- group; • X4 represents a nitrogen atom or a carbon atom; • Z represents a -NH- group or a -CH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group. In a more preferred embodiment, in the compound of Formula (I), • A represents a C3-7 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 C1-4 haloalkyl group, wherein the C3-7 cycloalkyl group, the C6-14 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a –(CH2)0-4-CONR’R’’ group; • B represents a -NR’- group, • C represents a phenyl group or a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C6-14 aryl 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, and a –(CH2)0-4-CONR’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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’; • X1 and X2 represent a carbon atom; • X3 and X5 each independently represent a nitrogen atom or a -CRc- group; • X4 represents a carbon atom; • Z represents a -NH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group. In a still more preferred embodiment, in the compound of Formula (I), • A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B represents a -NH- group; • 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group; • D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group; • X1, X2 and X4 each indepently represent a carbon atom; • X3 represents a nitrogen atom or a -CRc- group, preferably X3 represents a -CRc-group, and more preferably X3 represents a -CH- group; • X5 represents a nitrogen atom or a -CRc- group, preferably X3 represents a nitrogen atom or a -CH- group; • Z represents a -NH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group ; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom, and a linear or branched C1-4 alkyl group. In one embodiment, the compound of Formula (I) is represented by compound of Formula (II): Formula (II) wherein X3 and X5 each independently represents a nitrogen atom or a -CRc- group. In a preferred embodiment, in the compound of Formula (II), X3 represents a -CRc- group, preferably X3 represents a -CH- group. In another preferred embodiment, in the compound of Formula (II), X3 represents a a nitrogen atom. In a preferred embodiment, in the compound of Formula (II), X5 represents a nitrogen atom. In another preferred embodiment, in the compound of Formula (II), X5 represents a -CRc- group, preferably X5 represents a -CH- group. In a preferred embodiment, in the compound of Formula (II), • A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B represents a -NH- group; • 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group; • D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group; • X3 represents a nitrogen atom or a -CRc- group, preferably X3 represents a nitrogen atom or a -CH-group, and more preferably X3 represents a -CH- group; • X5 represents a nitrogen atom or a -CRc- group, preferably X5 represents a nitrogen atom or a -CH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom, and a linear or branched C1-4 alkyl group. In one embodiment, the compound of Formula (I) is represented by compound of Formula (III): wherein X3 and X5 each independently represents a nitrogen atom or a -CRc- group. In a preferred embodiment, in the compound of Formula (III), X3 represents a -CRc- group, preferably X3 represents a -CH- group. In another preferred embodiment, in the compound of Formula (III), X3 represents a nitrogen atom. In a preferred embodiment, in the compound of Formula (III), X5 represents a nitrogen atom. In another preferred embodiment, in the compound of Formula (III), X5 represents a -CRc- group, preferably X5 represents a -CH- group. In a preferred embodiment, in the compound of Formula (III), • A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B represents a -NH- group; • 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group; • D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group; • X3 represents a nitrogen atom or a -CRc- group, preferably X3 represents a nitrogen atom or a -CH-group, and more preferably X3 represents a -CH- group; • X5 represents a nitrogen atom or a -CRc- group, preferably X5 represents a nitrogen atom or a -CH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group ; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom, and a linear or branched C1-4 alkyl group. In one embodiment, the compound of Formula (I) is represented by compound of Formula (IV): wherein X3 and X5 each independently represents a nitrogen atom or a -CRc- group. In a preferred embodiment, in the compound of Formula (IV), X3 represents a -CRc- group, preferably X3 represents a -CH- group. In another preferred embodiment, in the compound of Formula (IV), X3 represents a nitrogen atom. In a preferred embodiment, in the compound of Formula (IV), X5 represents a nitrogen atom. In another preferred embodiment, in the compound of Formula (IV), X5 represents a -CRc- group, preferably X5 represents a -CH- group. In a preferred embodiment, in the compound of formula (IV), • A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B represents a -NH- group; • 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group; • D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group; • X3 represents a nitrogen atom or a -CRc- group, preferably X3 represents a nitrogen atom or a -CH-group, and more preferably X3 represents a -CH- group; • X5 represents a nitrogen atom or a -CRc- group, preferably X5 represents a nitrogen atom or a -CH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group ; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom, and a linear or branched C1-4 alkyl group. In one embodiment, the compound of Formula (I) is represented by compound of Formula (V): wherein X3 and X5 each independently represents a nitrogen atom or a -CRc- group. In a preferred embodiment, in the compound of Formula (V), X3 represents a -CRc- group, preferably X3 represents a -CH- group. In another preferred embodiment, in the compound of Formula (V), X3 represents a nitrogen atom. In a preferred embodiment, in the compound of Formula (V), X5 represents a nitrogen atom. In another preferred embodiment, in the compound of Formula (V), X5 represents a -CRc- group, preferably X5 represents a -CH- group. In a preferred embodiment, in the compound of Formula (V), • A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B represents a -NH- group; • 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group; • D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group; • X3 represents a nitrogen atom or a -CRc- group, preferably X3 represents a nitrogen atom or a -CH-group, and more preferably X3 represents a -CH- group; • X5 represents a nitrogen atom or a -CRc- group, preferably X5 represents a nitrogen atom or a -CH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group ; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom, and a linear or branched C1-4 alkyl group. In one embodiment, in the compound of Formula (I), • 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 pyridyl group, the pyrazinyl group, the pyrimidinyl group, the pyridazinyl group, the pyrrolopyridyl group, the imidazopyridyl group and the indolyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CF3 group, a -NH2 group, a -NHCH3 group, a –OH group, a –(CH2)0-1-OCH3 group, a fluorine atom, a chlorine atom, and a –CONH2 group; • B represents a -NH- group or a -O- atom; • 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 C1-4 alkyl group, a cyclopropyl group, a -CF3 group, a –OCH3 group, and a -CON(CH3)2 group; • D represents a -N(CH3)2 group, a -NH–(CH2)3-OH group, a -N(CH3)-(CH2)2OH group, a - N(CH2CH3)-(CH2)2OH group, a -N(CH3)-(CH2)2OMe group, a -N(CH3)-(CH2)2N(CH3) group, a -O–(CH2)2-OH group, a –(CH2)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[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, the 4,7-diazaspiro[2.5]octanyl group and the 2-oxa-5,8-diazaspiro[3.5]nonanyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CH2F group, a -CHF2 group, a -CF3 group, a -OH group, an oxo group, a –NH2 group and a –NHCH3 group; • X1 and X2 represent a carbon atom, • X3 represents a -CRc- group, X4 represent a carbon atom, X5 represents a nitrogen atom or a -CRc- group and Z represents a -NH- group, or X3 represents a -CH- group, X4 and X5 represent a nitrogen atom and Z represents a - CH- group, or X3 represents a N atom, X4 represents a carbon atom, X5 represents a nitrogen atom or a -CRc- group and Z represents a -NH- group; • R1 represents a hydrogen atom or a methyl group; • R2 represents a hydrogen atom, a methyl group, a ethyl group, an isobutyl group, a - CH2CF3 group or a –(CH2)2-OH group; • Rc is selected from the group consisting of a hydrogen atom, a methyl group or a -CN group. In a particular embodiment, it is preferred that 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)-3,5-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-(5-(methylamino)pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 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, 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, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-3-ol, 5-(2-aminopyridin-4-yl)-N-((6-((2-methoxyethyl)(methyl)amino)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-(pyrimidin-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(6-aminopyridin-3-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,3-difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-amino-3-methylpyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 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, 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, N-(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, 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, 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, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(2-(trifluoromethyl)pyridin-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(2-aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol, 3-((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-(6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-3- methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-2-methyl- 1H-pyrrolo[2,3-b]pyridin-4-amine, 3-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)propan- 1-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-amino-6-methylpyridin-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-(4-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,4-difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (S*)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (R*)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H,1'H-[3,5'-bipyrrolo[2,3- b]pyridin]-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 5-(3,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2,3-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5-(2,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(3-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,5-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2,5-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(4-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4-chlorophenyl)-N-((6-(piperazin-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)-3-(6-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(5-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-methylpyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(3,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, 5-(2,3-difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(3,4-difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((3-cyclopropyl-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(3-(piperazin-1-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,5-difluoro-2-methoxyphenyl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3-fluoropyridin-4-yl)-N-((6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-isopropyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3-chloropyridin-4-yl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3,4-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, (R*)-5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, (S*)-5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(2-aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((1S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3-(2-aminopyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(imidazo[1,2-a]pyridin-7-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(3,4-difluorophenyl)-N-(1-(2-(piperazin-1-yl)pyrimidin-4-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(1-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)oxy)ethan-1-ol, N1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)- N1,N2-dimethylethane-1,2-diamine, 2-(ethyl(6-(((5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)amino)ethan-1-ol, 5-(3,4-difluorophenyl)-2-methyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)azetidin-3-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)pyrrolidin-3-ol, 5-(2-aminopyridin-4-yl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(1-methyl-1H-pyrazol-4-yl)-N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 5-(2-aminopyridin-4-yl)-N-((4-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)(methyl)amino)ethan-1-ol, 4-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazin-2-one, 2-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-6-((3R,5S)-3,5- dimethylpiperazin-1-yl)-N,N-dimethylnicotinamide, 3-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-amine N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridazin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)picolinamide, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrazin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(6-aminopyrazin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4-aminopyrimidin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(6-aminopyrimidin-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-(6-(methylamino)pyrazin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (S)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydrofuran-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 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, N-((6-((3R,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-b]pyridin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4,4-difluorocyclohexyl)-N-((6-(piperazin-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-(6-(methylamino)pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-(methylamino)pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(2-(methylamino)pyridin-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-(methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-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)-3-(2-(methylamino)pyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(2- (methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 5-(2-amino-3-fluoropyridin-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)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- (methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, 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, 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, 5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, (R*)-5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, (S*)-5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)-2-fluorobenzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(1-methyl-1H-pyrazol-4-yl)-N-((4-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, N-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)-2-fluorobenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-4-ol, 5-(2-aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 2-(methyl(6-(((5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)amino)ethan-1-ol, 2-(methyl(6-(((5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)amino)ethan-1-ol, 5-(2-aminopyridin-4-yl)-N-(3-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-5-(pyrimidin-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(dimethylamino)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(dimethylamino)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2,2-dimethyltetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, 4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 3-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, (1R,4r)-4-(4-(((6-((R)-3-methylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, (1S,4s)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- amine, 5-(tetrahydro-2H-pyran-4-yl)-N-((6-(3,3,5,5-tetramethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((1s,4S)-4-fluorocyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(4-methoxycyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1H-indol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(tetrahydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3-aminoazetidin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-4-((5-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)methoxy)- 7H-pyrrolo[2,3-d]pyrimidine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 3-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-4-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methoxy)- 7H-pyrrolo[2,3-d]pyrimidine, N-((6-(2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 4-(((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol, N-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 3-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, 3-(3,6-dihydro-2H-pyran-4-yl)-4-(((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2- yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorotetrahydro-2H-pyran-4-ol, N-((6-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((1R*,4R*)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((1S*,4S*)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3,5-dimethylpyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)amino)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, (3S*,4S*)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3R*,4R*)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3S*,4R*)-4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3R*,4S*)-4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, N-((4-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,2-difluoro-3-methylcyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-(1-(4-(3,3-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R*,4R*)-2-methyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2S*,4S*)-2-methyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 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, 5-cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof. Of particular interest are the compounds: 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)-3,5-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-(5-(methylamino)pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 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, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrimidin-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(6-aminopyridin-3-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,3-difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-amino-3-methylpyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 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, 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, N-(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, 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, 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, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(2-aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 3-((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-(6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-3- methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-amino-6-methylpyridin-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-(4-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,4-difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (S*)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (R*)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H,1'H-[3,5'-bipyrrolo[2,3- b]pyridin]-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 5-(3,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2,3-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(3-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,5-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2,5-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(4-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4-chlorophenyl)-N-((6-(piperazin-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)-3-(6-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(5-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-methylpyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(3,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, 5-(2,3-difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(3,4-difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((3-cyclopropyl-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,5-difluoro-2-methoxyphenyl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3-chloropyridin-4-yl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3,4-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, (S*)-5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(2-aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((1S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3-(2-aminopyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(imidazo[1,2-a]pyridin-7-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(3,4-difluorophenyl)-N-(1-(2-(piperazin-1-yl)pyrimidin-4-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(1-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)- N1,N2-dimethylethane-1,2-diamine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)(methyl)amino)ethan-1-ol, 4-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazin-2-one, 3-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)picolinamide, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrazin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(6-aminopyrazin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4-aminopyrimidin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(6-aminopyrimidin-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-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (S)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydrofuran-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(4,4-difluorocyclohexyl)-N-((6-(piperazin-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-(6-(methylamino)pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-(methylamino)pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(2-(methylamino)pyridin-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-(methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-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)-3-(2-(methylamino)pyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(2- (methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 5-(2-amino-3-fluoropyridin-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)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- (methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, 5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, (R*)-5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, (S*)-5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, 4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 3-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, (1R,4r)-4-(4-(((6-((R)-3-methylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, 5-(tetrahydro-2H-pyran-4-yl)-N-((6-(3,3,5,5-tetramethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((1s,4S)-4-fluorocyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(4-methoxycyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1H-indol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 3-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 4-(((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 3-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, 3-(3,6-dihydro-2H-pyran-4-yl)-4-(((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2- yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((1R*,4R*)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((1S*,4S*)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)amino)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, (3R*,4R*)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3R*,4S*)-4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, N-((4-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,2-difluoro-3-methylcyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-(1-(4-(3,3-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R*,4R*)-2-methyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 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, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof. 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). In the Formula (XI), 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.
Scheme 1 Alternatively, compounds of formula (I) may also be prepared from compounds of Formula (X) in a two step synthesis, as illustrated in Scheme 2. In the fist step, 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). In the Formula (XII), 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. Scheme 2 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. In the particular case where B is a NR’ group, 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. Alternatively, 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. In the particular case where B is an oxygen atom, 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. Scheme 3 Alternatively, 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). In the Formula (XI), 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 to give compounds of Formula (XVI). In a second step, 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). In the particular case where B is a NR’ group, 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. Alternatively, 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. In the particular case where B is an oxygen atom, 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.
Scheme 4 In the particular case where R2 is hydrogen, 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. Scheme 5 In the particular case where R2 is hydrogen, 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. Scheme 6 In any step of the synthetic sequences described above, any reactant and intermediate can be used in a protected form to prevent certain functional groups from undergoing undesired reactions. In these cases, 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. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. In the cases where the above-described processes for the preparation of the compounds of this invention gives mixtures of stereoisomers, this stereoisomers may be separated at any convenient step of the synthetic route. In particular, 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. When more than one stereocenter is present in the molecules, mixtures of diastereomers may be obtained during the process of preparation of the compounds of this invention. In this cases, the use of conventional purification techniques may conduct to the isolation of single isomers or to the obtention of mixtures of two or more diastereomers, not necessarily in the same proportion. The syntheses of the compounds of the invention are illustrated by the following Examples (1 to 208) including Intermediates (1 to 155), and are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description. Starting compounds are commercially available or may be obtained following the conventional synthetic methods already known in the art. Abbreviations: ACN Acetonitrle BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl br Broad Celite® Diatomaceous earth d Doublet dd Doublet of doublets DCM Dichloromethane DEA Diethylamine DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO Dimethylsulfoxide DMSO-d6 Deuterated Dimethylsulfoxide EDCI.HCl 3-((Ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol h Hour HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate IPA Isopropanol m Multiplet MeOH Methanol min Minutes NMR Nuclear magnetic resonance Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) q Quartet s Singlet SFC Superfluid chromatography t Triplet td Triple doublet TFA Trifluoroacetic acid THF Tetrahydrofuran XantPhos 5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Analytical methods: LCMS method 1, LCMS 1 Apparatus: Waters Acquity UPLC I-Class system; Bin. Pump: BSM, SM with SO; PDA; TQD; ESI, pos/neg 160-900; column: Waters Acquity UPLC BEH C-18, 50x2.1mm, 1.7µm, 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 µL. 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 µm, 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. Pump: BSM, SM with SO; PDA; SQD; ESI, pos/neg 160- 900; column: Waters Acquity UPLC BEH C-18, 50x2.1mm, 1.7µm, 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. Pump: BSM, SM with SO; PDA; SQD; ESI, pos/neg 160- 900; column: Waters Acquity UPLC BEH C-18, 50x2.1mm, 1.7µm, 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 1H 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. Instrument type: Biotage Isolera® automated purification system equipped with a silica gel (40-63 µm) column (column sizes: 4-330 g) The solvent system and gradients used are indicated in the preparations. The appropriate fractions were collected and the solvents evaporated under reduced pressure. Reverse phase chromatography Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water- acetonitrile/MeOH (1:1) from 0% to 100% acetonitrile/MeOH (1:1) in 40 column volumes. The conditions “formic acid buffer” refer to the use of 0.1% v/v formic acid in both phases. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized. Preparative LC-MS Apparatus: Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. When a purification method refers to “buffered conditions”, Eluent A: 0.05% formic acid + 0.05% ammonia in water, Eluent B: 0.05% formic acid + 0.05% ammonia in acetonitrile/methanol (1/1). Column: Symmetry Prep C18, 300x19mm, 7 µm. Flow rate: 18mL/min. Make-up pump at 0.5mL/min using eluent C: 0.1% formic acid in water/methanol (1/1). When a purification method refers to “basic conditions”, Eluent A: 0.05% ammonia in water, Eluent B: 0.05% ammonia in acetonitrile/methanol (1/1). Column: XBridge prep C18, 150x19mm, 5 µm. Flow rate: 20mL/min. Make-up pump at 0.5mL/min using eluent C: 0.1% formic acid in water/methanol (1/1). EXAMPLES The syntheses of the compounds of the invention are illustrated by the following Examples which do not limit the scope of the invention in any way. INTERMEDIATE 1 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a of solution 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 21.5 mmol) in 70 mL acetone, methylbenzenesulfonyl chloride (4.1 g, 21.5 mmol) was added. Then an aqueous solution of NaOH (1 g in 9.7 mL of water, 25 mmol) was added and stirred overnight at room temperature. The reaction mixture was poured in a mixture of ice/water and the precipitate was filtered and washed with water. The solid obtained was dried in the vacuum oven overnight at 40 ºC to yield the title compound (7.4 g, 89% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 386-388 [M+1]+ LCMS 3 r.t. (min.): 1.90 INTERMEDIATE 2 5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine To a suspension of sodium hydride (268 mg, 11 mmol) in 10 mL DMF cooled in an ice-water bath was added 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 8.6 mmol) in 10 mL DMF. Gas evolution was generated. After 30 min., (2-(chloromethoxy)ethyl)trimethylsilane (1.6 g, 9.5 mmol) in 10 mL DMF was added and the mixture was slowly allowed to warm to room temperature stirring overnight. The reaction mixture was poured in a mixture of ice-water and extracted twice with ethyl acetate. The combined organic layers were washed water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (DCM to DCM/MeOH 98:2 gradient) to give the title compound (2.1 g, 67% yield) as a white solid. Purity based on LC-MS 67%. LRMS (m/z): 362-364 [M+1]+ LCMS 3 r.t. (min.): 2.11 INTERMEDIATE 3 4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained from 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, (2-(chloromethoxy)ethyl)trimethylsilane and sodium hydride following the synthetic procedure described in Intermediate 2. The crude product was purified using flash chromatography (hexanes/EtOAc gradient, 100:0 rising to 0:100) to yield the title compound (3.3 g, 75% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 410 [M+1]+ LCMS 3 r.t. (min.): 2.23 INTERMEDIATE 4 5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a suspension of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (1.2 g, 3.3 mmol) in 7 N ammonia in methanol (38 mL, 280 mmol) was stirred and heated overnight at 110 ºC in a sealed tube. The reaction mixture was evaporated and the crude product was purified using flash chromatography (hexanes/EtOAc gradient, 100:0 rising to 0:100) to yield the title compound (0.7 g, 61% yield) as an off-white solid. Purity based on LC-MS 98%. LRMS (m/z): 343-345 [M+1]+ LCMS 3 r.t. (min.): 1.70 INTERMEDIATE 5 3-Bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine 3-Bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine was obtained from 3,4-Dibromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine following the synthetic procedure described in Intermediate 1 to give the title compound (1.6 g, 94% yield) as a white solid. Purity based on LC-MS 98%. LCMS 2 r.t. (min.): 3.47 LRMS (m/z): 385-387 [M+1]+ INTERMEDIATE 6 3-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 3-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine was obtained from 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine following the synthetic procedure described in Intermediate 2. The crude product was purified using flash chromatography (hexanes- diethylether gradient, 100:0 rising to 60:40) to yield the title compound (1.56 g, 72%) as a colourless oil . Purity based on LC-MS 87%. LRMS (m/z): 361-363 [M+1]+ LCMS 3 r.t. (min.): 2.23 INTERMEDIATE 7 3,4-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine a) 3,4-Dibromo-1H-pyrrolo[2,3-b]pyridine To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (4 g, 20 mmol) in 100 mL DCM cooled in an ice-water bath, N-bromosuccinimide (3.7 g, 21 mmol) was added and stirred at 0 ºC for 1h. The precipite was filtered and washed with DCM. The solid obtained was dried in the vacuum oven overnight at 40 ºC to obtain the title compound (3.1 g) as an off-white solid. The organic filtered was concentrated under reduced pressure and purified using flash chromatography (DCM to DCM/MeOH 98:2 gradient, 100:0 rising to 60:40) to yield the title compound (5.3 g, 94% yield) as an off-white solid . Purity based on LC-MS 97%. LRMS (m/z): 275-277 [M+1]+ LCMS 3 r.t. (min.): 1.59 b) 3,4-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine The title compound was obtained from 3,4-dibromo-1H-pyrrolo[2,3-b]pyridine following the synthetic procedure described in Intermediate 2 as a colourless oil (0.7 g, 43% yield). Purity based on LC-MS 97%. LRMS (m/z): 405-407 [M+1]+ LCMS 3 r.t. (min.): 2.26 INTERMEDIATE 8 3,4-Dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine The title compound was obtained from 3,4-dibromo-1H-pyrrolo[2,3-b]pyridine following the synthetic procedure described in Intermediate 1. The reaction mixture was poured in a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude was macerated with hexanes/EtOAc (4:1) obtaining the title compound (1.2 g, 77% yield) as a solid. Purity based on LC-MS 95%. LRMS (m/z): 429-431 [M+1]+ LCMS 3 r.t. (min.): 2.06 INTERMEDIATE 9 3,4-Dibromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine A solution of 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 8, 100 mg, 0.23 mmol) in 5 mL THF was cooled to -78 ºC, and lithium diisopropylamide solution (2M in THF, 0.175 mL, 0.350 mmol) was added dropwise under an argon atmosphere. Stirring was continued at -78 ºC for 2 hours. Then iodomethane (5 mL, 0.35 mmol) was added dropwise and the mixture was stirred at -78 ºC for a further 2 hours. The cooling bath was removed and the mixture was quenched with a 4 M aqueous solution of sodium bicarbonate and warmed to room temperature. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure obtaining the desired compound (96 mg, 92% yield) as a brown oil. Purity based on LC- MS 85%. LRMS (m/z): 443-445 [M+1]+ LCMS 3 r.t. (min.): 2.14 INTERMEDIATE 10 4-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 4-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine was obtained from 4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine, (2-(chloromethoxy)ethyl)trimethylsilane following the synthetic procedure described in Intermediate 2. The crude product was purified using flash chromatography (hexanes/EtOAc, 100:0 rising to 0:100) to give the title compound (96 mg, 14% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 411 [M+1]+ LCMS 3 r.t. (min.): 2.13 INTERMEDIATE 11 3,4-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine a) 3,4-Dibromo-1H-pyrazolo[3,4-b]pyridine The title compound was obtained from 4-bromo-1H-pyrazolo[3,4-b]pyridine and N- bromosuccinimide following the experimental procedure describe for intermediate HB2C.1 stirring the reaction for 3 hours. The reaction crude was filtered and washed with dichloromethane. The solid obtained was dried in the vacuum oven overnight at 40 ºC to obtain the title compound (839 mg, 98% yield) as an off-white.. Purity based on LC-MS 97%. LRMS (m/z): 276-278 [M+1]+ LCMS 3 r.t. (min.): 1.48 b) 3,4-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine The title compound was obtained from 3,4-dibromo-1H-pyrazolo[3,4-b]pyridine, (2- (chloromethoxy)ethyl)trimethylsilane and sodium hydride following the synthetic procedure described for Intermediate 2. The crude product was purified using flash chromatography (hexanes/EtOAc gradient, 100:0 rising to 0:100) to give the title compound (2.7 g, 40% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 406-408 [M+1]+ LCMS 3 r.t. (min.): 2.29 INTERMEDIATE 12 4-Chloro-5-iodo-2-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine a) 4-Chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.65 g, 3.87 mmol) in 10 mL DMF, N-Iodosuccinimide (1.0 g, 4.44 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was poured in water and extracted twice in ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated to dryness to obtain the title compound (1.4 g, 98% yield ) as an orange oil. Purity based on LC-MS 75%. LRMS (m/z): 294 [M+1]+ LCMS 3 r.t. (min.): 1.90 b) 4-Chloro-5-iodo-2-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine 4-Chloro-5-iodo-2-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained from 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine following the synthetic procedure described in Intermediate 2. The crude product was purified using flash chromatography (hexanes-diethylether gradient, 100:0 rising to 60:40) to give the title compound (0.85 g, 37% yield) as a colourless oil. Purity based on LC-MS 98%. LRMS (m/z): 424 [M+1]+ LCMS 3 r.t. (min.): 2.16 INTERMEDIATE 13 (6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methanamine a) 6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)picolinonitrile A mixture of 6-fluoropicolinonitrile (1.00 g, 8.19 mmol), (2R,6S)-2,6-dimethylpiperazine (935 mg, 8.19 mmol) and DIEA (5.70 mL, 32.72 mmol) in 10 mL of DMSO was heated at 80 ºC for 1.5 hours. The solution was poured into water and the mixture was extracted with ethyl acetate (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (95:4.5:0.5) to give the title compound (1.44 g, 81% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 217 [M+1]+ LCMS 2 r.t. (min.): 0.95 b) (6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methanamine To a degassed solution of 6-((3R,5S)-3,5-dimethylpiperazin-1-yl)picolinonitrile (1.44 g, 6.66 mmol) in 15 mL of (methanol/7N ammonia) was added Nickel-Raney (water suspension, 5 mL) and the mixture was stirred at room temperature under hydrogen atmosphere for 20 hours. The reaction mixture was then filtered through a Celite® pad, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (1.40 g, 95% yield) as a clear green oil, which was used in the next step without any further purification. Purity based on LC-MS 100%. LRMS (m/z): 221 [M+1]+ LCMS 2 r.t. (min.): 0.32 INTERMEDIATE 14 1-(6-(Aminomethyl)pyridin-2-yl)piperidin-3-ol The title compound was prepared from 6-fluoropicolinonitrile and piperidin-3-ol following the experimental procedure described in Intermediate 13. Purity based on LC-MS 87%. LRMS (m/z): 208 [M+1]+ LCMS 3 r.t. (min.): 0.55 INTERMEDIATE 15 6-(Aminomethyl)-N-(2-methoxyethyl)-N-methylpyridin-2-amine The title compound was prepared from 6-fluoropicolinonitrile and 2-methoxy-N-methylethan-1- amine following the experimental procedure described in Intermediate 13. Purity based on LC- MS 100%. LRMS (m/z): 196 [M+1]+ LCMS 3 r.t. (min.): 0.61 INTERMEDIATE 16 6-Fluoro-N-methoxy-N-methylpicolinamide To a solution of 6-fluoropicolinic acid (1.00 g, 7.09 mmol) in 50 mL of DCM, oxalyl chloride (0.73 mL, 8.50 mmol) and DMF (3 drops) were added. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 ºC, N,O-dimethylhydroxylamine hydrochloride (761 mg, 7.80 mmol) and pyridine (1.25 mL, 15.60 mmol) were added and the reaction mixture was allowed to warm to room temperature. The solution was partitioned between saturated aqueous solution of sodium bicarbonate and DCM, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% hexane to hexane/ethyl acetate (25:75) to give the title compound (910 mg, 70% yield) as a clear oil. Purity based on LC-MS 100%. LRMS (m/z): 185 [M+1]+ LCMS 2 r.t. (min.): 1.57 INTERMEDIATE 17 1-(6-Fluoropyridin-2-yl)ethan-1-one To a -10 ºC cooled solution of 6-fluoro-N-methoxy-N-methylpicolinamide (100 mg, 0.54 mmol) in 2.5 mL of THF was added methylmagnesium bromide (3M solution in diethylether, 0.36 mL, 1.09 mmol) and the reaction mixture was stirred at -10 ºC until starting material was consumed. Saturated aqueous solution of ammonium chloride was added, the mixture was extracted with diethylether (x 2), the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (47 mg, 62% yield) as a clear oil, which was used in the next step without any further purification. Purity based on LC-MS 100%. LCMS 2 r.t. (min.): 1.90 INTERMEDIATE 18 1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine a) 1-(6-Fluoropyridin-2-yl)ethan-1-amine To a solution of 1-(6-fluoropyridin-2-yl)ethan-1-one (100 mg, 0.72 mmol) in 1 mL of ethanol was added hydroxylamine (50% in water, 50 µL, 0.81 mmol) and the reaction mixture was heated at 60 ºC for 1 hour. Zinc dust (235 mg, 3.59 mmol) and concentrated hydrochloric acid (3 drops) were added and the resulting mixture was stirred at room temperature for 1 hour. The suspension was filtered and the filtrate was concentrated to dryness to give the title compound (100 mg), which was used in the next step without any further purification. Purity based on LC-MS 70%. LRMS (m/z): 185 [M+1]+ LCMS 2 r.t. (min.): 1.57 b) 1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine A mixture of 1-(6-fluoropyridin-2-yl)ethan-1-amine (100 mg, 0.71 mmol) and (2R,6S)-2,6- dimethylpiperazine (325 mg, 2.85 mmol) in 1 mL of N,N-dimethylacetamide was heated at 100 ºC until starting material was consumed. The reaction mixture was directly purified by reverse phase chromatography eluting with water to ACN/MeOH (1:1) to give the title compound (113 mg). Purity based on LC-MS 70%. LRMS (m/z): 235 [M+1]+ LCMS 2 r.t. (min.): 0.30 INTERMEDIATE 19 (R)-N-((S)-1-(6-Fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide a) (R,E)-N-(1-(6-Fluoropyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide A mixture of 1-(6-fluoropyridin-2-yl)ethan-1-amine (622 mg, 4.47 mmol), tetraethoxytitanium (1.7 mL, 8.25 mmol) and (R)-2-methylpropane-2-sulfinamide (500 mg, 4.12 mmol) in 20 mL of THF was heated at 70ºC for 18 hours. The reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and brine. The mixture was stirred at room temperature for 30 minutes, the resulting suspension was filtered through a Celite® pad and concentrated to dryness. The crude product was purified by flash chromatography eluting with 100% hexane to hexane/ethyl acetate (70:30) to give the title compound (650 mg, 65% yield) as a yellow oil. Purity based on LC-MS 95%. LRMS (m/z): 243 [M+1]+ LCMS 2 r.t. (min.): 2.58 b) (R)-N-((S)-1-(6-Fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide To a -78 ºC cooled solution of (R,E)-N-(1-(6-fluoropyridin-2-yl)ethylidene)-2-methylpropane-2- sulfinamide (640 mg, 2.64 mmol) in 15 mL of THF was added L-selectride (1M in THF, 8.0 mL, 8.00 mmol) and the reaction mixture was stirred at -78 ºC for 1h. Additional L-selectride (1M in THF, 8.0 mL, 8.00 mmol) was added and the mixture was stirred at -78 ºC for 2.5 hours. Saturated aqueous solution of ammonium chloride was added and the resulting mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the organic layer was separated and the aqueous phase was extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with hexane/ethyl acetate (50:50) to 100% ethyl acetate to give the title compound (585 mg, 89% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 245 [M+1]+ LCMS 2 r.t. (min.): 2.20 INTERMEDIATE 20 (S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine a) (R)-N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-2-methylpropane- 2-sulfinamide A mixture of (R)-N-((S)-1-(6-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (585 mg, 1.11 mmol) and (2R,6S)-2,6-dimethylpiperazine (507 mg, 4.44 mmol) in 2.5 mL of N,N- dimethylacetamide was heated at 100 ºC for 96 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (95:4.5:0.5) to give the title compound (463 mg, 57% yield) as a yellow oil. Purity based on LC-MS 100%. LRMS (m/z): 339 [M+1]+ LCMS 2 r.t. (min.): 1.45 b) (S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine To a solution of (R)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-2- methylpropane-2-sulfinamide (325 mg, 0.79 mmol) in 2 mL of MeOH was added hydrochloric acid (4N solution in dioxane, 1.0 mL, 4.00 mmol)and the solution was stirred at room temperature for 1 hour. The solvent was concentrated to dryness, the residue was triturated with water, the pH of the solution was adjusted to 12 by addition of 6N sodium hydroxide solution and the mixture was extracted with ethyl acetate (x 3). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (318 mg, 100 % yield) as a yellow oil. Purity based on LC-MS 91%. LRMS (m/z): 235 [M+1]+ LCMS 2 r.t. (min.): 1.47 INTERMEDIATE 21 (2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methanamine a) 2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidine-4-carbonitrile A mixture of 2-chloropyrimidine-4-carbonitrile (500 mg, 3.58 mmol), (2R,6S)-2,6- dimethylpiperazine (510 mg, 4.46 mmol) and triethylamine (0.65 mL, 4.49 mmol) in 5 mL of ACN was heated in a microwave reactor at 150 ºC for 1 hour. The mixture was poured into water, extracted with ethyl acetate (x3), the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (640 mg, 82% yield) as a yellow oil, which was used in the next step without any further purification. Purity based on LC-MS 91%. LRMS (m/z): 218 [M+1]+ LCMS 3 r.t. (min.): 0.44 b) (2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methanamine To a solution of 2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidine-4-carbonitrile (640 mg, 2.94 mmol) in 5 mL of MeOH was added 10% palladium on carbon (18 mg, 0.017 mmol) and the suspension was stirred under a hydrogen atmosphere at room temperature for 3 hours. Additional 10% palladium on carbon (18 mg, 0.017 mmol) was added and the suspension was stirred under hydrogen atmosphere for additional 18 h. The catalyst was then filtered through a Celite® pad, washing with methanol several times. The filtrate and washings were combined and the solvent was evaporated to dryness to give the title compounds (780 mg, 96% yield) as light green oil, which was used in the next step without any further purification. LRMS (m/z): 222 [M+1]+ LCMS 3 r.t. (min.): 0.20 INTERMEDIATE 22 (6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazin-2-yl)methanamine a) 6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazine-2-carbonitrile To a solution of 6-chloropyrazine-2-carbonitrile (250 mg, 1.79 mmol) in 2 mL of butan-1-ol was added (2R,6S)-2,6-dimethylpiperazine and the reaction mixture was stirred at 90 ºC for 10 min. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography eluting with 100% DCM to DCM/7N ammonia in MeOH (80:18:2) to give the title compound (325 mg, 83% yield) as a yellow solid. Purity based on LC-MS 93%. LRMS (m/z): 218 [M+1]+ LCMS 2 r.t. (min.): 1.78 b) (6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazin-2-yl)methanamine To a solution of 6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazine-2-carbonitrile (275 mg, 1.27 mmol) in ammonia (7N in MeOH, 17 mL) was added Nickel-Raney (water suspension, 1 mL) and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through a Celite® pad, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (317 mg, 100% yield) as a clear green oil. Purity based on LC-MS 80%. LRMS (m/z): 222 [M+1]+ LCMS 2 r.t. (min.): 1.17 INTERMEDIATE 23 (6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methanamine a) (3R,5S)-1-(6-Chloro-4-(trifluoromethyl)pyridin-2-yl)-3,5-dimethylpiperazine A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (2.00 g, 9.25 mmol), (2R,6S)-2,6- dimethylpiperazine (1.0g, 9.19 mmol) and triethylamine (5.1 mL, 37.00 mmol) in 46 mL of 1,4- dioxane was stirred at 90 ºC overnight. The mixture was cooled down to room temperature, the suspension was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.41 g, 89% yield) as an orange solid. Purity based on LC-MS 95%. LRMS (m/z): 294 [M+1]+ LCMS 2 r.t. (min.): 1.72 b) (3R,5S)-1-(6-Chloro-4-(trifluoromethyl)pyridin-2-yl)-3,5-dimethylpiperazine To a solution of (3R,5S)-1-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3,5-dimethylpiperazine (1.00 g, 3.40 mmol) in 12 mL of DMF/water (99:1) was added zinc cyanide (24 mg, 2.04 mmol), Pd2(dba)3 (156 mg, 0.17 mmol) and dppf (189 mg, 0.34 mmol) under argon atmosphere. The reaction mixture was stirred at 120 ºC for 1 hour. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (95:4.5:0.5) to give the title compound (756 mg, 78% yield) as a brown solid. Purity based on LC-MS 89%. LRMS (m/z): 285 [M+1]+ LCMS 2 r.t. (min.): 1.48 c) (6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methanamine To a solution of (3R,5S)-1-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-3,5-dimethylpiperazine (656 mg, 2.31 mmol) in 50 mL of ammonia (7N in MeOH) was added Nickel-Raney (water suspension, 5 mL) and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through a Celite® pad, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (317 mg, 100% yield) as a clear green oil. Purity based on LC-MS 80%. LRMS (m/z): 289 [M+1]+ LCMS 2 r.t. (min.): 0.37 INTERMEDIATE 24 2-((6-(Aminomethyl)-4-(trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol The title compound was prepared from 2,6-dichloro-4-(trifluoromethyl)pyridine and 2- (methylamino)ethan-1-ol following the experimental procedure described in Intermediate 23. Purity based on LC-MS 98%. LRMS (m/z): 255 [M+1]+ LCMS 2 r.t. (min.): 2.80 INTERMEDIATE 25 3-Amino-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol a) (E)-N-((6-Fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of 6-fluoropicolinaldehyde (500 mg, 4.00 mmol) and 2-methylpropane-2-sulfinamide (581 mg, 4.80 mmol) in 10 mL of DCM was added copper (II) sulphate (1.28 g, 8.02 mmol) and the reaction mixture was stirred at room temprature for 72 hours. The mixture was filtered through a Celite® pad and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography eluting with hexane/ethyl acetate (50:50) to 100% ethyl acetate to give the title compound (860 mg, 94%) as a yellow oil. Purity based on LC-MS 99%. LRMS (m/z): 229 [M+1]+ LCMS 2 r.t. (min.): 2.42 b) Ethyl 3-((tert-butylsulfinyl)amino)-3-(6-fluoropyridin-2-yl)propanoate A mixture of ethyl acetate (1.1 mL, 11.26 mmol) and THF (8 mL) was cooled to -78 ºC and lithium diisopropylamide (2M in THF, 5.5 mL, 11.00 mmol) was added. The mixture was stirred at -78 ºC for 30 minutes, a solution of (E)-N-((6-fluoropyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide (860 mg, 3.77 mmol) in 4 mL of THF was added and the mixture was stirred at -78 ºC for 30 minutes. Saturated aqueous solution of ammonium chloride was added, the mixture was extracted with ethyl acetate (x3), the combined organic layers were washed with brine, dried over magnesium sulphate and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography eluting with hexane/ethyl acetate (50:50) to 100% ethyl acetate to give the title compound (910 mg, 76% yield) as pale yellow oil. Purity based on LC-MS 90%. LRMS (m/z): 317 [M+1]+ LCMS 2 r.t. (min.): 2.40 c) Ethyl 3-((tert-butylsulfinyl)amino)-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)propanoate A mixture of ethyl 3-((tert-butylsulfinyl)amino)-3-(6-fluoropyridin-2-yl)propanoate (900 mg, 2.84 mmol) and (2R,6S)-2,6-dimethylpiperazine (1.30 g, 11.38 mmol) in 6 mL of N,N- dimethylacetamide was heated at 100 ºC. The 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. (min.): 1.60 d) Ethyl 3-amino-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propanoate To a solution of ethyl 3-((tert-butylsulfinyl)amino)-3-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)propanoate (325 mg, 0.79 mmol) in 2 mL of MeOH was added hydrochloric acid (4N in dioxane, 1.0 mL, 4.0 mmol) and the mixture was stirred at room temperature for 1,5 hours. The solvent was concentrated to dryness, water was added and the pH of the solution was adjusted to 10 by addition of 6N sodium hydroxide solution. The solution was extracted with ethyl acetate (x3), the combined organic layers were washed with brine, dried over magnesium sulphate and the solvent was evaporated under vacuum to give the title compound (193 mg, 79% yield) as a yellow oil, which was used without any further purification. Purity based on LC-MS 90%. LRMS (m/z): 307 [M+1]+ LCMS 2 r.t. (min.): 0.42, 0.62 e) 3-Amino-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol To a 0 ºC cooled solution of ethyl 3-amino-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)propanoate (147 mg, 0.48 mmol) in 2 mL of THF was added lithium aluminium hydride (1M in THF, 0.96 mL, 0.96 mmol) and the mixture was stirred at 0 ºC for 30 min. Water and 2M sodium hydroxide solution were added, the mixture was extracted with ethyl acetate (x3), the combined organic layeres were washed with brine, dried over magnesium sulphate and the solvent was evaporated under vacuum to give the title compound (35 mg, 27% yield) as a yellow oil, which was used without any further purification. LRMS (m/z): 265 [M+1]+ LCMS 2 r.t. (min.): 0.33 INTERMEDIATE 26 (R)-N-((S)-1-(6-Fluoropyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide a) 1-(6-Fluoropyridin-2-yl)propan-1-one The title compound was prepared from 6-fluoro-N-methoxy-N-methylpicolinamide and ethylmagnesium bromide following the experimental procedure described in Intermediate 17. Purity based on LC-MS 99%. LRMS (m/z): 154 [M+1]+ LCMS 2 r.t. (min.): 2.37 b) (R,E)-N-(1-(6-Fluoropyridin-2-yl)propylidene)-2-methylpropane-2-sulfinamide The title compound was prepared from 1-(6-fluoropyridin-2-yl)propan-1-one following the experimental procedure described in Intermediate 19a. Purity based on LC-MS 96%. LRMS (m/z): 257 [M+1]+ LCMS 2 r.t. (min.): 2.75 c) (R)-N-((S)-1-(6-Fluoropyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide The title compound was prepared from (R,E)-N-(1-(6-fluoropyridin-2-yl)propylidene)-2- methylpropane-2-sulfinamide following the experimental procedure described in Intermediate 19b. Purity based on LC-MS 96%. LRMS (m/z): 259 [M+1]+ LCMS 2 r.t. (min.): 2.30 INTERMEDIATE 27 (S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-amine The title compound was prepared from (R)-N-((S)-1-(6-fluoropyridin-2-yl)propyl)-2- methylpropane-2-sulfinamide and (2R,6S)-2,6-dimethylpiperazine following the experimental procedure described in Intermediate 20. Purity based on LC-MS 96%. LRMS (m/z): 249 [M+1]+ INTERMEDIATE 28 (R)-N-((S)-1-(6-Fluoropyridin-2-yl)-3-methylbutyl)-2-methylpropane-2-sulfinamide The title compound was prepared from 6-fluoro-N-methoxy-N-methylpicolinamide and isobutylmagnesium bromide following the experimental procedure described in Intermediate 26. Purity based on LC-MS 94%. LRMS (m/z): 287 [M+1]+ LCMS 2 r.t. (min.): 2.72 INTERMEDIATE 29 (S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)-3-methylbutan-1-amine The title compound was prepared from (R)-N-((S)-1-(6-fluoropyridin-2-yl)-3-methylbutyl)-2- methylpropane-2-sulfinamide and (2R,6S)-2,6-dimethylpiperazine following the experimental procedure described in Intermediate 20. Purity based on LC-MS 88%. LRMS (m/z): 277 [M+1]+ LCMS 2 r.t. (min.): 0.47, 0.78 INTERMEDIATE 30 3-(6-(Aminomethyl)pyridin-2-yl)propan-1-ol a) 6-(3-Hydroxyprop-1-yn-1-yl)picolinonitrile A mixture of 6-bromopicolinonitrile (2.00 g, 10.93 mmol), prop-2-yn-1-ol (0.44 mL, 11.24 mmol), tetrakis(triphenylphosphine)palladium(0) (631 mg, 0.55 mmol) and copper (I) iodide (145 mg, 0.76 mmol) in 20 mL of DCM/triethylamine (50:50) was heated at 70 ºC overnight, under argon atmosphere. The mixture was filtered through a Celite® pad, washed with ethyl acetate and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography eluting with 100% DCM to DCM/MeOH (98:2) to give the title compound (896 mg, 52% yield). Purity based on LC-MS 100%. LRMS (m/z): 159 [M+1]+ LCMS 3 r.t. (min.): 0.74 b) 6-(3-Hydroxypropyl)picolinonitrile To a solution of 6-(3-hydroxyprop-1-yn-1-yl)picolinonitrile (250 mg, 1.58 mmol) in 2 mL of MeOH was added dihydroxypalladium (20% w/w, 50 mg, 0.07 mmol) and the mixture was stirred under hydrogen atmosphere for 7 hours. The mixture was filtered, washing several times with MeOH and the combined organic layers were evaporated under reduced pressure to give the title compound (222 mg, 86% yield) as a deep yellow oil, which was used in the next step without any further purification. Purity based on LC-MS 78%. LRMS (m/z): 163 [M+1]+ LCMS 3 r.t. (min.): 0.78 c) 3-(6-(Aminomethyl)pyridin-2-yl)propan-1-ol To a solution of 6-(3-hydroxypropyl)picolinonitrile (222 mg, 1.37 mmol) in 8 mL of ammonia (7N solution in MeOH) was added Nickel-Raney (water suspension, 5 mL) and the mixture was stirred at room temperature under hydrogen atmosphere for 3.5 hours. The reaction mixture was then filtered through a Celite® pad, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (277 mg, 100% yield) as a yellow oil. Purity based on LC-MS 37%. LRMS (m/z): 167 [M+1]+ LCMS 3 r.t. (min.): 0.32 INTERMEDIATE 31 (6-(3-(Fluoromethyl)piperazin-1-yl)pyridin-2-yl)methanamine The title compound was prepared from 6-fluoropicolinonitrile and 2-(fluoromethyl)piperazine dihydrochloride following the experimental procedure described in Intermediate 13. Purity based on LC-MS 98%. LRMS (m/z): 225 [M+1]+ LCMS 3 r.t. (min.): 0.25 INTERMEDIATE 32 Tert-butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 6-fluoropicolinonitrile and tert-butyl (2R,6S)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 13. Purity based on LC-MS 96%. LRMS (m/z): 322 [M+1]+ LCMS 3 r.t. (min.): 1.26 INTERMEDIATE 33 Tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate The title compound was prepared from 6-fluoropicolinonitrile and tert-butyl 2,2- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 13. Purity based on LC-MS 100%. LRMS (m/z): 322 [M+1]+ LCMS 3 r.t. (min.): 1.19 INTERMEDIATE 34 Tert-butyl 8-(6-(aminomethyl)pyridin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate a) 6-(2-Oxa-5,8-diazaspiro[3.5]nonan-8-yl)picolinonitrile The title compound was prepared from 6-fluoropicolinonitrile and 2-oxa-5,8- diazaspiro[3.5]nonane hydrochloride following the experimental procedure described in Intermediate 13a, followed by purification eluting with 100% hexane to 100% ethyl acetate. Purity based on LC-MS 95%. LRMS (m/z): 232 [M+1]+ LCMS 3 r.t. (min.): 0.65 b) Tert-butyl 8-(6-cyanopyridin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate To a solution of 6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)picolinonitrile (530 mg, 2.30 mmol) in 5 mL of THF were added di-tert-butyl dicarbonate (525 mg, 2.40 mmol) in 5 mL of THF and triethylamine (0.64 mL, 4.60 mmol). The resulting solution was stirred at room temperature overnight, poured into water and extracted with ethyl acetate (x2). The combined organic layers were washed with 4% aqueous solution of sodium bicarbonate, brine, dried over magnesium sulphate and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography eluting with 100% hexane to 100% ethyl acetate to give the title compound (609 mg, 80% yield) as a deep yellow oil. Purity based on LC-MS 100%. LRMS (m/z): 331 [M+1]+ LCMS 3 r.t. (min.): 1.63 c) Tert-butyl 8-(6-(aminomethyl)pyridin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5- carboxylate The title compound was prepared from tert-butyl 8-(6-cyanopyridin-2-yl)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate following the experimental procedure described in Intermediate 13b. Purity based on LC-MS 99%. LRMS (m/z): 335 [M+1]+ LCMS 3 r.t. (min.): 1.00 INTERMEDIATE 35 Tert-butyl (2R,6S)-4-(6-(aminomethyl)-5-methylpyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate a) Tert-butyl (2R,6S)-4-(6-cyano-5-methylpyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate A mixture of 6-chloro-3-methylpicolinonitrile (100 mg, 0.65 mmol), tert-butyl (2R,6S)-2,6- dimethylpiperazine-1-carboxylate (210 mg, 0.98 mmol) and potassium carbonate (181 mg, 1.31 mmol) in 1.5 mL of DMF was heated at 120 ºC for 48 h. The mixture was partitioned between water and ethyl acetate, the layers were separated and the aqueous phase was extracted with ethyl acetate (x2). The combined organic layers were washed with water (x2), brine, dried over magnesium sulphate and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography eluting from 100% hexane to 100% ethyl acetate to give the title compound (98 mg, 45% yield). Purity based on LC-MS 81%. LRMS (m/z): 331 [M+1]+ LCMS 3 r.t. (min.): 1.92 b) Tert-butyl (2R,6S)-4-(6-(aminomethyl)-5-methylpyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-cyano-5-methylpyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 13b. Purity based on LC-MS 100%. LRMS (m/z): 335 [M+1]+ LCMS 3 r.t. (min.): 1.28 INTERMEDIATE 36 Tert-butyl 4-(3-(aminomethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate a) Tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)piperidine-1-carboxylate To a 0 ºC cooled mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol), N,N- dimethylpyridin-4-amine (12 mg, 0.10 mmol) and triethylamine (1.5 mL, 10.7 mmol) in 30 mL of DCM was added methanesulfonyl chloride (0.8 mL, 10.33 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was poured into water, extracted with DCM (x3), the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to give the title compound (2.80 g, 100% yield) as an oil, which was used in the next step without any further purification. b) Tert-butyl 4-(3-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)piperidine-1-carboxylate (1.10 g, 3.94 mmol), 1H-pyrazole-3-carbonitrile (300 mg, 3.22 mmol) and potassium carbonate (415 mg, 4.19 mmol) in 15 mL of CAN was heated at 90 ºC for 72 hours. The solvent was concentrated to dryness and saturated solution of sodium bicarbonate was added. The suspension was extracted with ethyl acetate (x3), the combined organic layers were washed with saturated solution of sodium bicarbonate, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography eluting with 100% DCM to DCM/MeOH (95:5) to give 361 mg of a mixture of tert-butyl 4-(3-cyano-1H-pyrazol-1-yl)piperidine- 1-carboxylate and tert-butyl 4-(5-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (50:50). The mixture of regioisomers was purified by preparative HPLC-MS to give the title compound (115 mg, 13% yield). Purity based on LC-MS 100%. LRMS (m/z): 277 [M+1]+ LCMS 3 r.t. (min.): 1.54 b) Tert-butyl 4-(3-(aminomethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate The title compound was prepared from tert-butyl 4-(3-cyano-1H-pyrazol-1-yl)piperidine-1- carboxylate following the experimental procedure described in Intermediate 13b. Purity based on LC-MS 99%. LRMS (m/z): 281 [M+1]+ LCMS 3 r.t. (min.): 0.87 INTERMEDIATE 37 Tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared from 6-fluoropicolinonitrile and tert-butyl piperazine-1- carboxylate following the experimental procedure described in Intermediate 13. Purity based on LC-MS 100%. LRMS (m/z): 293 [M+1]+ LCMS 3 r.t. (min.): 1.06 INTERMEDIATE 38 Tert-butyl (2R,6S)-4-(6-(aminomethyl)-5-cyclopropylpyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate a) 6-Chloro-3-cyclopropylpicolinonitrile A mixture of 3-bromo-6-chloropicolinonitrile (300 mg, 1.38 mmol), cyclopropylboronic acid (154 mg, 1.79 mmol), potassium phosphate (966 mg, 4.55 mmol), tricyclohexylphosphane (35 mg, 0.12 mmol) and palladium(II) acetate (14 mg, 0.06 mmol) in 7 mL of toluene was heated at 100 ºC overnight. The mixture was cooled to room temperature and additional cyclopropylboronic acid (75 mg, 0.90 mmol), ), tricyclohexylphosphane (35 mg, 0.12 mmol) and palladium(II) acetate (14 mg, 0.062 mmol) were added. The mixture was stirred at 100 ºC for 2 hours, cooled to room temperature, filtered through a Celite® pad, washed with ethyl acetate and the filtrate was concentrated to dryness. The crude was purified by flash chromatography eluting with 100% hexane to hexane/ethyl acetate (50:50) to give the title compound (178 mg, 72% yield) as light yellow solid. Purity based on LC-MS 100%. LRMS (m/z): 179 [M+1]+ LCMS 3 r.t. (min.): 1.43 b) Tert-butyl (2R,6S)-4-(6-cyano-5-cyclopropylpyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate A mixture of 6-chloro-3-cyclopropylpicolinonitrile (178 mg, 0.99 mmol), tert-butyl (2R,6S)-2,6- dimethylpiperazine-1-carboxylate (256 mg, 1.19 mmol) and cesium carbonate (357 mg, 1.09 mmol) in 2 mL of 1-methylpyrrolidin-2-one was stirred at 120 ºC overnight. Additional amount of 2,6-dimethylpiperazine-1-carboxylate (256 mg, 1.19 mmol) and cesium carbonate (150 mg, 0.45 mmol) were added and the mixture was stirred at 130 ºC overnight. The reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate (x3), the combined organic layers were washed with water (x2), brine, dried over magnesium sulphate and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% hexane to hexane/ethyl acetate (50:50) to give the title compound (123 mg, 35% yield) as beige solid. Purity based on LC-MS 100%. LRMS (m/z): 301 [M+1]+ LCMS 3 r.t. (min.): 2.00 c) Tert-butyl (2R,6S)-4-(6-(aminomethyl)-5-cyclopropylpyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-cyano-5-cyclopropylpyridin-2-yl)- 2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 13b. Purity based on LC-MS 100%. LRMS (m/z): 361 [M+1]+ LCMS 3 r.t. (min.): 1.41 INTERMEDIATE 39 Tert-butyl 4-(4-(aminomethyl)pyrimidin-2-yl)piperazine-1-carboxylate a) Tert-butyl 4-(4-cyanopyrimidin-2-yl)piperazine-1-carboxylate To a solution of 2-chloropyrimidine-4-carbonitrile (2.00 g, 14.3 mmol) in 20 mL of DMF was added triethylamine (3.0 mL, 21.5 mmol) and tert-butyl piperazine-1-carboxylate (2.97 g, 15.9 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous phase was extracted with ethyl acetate (x2). The combined organic layers were washed with water (x4), brine, dried over magnesium sulphate, filtred and the solvent was evaporated under reduced pressure to give the title compound (4.08 g, 14.1 mmol) as a white solid, which was used in the next step without any further purification. Purity based on LC-MS 100%. LRMS (m/z): 290 [M+1]+ LCMS 3 r.t. (min.): 1.71 b) Tert-butyl 4-(4-(aminomethyl)pyrimidin-2-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-cyanopyrimidin-2-yl)piperazine-1-carboxylate (2.00 g, 6.91 mmol) in a 120 mL of MeOH/THF (5:1) was added 10% palladium on charcoal (150 mg, 1.41 mmol) and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered through a Celite® pad, washed several times with MeOH and the solvent was evaporated under reduced pressure to give the title compound (2.01 g, 99% yield) as a colourless oil, which was used in the next step without any further purification. Purity based on LC-MS 94%. LRMS (m/z): 294 [M+1]+ LCMS 3 r.t. (min.): 0.96 INTERMEDIATE 40 Tert-butyl 4-(3-(aminomethyl)phenyl)piperazine-1-carboxylate a) Tert-butyl 4-(3-cyanophenyl)piperazine-1-carboxylate A mixture of 3-bromobenzonitrile (270 mg, 148 mol), tert-butyl piperazine-1-carboxylate (250 mg, 1.34 mol), cesium carbonate (656 mg, 2.01 mmol), 2,2'-bis(diphenylphosphaneyl)-1,1'- binaphthalene (50 mg, 0.08 mmol) and palladium diacetate (12 mg, 0.05 mmol) in 4 mL of toluene was heated at 120 ºC for 4 hours. The mixture was cooled to room temperature, filtered through a Celite® pad, washed with ethyl acetate and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography eluting from 100% hexane to 100% diethylether to give the title compound (276 mg, 71%). Purity based on LC-MS 98%. LRMS (m/z): 288 [M+1]+ LCMS 3 r.t. (min.): 1.74 b) Tert-butyl 4-(3-(aminomethyl)phenyl)piperazine-1-carboxylate The title compound was prepared from tert-butyl 4-(3-cyanophenyl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 39b, followed by purification by flash chromatography eluting with 100% DCM to DCM/MeOH (90:10). Purity based on LC-MS 95%. LRMS (m/z): 292 [M+1]+ LCMS 3 r.t. (min.): 1.08 INTERMEDIATE 41 Tert-butyl (1-(6-(aminomethyl)pyridin-2-yl)azetidin-3-yl)(methyl)carbamate The title compound was prepared from 6-fluoropicolinonitrile and tert-butyl azetidin-3- yl(methyl)carbamate following the experimental procedure described in Intermediate 13. Purity based on LC-MS 100%. LRMS (m/z): 293 [M+1]+ LCMS 3 r.t. (min.): 1.02 INTERMEDIATE 42 (6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methanamine The title compound was prepared from 6-fluoropicolinonitrile and 4,7-diazaspiro[2.5]octane dihydrochloride following the experimental procedure described in Intermediate 34. Purity based on LC-MS 100%. LRMS (m/z): 219 [M+1]+ INTERMEDIATE 42b Tert-butyl 7-(6-(aminomethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate The title compound was prepared from 6-fluoropicolinonitrile and tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate following the experimental procedure described in Intermediate 34. Purity based on LC-MS 100%. LRMS (m/z): 319 [M+1]+ LCMS 3 r.t. (min.): 1.12 INTERMEDIATE 43 Tert-butyl 4-(6-acetylpyridin-2-yl)piperazine-1-carboxylate A mixture of 1-(6-bromopyridin-2-yl)ethan-1-one (1.00 g, 4.99 mmol), tert-butyl piperazine-1- carboxylate (2.80 g, 15.03 mmol) and potassium carbonate (1.00 g, 10.09 mmol) in 5 mL of DMF was heated at 120 ºC overnight. The mixture was cooled to room temperature, water and diethylether were added, the organic layer was separated and the aqueous phase was extracted with diethylether (x3). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% hexane to hexane/diethylether (50:50) to give the title compound (1.26 g, 82% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 306 [M+1]+ LCMS 3 r.t. (min.): 1.76 INTERMEDIATE 44 Tert-butyl 4-(6-(1-aminoethyl)pyridin-2-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(6-acetylpyridin-2-yl)piperazine-1-carboxylate (1.265 g, 4.12 mmol) and hydroxylamine (50% in water, 9 mL, 70.83 mmol) in 30 mL of MeOH was stirred and heated at 75ºC for 2 h. The reaction mixture was poured in water and saturated ammonia chloride solution and extracted three times in DCM. The combined organic phases were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was solved in 20 mL of MeOH and Nickel-Raney (2 mL, water suspension) was added and the mixture was stirred under hydrogen atmosphere at 40 psi for 72 h. The reaction mixture was then filtered through a Whatman Glass Microfibe Filter washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (1.3 g, 87% yield) as a colourless oil. Purity based on LC-MS 80%. LRMS (m/z): 307 [M+1]+ LCMS 3 r.t. (min.): 1.15 INTERMEDIATE 45 (6-(3-(Trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methanamine The title compound was prepared from 6-fluoropicolinonitrile and 2-(trifluoromethyl)piperazine following the experimental procedure described in Intermediate 13. Purity based on LC-MS 100%. LRMS (m/z): 261 [M+1]+ LCMS 3 r.t. (min.): 0.45 INTERMEDIATE 46 (6-((1R)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methanamine The title compound was prepared from 6-fluoropicolinonitrile and 3,8-diazabicyclo[3.2.1]octane dihydrochloride following the experimental procedure described in Intermediate 13. Purity based on LC-MS 90%. LRMS (m/z): 219 [M+1]+ LCMS 3 r.t. (min.): 0.25 INTERMEDIATE 47 1-(2-Chloropyrimidin-4-yl)ethan-1-one A mixture of 2,4-dichloropyrimidine (0.5 g, 3.35 mmol), tributyl(1-ethoxyvinyl)stannane (1.2 mL, 3.55 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.047 g, 0.06 mmol) in 10 mL DMF stirred and heated at 70 ºC under nitrogen atmosphere for 90min. The mixture was then allowed to reach room temperature and potassium fluoride (40% on alumina, 0.5 g, 3.35 mmol) was added and stirred at room temperature for 1h. The 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. The crude product was purified by flash chromatography eluting with hexanes/diethylether (90:10) to give the title compound (0.42 g, 81% yield) as a yellow oil. Purity based on LC-MS 99%. LRMS (m/z): 157 [M+1]+ LCMS r.t. (min.): 0.98 INTERMEDIATE 48 Tert-butyl 4-(4-(1-aminoethyl)pyrimidin-2-yl)piperazine-1-carboxylate a) Tert-butyl 4-(4-acetylpyrimidin-2-yl)piperazine-1-carboxylate A mixture of 1-(2-chloropyrimidin-4-yl)ethan-1-one (0.052 g, 0.33 mmol), tert-butyl piperazine-1- carboxylate (0.14 g, 0.82 mmol) in 3mL THF was stirred and heated at 90 ºC for 4 h. The crude product was filtered and the filtered washing was evaporated to dryness and macerated with hexanes to obtain the title compound (60 mg, 59% yield) as a yellow solid. Purity based on LC- MS 97%. LRMS (m/z): 307 [M+1]+ LCMS 3 r.t. (min.): 1.77 b) Tert-butyl 4-(4-(1-aminoethyl)pyrimidin-2-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(4-acetylpyrimidin-2-yl)piperazine-1-carboxylate (0.21 g, 0.69 mmol) and hydroxylamine (50% in water, 1.5 mL, 11.8 mmol) in 5mL of MeOH was stirred and heated at 75 ºC for 2 h. The reaction mixture was poured in water and saturated ammonia chloride solution and extracted three times in DCM. The combined organic phases were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was solved in 20 mL of MeOH and Nickel-Raney (2 mL, water suspension) was added and the mixture was stirred under hydrogen atmosphere at 40 psi for 72 h. The reaction mixture was then filtered through a Celite® pad, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (0.15 g, 74% yield) as a colourless oil. Purity based on LC-MS 80%. LRMS (m/z): 308 [M+1]+ LCMS 3 r.t. (min.): 1.08 INTERMEDIATE 49 Tert-butyl (2-((6-(aminomethyl)pyridin-2-yl)(methyl)amino)ethyl)(methyl)carbamate The title compound was prepared from 6-fluoropicolinonitrile and tert-butyl methyl(2- (methylamino)ethyl)carbamate following the experimental procedure described in Intermediate 13. Purity based on LC-MS 100%. LRMS (m/z): 295 [M+1]+ LCMS 3 r.t. (min.): 1.10 INTERMEDIATE 50 2-((6-(Aminomethyl)pyridin-2-yl)(ethyl)amino)ethan-1-ol The title compound was prepared from 6-fluoropicolinonitrile and 2-(ethylamino)ethan-1-ol following the experimental procedure described in Intermediate 13. Purity based on LC-MS 91%. LRMS (m/z): 196 [M+1]+ LCMS 3 r.t. (min.): 0.57 INTERMEDIATE 51 (6-(4-Methylpiperazin-1-yl)pyridin-2-yl)methanamine a) 6-(4-Methylpiperazin-1-yl)picolinonitrile A mixture of 6-fluoropicolinonitrile (1.00 g, 8.19 mmol), 1-methylpiperazine (820 mg, 8.19 mmol) and DIEA (3 mL, 17.22 mmol) in 10 mL of DMSO was heated at 80 ºC overnight. The solution was poured into water and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with hexanes/AcOEt (0:100) to give the title compound (1.46 g, 88% yield) as a yellow oil. Purity based on LC-MS 99%. LRMS (m/z): 203 [M+1]+ LCMS 3 r.t. (min.): 0.47 b) (6-(4-Methylpiperazin-1-yl)pyridin-2-yl)methanamine To a degassed solution of 6-(4-methylpiperazin-1-yl)picolinonitrile (1.46 g, 7.21 mmol) in 95 mL of MeOH, Pd/C 10% (770 mg, 0.72 mmol) was added and the mixture was stirred under hydrogen atmosphere at 50 psi for 18 h. The reaction mixture was then filtered through a Whatman Glass Microfibe Filter® washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness to give the title compound (1.5 g, 99% yield) as an colourless oil.. Purity based on LC-MS 85%. LRMS (m/z): 207[M+1]+ LCMS3 r.t. (min.): 0.2 INTERMEDIATE 52 1-(6-(Aminomethyl)pyridin-2-yl)pyrrolidin-3-ol The title compound was prepared from 6-fluoropicolinonitrile and pyrrolidin-3-ol following the experimental procedure described in Intermediate 13. Purity based on LC-MS 100%. LRMS (m/z): 194 [M+1]+ LCMS 3 r.t. (min.): 0.32 INTERMEDIATE 53 Tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)piperidine-1-carboxylate a) Tert-butyl 6-cyano-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate A mixture of 6-bromopicolinonitrile (1.4 g, 7.65 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4 g, 12.93 mmol), Pd(dppf)Cl2 (0.37 g, 0.45 mmol)) and cesium carbonate (7.4 g, 22.7 mmol) in 20 mL of and 5 mL of water. The reaction mixture was stirred and heated at 100 ºC under nitrogen atmosphere. The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate, filtered through Celite® and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with hexanes/AcOEt (50:50) to give the title compound (2.1 g, 98% yield) as a yellow oil. Purity based on LC-MS 86%. LRMS (m/z): 286 [M+1]+ LCMS3 r.t. (min.): 1.73 b) Tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)piperidine-1-carboxylate To a degassed solution of tert-butyl 6-cyano-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (2.15 g, 7.54 mmol) in 50 mL of MeOH, Pd/C 10% (0.5 g, 4.69 mmol) was added and the mixture was stirred under hydrogen atmosphere at 40 psi for 20 h. The reaction mixture was then filtered through a Whatmen Glass Microfibe Filter®, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness. was filtered thought a concentrated under reduced pressure to give the title compound (1.4 g, 65% yield) as an colourless oil.. Purity based on LC-MS 70%. LRMS (m/z): 292[M+1]+ LCMS 3 r.t. (min.): 1.09 INTERMEDIATE 54 Tert-butyl 4-(2-(aminomethyl)pyridin-4-yl)piperidine-1-carboxylate The title compound was prepared from 4-bromopyrimidine-2-carbonitrile and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following the experimental procedure described in Intermediate 53. LRMS (m/z): 292 [M+1]+ INTERMEDIATE 55 2-((6-(Aminomethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol The title compound was prepared from 6-fluoropicolinonitrile and 2-(methylamino)ethan-1-ol following the experimental procedure described in Intermediate 13. Purity based on LC-MS 89%. LRMS (m/z): 182 [M+1]+ LCMS 3 r.t. (min.): 0.43 INTERMEDIATE 56 4-(6-(Aminomethyl)pyridin-2-yl)piperazin-2-one The title compound was prepared from 6-fluoropicolinonitrile and piperazin-2-one following the experimental procedure described in Intermediate 51. Purity based on LC-MS 55%. LRMS (m/z): 207 [M+1]+ LCMS 3 r.t. (min.): 0.35 INTERMEDIATE 57 2-(Aminomethyl)-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N,N-dimethylnicotinamide a) Methyl 6-chloro-2-cyanonicotinate To a solution of methyl 2,6-dichloronicotinate (3 g, 14.5 mmol) in 13 mL NMP, cooper cyanide (1.85 g, 20.7 mmol) was added and the mixture was heated at 180 ºC for 2 h under microwave irradiation. Then the reaction mixture was diluted in 10 % aqueous ammonia (22 mL) and filtered thought Celite® pad. The filtered was diluted in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with hexanes/EtOAc (80:20) obtaining the title compound (0.87 g, 31% yield) as a solid. Purity based on LC-MS 91%. LRMS (m/z): 197 [M+1]+ LCMS 3 r.t. (min.): 1.16 b) Tert-butyl (2R,6S)-4-(6-cyano-5-(methoxycarbonyl)pyridin-2-yl)-2,6-dimethylpiperazine- 1-carboxylate. A mixture of methyl 6-chloro-2-cyanonicotinate (0.400 g, 2.03 mmol), tert-butyl (2R,6S)-2,6- dimethylpiperazine-1-carboxylate (0.44 g, 2.05 mmol) and DIEA (0.53 mL, 3.10 mmol ) in 2 mL of NMP was heated at 160 ºC for 1 h under microwave irradiation. The solution was poured into water and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with hexanes/EtOAc (40:60) to give the title compound (0.25 g, 33% yield) as a white solid. A part of acid derivative was also isolated (0.065 g, 9% yield). LRMS (m/z): 375 [M+1]+ LCMS 3 r.t. (min.): 1.82 c) 6-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-cyanonicotinic acid To a solution of tert-butyl (2R,6S)-4-(6-cyano-5-(methoxycarbonyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate in 2 mL of MeOH and 2 mL of THF, aquoeus NaOH was added and stirred at room temperature for 18 h. The organic solvent was evaporated and acidified with HCl 5N. The aquoeus solution was extracted twice with AcOEt. The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to obtain the desired product as a white solid. The aqueous layer contained final product and was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1) to give the title compound. As result of combination of final compound (0.22g, 90% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 359 [M+1]+ LCMS 3 r.t. (min.): 1.66 d) Tert-butyl (2R,6S)-4-(6-cyano-5-(dimethylcarbamoyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate A mixture of 6-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-cyanonicotinic acid (0.29 g, 0.80 mmol), ethyl (E)-2-cyano-2-(hydroxyimino)acetate (0.13 g, 0.91 mmol) and EDC (0.17 g, 0.89 mmol) in 4 mL of DMF was stirred at room temperature for 15 min. Then N- methylmethanamine (0.51 mL, 1.02 mmol) was added and the reaction mixture was stirred for 4 h. The solution was poured into water-ice bath and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with DCM/MeOH (95:5) to give the title compound (0.28 g, 92% yield) as a yellow oil. Purity based on LC-MS 96%. LRMS (m/z): 388[M+1]+ LCMS 3 r.t. (min.): 1.67 e) 2-(Aminomethyl)-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N,N-dimethylnicotinamide To a degassed solution of tert-butyl (2R,6S)-4-(6-cyano-5-(dimethylcarbamoyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate (0.15 g, 0.38 mmol) in 20 mL of methanol , aqueous HCl (37%, 0.04 mL, 0.38 mmol) was added. Then Pd/C 10% (0.05 g, 0.05 mmol) was added and the mixture was stirred at 30 psi for 18 h. The reaction mixture was then filtered through a Celite® pad, washing with methanol several times. The filtrate washings were combined and the solvent was evaporated to dryness. The crude product was basified with NaOH and extracted twice with AcOEt. The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1) to give the title compound (16 mg, 14% yield) as a white solid. Purity based on LC-MS 97%. LRMS (m/z): 293 [M+1]+ LCMS 3 r.t. (min.): 0.21 INTERMEDIATE 58 Tert-butyl (2S,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 6-fluoropicolinonitrile and (2S,6S)-2,6-dimethylpiperazine dihydrochloride following the experimental procedure described in Intermediate 34. Purity based on LC-MS 100%. LRMS (m/z): 321 [M+1]+ LCMS 3 r.t. (min.): 1.28 INTERMEDIATE 59 Tert-butyl (2R,6R)-4-(6-(aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 6-fluoropicolinonitrile and (2R,6R)-2,6-dimethylpiperazine dihydrochloride following the experimental procedure described in Intermediate 34. Purity based on LC-MS 100%. LRMS (m/z): 321 [M+1]+ LCMS 3 r.t. (min.): 1.27 INTERMEDIATE 60 5-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.53 g, 3.95 mmol), (6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)methanamine (1.45 g, 5.92 mmol) and DIEA (4.1 mL, 23.53 mmol) were heated in ACN (10 mL) at 70ºC for 1 h. Water was added, the organic phase was separated and the aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with 100% dichloromethane to 100% dichloromethane/MeOH/NH3 7M (95:4:1) to give the title compound (1.69g, 73% yield) as a white solid. Purity based on LC- MS 98%. LRMS (m/z): 570, 572 [M+1]+ LCMS3 r.t. (min.): 2.02 INTERMEDIATE 61 1-(6-(((5-Bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-3-ol 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (298.5 mg, 0.77 mmol), 1-(6- (aminomethyl)pyridin-2-yl)piperidin-3-ol (245 mg, 0.97 mmol) and sodium carbonate (614 mg, 5.79 mmol) were heated in ACN (10 mL) at 70ºC for 18 h. Water was added, the organic phase was separated and the aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with 100% hexane to 100% EtOAc to give the title compound (121 mg, 28% yield) as an oil. Purity based on LC-MS 96%. LRMS (m/z): 557, 559 [M+1]+ LCMS3 r.t. (min.): 1.82 INTERMEDIATE 62 5-Bromo-N-((6-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and 6-(aminomethyl)-N-(2-methoxyethyl)-N-methylpyridin-2-amine following the experimental procedure described in Intermediate 61. Purity based on LC-MS 90%. LRMS (m/z): 545, 547 [M+1]+ LCMS 3 r.t. (min.): 1.90 INTERMEDIATE 63 5-Bromo-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and 1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine following the experimental procedure described in Intermediate 61. Purity based on LC-MS 98%. LRMS (m/z): 584, 586 [M+1]+ LCMS 2 r.t. (min.): 2.17 INTERMEDIATE 64 5-Bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (325 mg, 0.84 mmol), (S)-1-(6-((3R,5S)- 3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine;hydrochloride (232 mg, 0.84 mmol) and DIEA (293 μL, 1.687 mmol) were heated in n-butanol (3 mL) at 100ºC for 40h. The reaction mixture was concentrated. The pale brown solid was purified by eluting with 100% dichloromethane to 75% dichloromethane/MeOH/NH3 (7N in MeOH) 9:0.85:0.15 to give the title compound (600 mg, 79% yield) as a brownish foam. Purity based on LC-MS 99%. LRMS (m/z): 584, 586 [M+1]+ LCMS 2 r.t. (min.): 2.22 INTERMEDIATE 65 5-Bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.78 mmol), (2-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyrimidin-4-yl)methanamine (200 mg, 0.90 mmol) and DIEA (0.40 mL, 2.32 mmol) were heated in EtOH (5 mL) at 90ºC for 3 h. Water was added, the organic phase was separated and the aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude (460 mg, 83% yield) as a yellow solid was used in the next synthetic step without further purification. Purity based on LC-MS 95%. LRMS (m/z): 571, 573 [M+1]+ LCMS3 r.t. (min.): 1.34 INTERMEDIATE 66 3-Bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridin-4-amine A mixture of 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.70 mmol), (2-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyrimidin-4-yl)methanamine (210 mg, 0.95 mmol), Pd(OAc)2 (15 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol) and cesium carbonate (400 mg, 1.23 mmol) in dioxane (5 mL) was stirred at 110ºC under nitrogen atmosphere until the starting material was consumed (3 hours). The mixture was then allowed to reach room temperature, and was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by eluting with 100% dichloromethane to 20% MeOH to give the title compound (200 mg, 30% yield) as a yellow oil which solidifies in cyclohexane. Purity based on LC-Purity based on LC-MS 64%. LRMS (m/z): 570, 572 [M+1]+ LCMS3 r.t. (min.): 1.39 INTERMEDIATE 67 5-Bromo-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methanamine following the experimental procedure described in Intermediate 64. Purity based on LC-MS 98%. LRMS (m/z): 571, 573 [M+1]+ LCMS 2 r.t. (min.): 1.57 INTERMEDIATE 68 5-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methanamine following the experimental procedure described in Intermediate 64. Purity based on LC-MS 99%. LRMS (m/z): 571, 573 [M+1]+ LCMS 2 r.t. (min.): 1.95 INTERMEDIATE 69 2-((6-(((5-Bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and 2-((6-(aminomethyl)-4-(trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol following the experimental procedure described in Intermediate 60. Purity based on LC-MS 96%. LRMS (m/z): 599, 601 [M+1]+ LCMS 2 r.t. (min.): 3.42 INTERMEDIATE 70 3-((5-Bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-(6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and 3-amino-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol following the experimental procedure described in Intermediate 64. Purity based on LC-MS 89%. LRMS (m/z): 614, 616 [M+1]+ LCMS 2 r.t. (min.): 1.97 INTERMEDIATE 71 5-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)- 7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 64. Purity based on LC-MS 99%. LRMS (m/z): 638, 640 [M+1]+ LCMS 2 r.t. (min.): 2.27 INTERMEDIATE 72 5-Bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-amine following the experimental procedure described in Intermediate 64. Purity based on LC-MS 98%. LRMS (m/z): 598, 600 [M+1]+ LCMS 2 r.t. (min.): 2.32 INTERMEDIATE 73 5-Bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-3-methylbutyl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-3-methylbutan-1-amine following the experimental procedure described in Intermediate 64. Purity based on LC-MS 95%. LRMS (m/z): 626, 628 [M+1]+ LCMS 2 r.t. (min.): 2.52 INTERMEDIATE 74 3-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl-1-tosyl- 1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 75%. LRMS (m/z): 584, 586 [M+1]+ LCMS 3 r.t. (min.): 1.58 INTERMEDIATE 75 3-(6-(((5-Bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)propan- 1-ol The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and 3-(6-(aminomethyl)pyridin-2-yl)propan-1-ol following the experimental procedure described in Intermediate 61. Purity based on LC-MS 99%. LRMS (m/z): 516, 518 [M+1]+ LCMS 3 r.t. (min.): 1.61 INTERMEDIATE 76 5-Bromo-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 574, 576 [M+1]+ LCMS 3 r.t. (min.): 1.40 INTERMEDIATE 77 3-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine and (6- ((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 95%. LRMS (m/z): 569, 571 [M+1]+ LCMS 3 r.t. (min.): 1.50 INTERMEDIATE 78 3-Bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine and (S)-1- (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 88%. LRMS (m/z): 583, 585 [M+1]+ LCMS 3 r.t. (min.): 1.52 INTERMEDIATE 79 3-Bromo-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine and (4- ((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 96%. LRMS (m/z): 570, 572 [M+1]+ LCMS 3 r.t. (min.): 1.17 INTERMEDIATE 80 Tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)-2,2-dimethylpiperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 61. Purity based on LC-MS 95%. LRMS (m/z): 670, 672 [M+1]+ LCMS 3 r.t. (min.): 2.27 INTERMEDIATE 81 Tert-butyl 8-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 8-(6-(aminomethyl)pyridin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 98%. LRMS (m/z): 684, 686 [M+1]+ LCMS 3 r.t. (min.): 2.22 INTERMEDIATE 82 Tert-butyl 4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)- 2,2-dimethylpiperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine and tert- butyl 4-(6-(aminomethyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 85%. LRMS (m/z): 669, 671 [M+1]+ LCMS 3 r.t. (min.): 2.25 INTERMEDIATE 83 Tert-butyl (2R,6S)-4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)- 5-methylpyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl (2R,6S)-4-(6-(aminomethyl)-5-methylpyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 684, 686 [M+1]+ LCMS 3 r.t. (min.): 2.33 INTERMEDIATE 84 Tert-butyl 4-(3-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-1H- pyrazol-1-yl)piperidine-1-carboxylate 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.52 mmol), tert-butyl 4-(3- (aminomethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (110 mg, 0.52 mmol), cessium fluoride (24 mg, 0.16 mmol) and DIEA (0.65 mL, 3.73 mmol) were heated in tert-butanol (3 mL) at 100ºC for 18 h. The solvent was evaporated under reduced pressure, the residue was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by eluting with 100% DCM to 10% MeOH to give the title compound (160 mg, 65% yield) as a colourless oil. Purity based on LC-MS 85%. LRMS (m/z): 630, 632 [M+1]+ LCMS3 r.t. (min.): 2.02 INTERMEDIATE 85 Tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 65. Purity based on LC-MS 96%. LRMS (m/z): 642, 644 [M+1]+ LCMS 3 r.t. (min.): 2.19 INTERMEDIATE 86 Tert-butyl (2R,6S)-4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine and tert- butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 95%. LRMS (m/z): 669, 671 [M+1]+ LCMS 3 r.t. (min.): 2.26 INTERMEDIATE 87 Tert-butyl 4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine and tert- butyl 4-(6-(aminomethyl)pyridin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 98%. LRMS (m/z): 641, 643 [M+1]+ LCMS 3 r.t. (min.): 2.18 INTERMEDIATE 88 Tert-butyl 4-(4-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin- 2-yl)piperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(4-(aminomethyl)pyrimidin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 65. Purity based on LC-MS 96%. LRMS (m/z): 644, 646 [M+1]+ LCMS 3 r.t. (min.): 2.13 INTERMEDIATE 89 Tert-butyl (2R,6S)-4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)- 5-cyclopropylpyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl (2R,6S)-4-(6-(aminomethyl)-5-cyclopropylpyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 100%. LRMS (m/z): 711, 713 [M+1]+ LCMS 3 r.t. (min.): 2.39 INTERMEDIATE 90 Tert-butyl 4-(3-(((5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)phenyl)piperazine-1-carboxylate The title compound was prepared from 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(3-(aminomethyl)phenyl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 65. Purity based on LC-MS 85%. LRMS (m/z): 689 [M+1]+ LCMS 3 r.t. (min.): 2.16 INTERMEDIATE 91 5-Bromo-N-((6-fluoropyridin-2-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine 5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (250 mg, 0.73 mmol) and 6-fluoropicolinaldehyde (118 mg, 0.94 mmol) were dissolved in DMF (3.5 mL) and stirred overnight at room temperature. Then sodium borohydride (33.5 mg, 0.87 mmol) was added to the reaction mixture and it was stirred during additional 90 min. at room temperature. Saturated solution of ammonium chloride was added to the reaction mixture and it was stirred for 1 hour. EtOAc was added and then filtered through Celite®. Phases were separated and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with water (x2) and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by eluting with 100% DCM to 70% DCM/ MeOH 9:1 to give the title compound (245 mg, 74% yield) as a brownish solid. Purity based on LC-MS 93%. LRMS (m/z): 452, 454 [M+1]+ LCMS 3 r.t. (min.): 2.04 INTERMEDIATE 92 5-Bromo-N-((6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5-Bromo-N-((6-fluoropyridin-2-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine (80 mg, 0.18 mmol), (2R,6S)-1,2,6-trimethylpiperazine (50 mg, 0.38 mmol) and DIEA (0.12 mL, 0.70 mmol) were heated in DMSO (0.9 mL) at 120ºC for 24 h. Water was added, the organic phase was separated and the aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with 100% dichloromethane to 100% dichloromethane/MeOH 9:1+0.1% NH37M to give the title compound (57 mg, 58% yield) as an orange oil. Purity based on LC-MS 94%. LRMS (m/z): 561, 563 [M+1]+ LCMS 3 r.t. (min.): 1.57 INTERMEDIATE 93 2-((6-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)oxy)ethan-1-ol Ethane-1,2-diol (0.2 mL, 3.6 mmol) and potassium tert-butylate (60 mg, 0.54 mmol) were mixed in 1,4-dioxane (1 mL) at room temperature and stirred for 20 min.5-Bromo-N-((6-fluoropyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.18 mmol) in 1,4-dioxane (0.5 mL) was added and heated at 90ºC for 8 h. Water was added, the organic phase was separated and the aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with 100% hexane to 100% EtOAc to give the title compound (43 mg, 49% yield) as a dark oil. Purity based on LC-MS 83%. LRMS (m/z): 494, 496 [M+1]+ LCMS 3 r.t. (min.): 1.94 INTERMEDIATE 94 1-(6-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)azetidin-3-ol The title compound was prepared from 5-bromo-N-((6-fluoropyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and azetidin-3-ol hydrochloride following the experimental procedure described in Intermediate 92. Purity based on LC-MS 100%. LRMS (m/z): 505, 507 [M+1]+ LCMS 3 r.t. (min.): 1.72 INTERMEDIATE 95 5-Bromo-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and (6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 60. Purity based on LC-MS 100%. LRMS (m/z): 550, 552 [M+1]+ LCMS 3 r.t. (min.): 1.56 INTERMEDIATE 96 Tert-butyl (1-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)methyl)pyridin-2-yl)azetidin-3-yl)(methyl)carbamate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl (1-(6-(aminomethyl)pyridin-2-yl)azetidin-3- yl)(methyl)carbamate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 93%. LRMS (m/z): 619, 621 [M+1]+ LCMS 3 r.t. (min.): 2.26 INTERMEDIATE 97 Tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 100%. LRMS (m/z): 647, 649 [M+1]+ LCMS 3 r.t. (min.): 2.39 INTERMEDIATE 98 N-((6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and (6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 544, 546 [M+1]+ LCMS 3 r.t. (min.): 1.62 INTERMEDIATE 98b Tert-butyl 7-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)methyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl 7-(6-(aminomethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane- 4-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 644, 646 [M+1]+ LCMS 3 r.t. (min.): 2.34 INTERMEDIATE 99 Tert-butyl 4-(6-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(6-(1-aminoethyl)pyridin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 90%. LRMS (m/z): 632, 634 [M+1]+ LCMS 3 r.t. (min.): 1.71 INTERMEDIATE 100 3-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 92%. LRMS (m/z): 545, 547 [M+1]+ LCMS 2 r.t. (min.): 1.87 INTERMEDIATE 101 3-Bromo-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and (6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 95%. LRMS (m/z): 585, 587 [M+1]+ LCMS 3 r.t. (min.): 2.05 INTERMEDIATE 102 N-((6-((1S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and (6-((1R)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 100%. LRMS (m/z): 543, 545 [M+1]+ LCMS 3 r.t. (min.): 1.53 INTERMEDIATE 103 Tert-butyl (2R,6S)-4-(6-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and tert-butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 100%. LRMS (m/z): 645, 647 [M+1]+ LCMS 3 r.t. (min.): 2.36 INTERMEDIATE 104 Tert-butyl 4-(4-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(4-(1-aminoethyl)pyrimidin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 633, 635 [M+1]+ LCMS 3 r.t. (min.): 2.36 INTERMEDIATE 105 3-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methanamine following the experimental procedure described in Intermediate 66. Purity based on LC-MS 95%. LRMS (m/z): 613, 615 [M+1]+ LCMS 2 r.t. (min.): 2.20 INTERMEDIATE 106 Tert-butyl (2-((6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)methyl)pyridin-2-yl)(methyl)amino)ethyl)(methyl)carbamate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl (2-((6-(aminomethyl)pyridin-2- yl)(methyl)amino)ethyl)(methyl)carbamate following the experimental procedure described in Intermediate 61. Purity based on LC-MS 100%. LRMS (m/z): 621, 623 [M+1]+ LCMS 3 r.t. (min.): 2.26 INTERMEDIATE 107 2-((6-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)(ethyl)amino)ethan-1-ol The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and 2-((6-(aminomethyl)pyridin-2-yl)(ethyl)amino)ethan-1-ol following the experimental procedure described in Intermediate 60. Purity based on LC-MS 100%. LRMS (m/z): 521, 523 [M+1]+ LCMS 3 r.t. (min.): 1.88 INTERMEDIATE 108 Tert-butyl 4-(6-(((5-iodo-2-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared from 4-chloro-5-iodo-2-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(6- (aminomethyl)pyridin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 680, 682 [M+1]+ LCMS 3 r.t. (min.): 2.38 INTERMEDIATE 109 5-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 61. INTERMEDIATE 110 5-Bromo-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and (6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 84. Purity based on LC-MS 95%. LRMS (m/z): 586, 588 [M+1]+ LCMS 3 r.t. (min.): 2.10 INTERMEDIATE 111 5-Bromo-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and (6-(4-methylpiperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 61. Purity based on LC-MS 95%. LRMS (m/z): 532, 534 [M+1]+ LCMS 3 r.t. (min.): 1.55 INTERMEDIATE 112 1-(6-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)pyrrolidin-3-ol The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and 1-(6-(aminomethyl)pyridin-2-yl)pyrrolidin-3-ol following the experimental procedure described in Intermediate 61. Purity based on LC-MS 100%. LRMS (m/z): 519, 521 [M+1]+ LCMS 3 r.t. (min.): 1.62 INTERMEDIATE 113 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 The title compound was prepared from 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(4-(aminomethyl)pyrimidin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 65. Purity based on LC-MS 87%. LRMS (m/z): 667 [M+1]+ INTERMEDIATE 114 Tert-butyl 4-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)methyl)pyridin-2-yl)piperidine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)piperidine-1-carboxylate following the experimental procedure described in Intermediate 84. Purity based on LC-MS 85%. LRMS (m/z): 617-619 [M+1]+ INTERMEDIATE 115 N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-iodo-2-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 4-chloro-5-iodo-2-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and (6-((3R,5S)-3,5-dimethylpiperazin- 1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 65. Purity based on LC-MS 91%. LRMS (m/z): 608 [M+1]+ LCMS 3 r.t. (min.): 1.69 INTERMEDIATE 116 2-((6-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)(methyl)amino)ethan-1-ol The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and 2-((6-(aminomethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol following the experimental procedure described in Intermediate 84. Purity based on LC-MS 100%. LRMS (m/z): 507, 509 [M+1]+ LCMS 3 r.t. (min.): 1.77 INTERMEDIATE 117 4-(6-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)piperazin-2-one The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and 4-(6-(aminomethyl)pyridin-2-yl)piperazin-2-one following the experimental procedure described in Intermediate 84. Purity based on LC-MS 89%. LRMS (m/z): 532, 534 [M+1]+ LCMS 3 r.t. (min.): 1.91 INTERMEDIATE 118 2-(((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N,N-dimethylnicotinamide The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and 2-(aminomethyl)-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N,N- dimethylnicotinamide following the experimental procedure described in Intermediate 84. Purity based on LC-MS 95%. LRMS (m/z): 618, 620 [M+1]+ LCMS 3 r.t. (min.): 1.53 INTERMEDIATE 119 Tert-butyl 4-(6-(1-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and tert-butyl 4-(6-(1-aminoethyl)pyridin-2-yl)piperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 82%. LRMS (m/z): 631, 633 [M+1]+ LCMS 3 r.t. (min.): 2.34 INTERMEDIATE 120 Tert-butyl (S)-4-(6-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl (S)-4-(6-(1-aminoethyl)pyridin-2-yl)piperazine-1- carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 100%. LRMS (m/z): 633, 635 [M+1]+ LCMS 3 r.t. (min.): 2.35 INTERMEDIATE 121 Tert-butyl (2R,6S)-4-(4-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl (2R,6S)-4-(4-(aminomethyl)pyrimidin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 65. Purity based on LC-MS 100%. LRMS (m/z): 648, 650 [M+1]+ LCMS 3 r.t. (min.): 2.43 INTERMEDIATE 122 4-Chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine A mixture of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 1.46 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (307 mg, 1.46 mmol), Pd(dppf)Cl2 (120 mg, 0.15 mmol) and 2M cessium carbonate solution (2.2 mL, 4.4 mmol) in 1,4-dioxane (10 mL) was stirred at 90ºC under nitrogen atmosphere until the starting material was consumed (2 hours). The mixture was then allowed to reach room temperature, water was added, the organic phase was separated and the aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with 100% hexane to 100% EtOAc to give the title compound (200 mg, 37% yield) as a yellow oil. Purity based on LC-MS 91%. LRMS (m/z): 367 [M+1]+ LCMS3 r.t. (min.): 2.06 INTERMEDIATE 123 Tert-butyl 4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1- carboxylate The title compound was prepared from 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(6- (aminomethyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 92. Purity based on LC-MS 93%. LRMS (m/z): 651 [M+1]+ LCMS 3 r.t. (min.): 2.31 INTERMEDIATE 124 Tert-butyl (2S,6S)-4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl (2S,6S)-4-(6- (aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 92. Purity based on LC-MS 93%. LRMS (m/z): 651 [M+1]+ LCMS 3 r.t. (min.): 2.34 INTERMEDIATE 125 Tert-butyl 4-(4-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)-2,2-dimethylpiperazine-1- carboxylate The title compound was prepared from 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(4- (aminomethyl)pyrimidin-2-yl)-2,2-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 92. Purity based on LC-MS 95%. LRMS (m/z): 652 [M+1]+ LCMS 3 r.t. (min.): 2.33 INTERMEDIATE 126 Tert-butyl (2R,6R)-4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl (2R,6R)-4-(6- (aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 92. Purity based on LC-MS 100%. LRMS (m/z): 651 [M+1]+ LCMS 3 r.t. (min.): 2.34 INTERMEDIATE 127 Tert-butyl (2R,6S)-4-(4-((S)-1-((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyrimidin-2-yl)- 2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and tert-butyl (2R,6S)-4-(4-((S)-1- aminoethyl)pyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 95%. LRMS (m/z): 666 [M+1]+ LCMS 3 r.t. (min.): 2.30 INTERMEDIATE 128 Tert-butyl 4-(6-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)-2,2-dimethylpiperazine-1- carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 100%. LRMS (m/z): 646, 648 [M+1]+ LCMS 3 r.t. (min.): 2.44 INTERMEDIATE 129 Tert-butyl (2R,6S)-4-(4-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine and tert-butyl (2R,6S)-4-(4-(aminomethyl)pyrimidin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 95%. LRMS (m/z): 647, 649 [M+1]+ LCMS 3 r.t. (min.): 2.42 INTERMEDIATE 130 Tert-butyl (2R,6S)-4-(6-(((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-d]pyrimidine and tert-butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 60. Purity based on LC-MS 85%. LRMS (m/z): 696 [M+1]+ LCMS 3 r.t. (min.): 2.43 INTERMEDIATE 131 Tert-butyl (2R,6S)-4-(6-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 3,4-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-b]pyridine and tert-butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 66. Purity based on LC-MS 95%. LRMS (m/z): 647, 649 [M+1]+ LCMS 3 r.t. (min.): 2.45 INTERMEDIATE 132 5-Bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and (S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethan-1-amine following the experimental procedure described in Intermediate 64. Purity based on LC-MS 100%. LRMS (m/z): 584, 586 [M+1]+ LCMS 3 r.t. (min.): 1.64 INTERMEDIATE 133 5-Bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-4-chloro-2-methyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine and (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methanamine following the experimental procedure described in Intermediate 60. Purity based on LC-MS 100%. LRMS (m/z): 584, 587 [M+1]+ LCMS 3 r.t. (min.): 1.62 INTERMEDIATE 134 Tert-butyl (2R,6S)-4-(6-(((5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)methyl)pyridin-2- yl)-2,6-dimethylpiperazine-1-carboxylate The title compound was prepared from 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine and tert-butyl (2R,6S)-4-(6-(aminomethyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 65. Purity based on LC-MS 100%. LRMS (m/z): 516, 518 [M+1]+ LCMS 3 r.t. (min.): 2.20 INTERMEDIATE 135 Tert-butyl (2R,6S)-4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate A mixture of tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (400 mg, 0.62 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 mg, 0.93 mmol), Pd(dppf)Cl2 (45 mg, 0.06 mmol) and dicesium carbonate (604 mg, 1.85 mmol) in a mixture of dioxane (6 mL) and water (1.5 mL) was stirred at 100 ºC under nitrogen atmosphere in an oil bath until the starting material was consumed (2 h). The mixture was then allowed to reach room temperature, filtered through Celite® and the solvent was evaporated to dryness. The crude product was purified by flash chromatography eluting with 100% hexane to 70% EtOAc to give the title compound (350 mg, 84% yield) as a colourless oil. Purity based on LC-MS 96%. LRMS (m/z): 650, 652 [M+1]+ LCMS3 r.t. (min.): 2.27 INTERMEDIATE 136 5-(3,6-Dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-amine and 2-(3,6-dihydro-2H-pyran-4- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 100%. LRMS (m/z): 420 [M+1]+ LCMS 3 r.t. (min.): 1.42 INTERMEDIATE 137 Tert-butyl 4-(6-(1-((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(6-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate (154 mg, 0.24 mmol), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (103 mg, 0.49 mmol), Pd(dppf)Cl2 (20 mg, 0.03 mmol) and 2M cesium carbonate solution (0.4 mL, 0.72 mmol) in dioxane (3 mL) was stirred at 100ºC under nitrogen atmosphere until the starting material was consumed (3 hours). The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate, filtered through Celite® and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% hexane to 100% diethylether to give the title compound (65 mg, 42% yield) as a yellowish oil.. Purity based on LC- MS 90%. LRMS (m/z): 636 [M+1]+ LCMS3 r.t. (min.): 2.26 INTERMEDIATE 138 Tert-butyl 7-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate The title compound was prepared from tert-butyl 7-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 87%. LRMS (m/z): 649 [M+1]+ LCMS 3 r.t. (min.): 2.32 INTERMEDIATE 139 Tert-butyl (S)-4-(6-(1-((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate A mixture of tert-butyl (S)-4-(6-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate (320 mg, 0.51 mmol), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.62 mmol), Pd(dppf)Cl2 (41 mg, 0.05 mmol) and potassium phosphate (325 mg, 1.53 mmol) in a mixture of dioxane (9 mL) and water (2 mL) was stirred at 80ºC under nitrogen atmosphere in a microwave oven until the starting material was consumed (1 h). The mixture was then allowed to reach room temperature, it was diluted with DCM (25 mL) and water (5 mL), and the phases were separated. The aqueous layer was further extracted with EtOAc (x3). The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by flash chromatography eluting with 100% hexane to 100% diethylether to give the title compound (210 mg, 65% yield) as a colourless oil. Purity based on LC-MS 95%. LRMS (m/z): 637 [M+1]+ LCMS3 r.t. (min.): 2.34 INTERMEDIATE 140 Tert-butyl (2R,6S)-4-(6-(((5-(5,6-dihydro-2H-pyran-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 83%. LRMS (m/z): 651 [M+1]+ LCMS 3 r.t. (min.): 2.33 INTERMEDIATE 141 Tert-butyl (2R,6S)-4-(6-(((5-(2,5-dihydrofuran-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 73%. LRMS (m/z): 635 [M]+ LCMS 3 r.t. (min.): 2.31 INTERMEDIATE 142 Tert-butyl (2R,6S)-4-(4-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(4-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 79%. LRMS (m/z): 652 [M+1]+ LCMS 3 r.t. (min.): 2.32 INTERMEDIATE 143 3-(3,6-Dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine To a mixture of 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1-tosyl- 1H-pyrrolo[2,3-b]pyridin-4-amine (133 mg, 0.23 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (59 mg, 0.28 mmol), Pd(dppf)Cl2 (15 mg, 0.019 mmol) in dioxane (3 mL), a 2 M aqueous solution of cesium carbonate (0.233 mL, 0.47 mmol) was added. The mixture was heated in a sealed tube under inert atmosphere at 100 ºC for 2 hours until the starting material was consumed. Then, a 2 M aqueous solution of sodium hydroxide (1 mL) was added and the mixture was heated at 80 ºC until no tosyl-protected product was detected (overnight). The resulting mixture was then diluted with EtOAc, filtered through Celite® dried over magnesium sulfate and the solvents removed under reduced pressure. The crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (38 mg, 39% yield) as a white solid. Purity based on LC-MS 95%. LRMS (m/z): 419 [M+1]+ LCMS 3 r.t. (min.): 0.77 INTERMEDIATE 144 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 The title compound was prepared from tert-butyl (2R,6S)-4-(4-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 95%. LRMS (m/z): 686 [M+1]+ LCMS 3 r.t. (min.): 2.37 INTERMEDIATE 145 (4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid A mixture of 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.35 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.203 mL, 1.40 mmol), Pd2(dba)3 (16 mg, 0.017 mmol), X-Phos (17 mg, 0.035 mmol) and triethylamine (0.195 mL, 1.93 mmol) in dioxane (2 mL) was heated at 100 ºC under inert atmosphere for 1 hour. Water was added and the aqueous layer was extracted with EtOAc (x3). He combined organic layers were dried over magnesium sulfate and the solvents were removed under reduced pressure. The crude product was used without further purification. Purity based on LC-MS 52% boronic acid, 15% boronic ester. LRMS (m/z): 419 [M+1]+ LCMS 2 r.t. (min.): 1.68 INTERMEDIATE 146 Tert-butyl 4-(6-(((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl 4-(6-(((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,2- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 80%. LRMS (m/z): 650 [M+1]+ LCMS 3 r.t. (min.): 2.14 INTERMEDIATE 147 Tert-butyl (2R,6S)-4-(4-(((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(4-(((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 75%. LRMS (m/z): 651 [M+1]+ LCMS 3 r.t. (min.): 2.14 INTERMEDIATE 148 Tert-butyl (2R,6S)-4-(6-(((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 100%. LRMS (m/z): 652 [M+1]+ LCMS 3 r.t. (min.): 2.36 INTERMEDIATE 149 Tert-butyl (2R,6S)-4-(6-(((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 87%. LRMS (m/z): 651 [M+1]+ LCMS 3 r.t. (min.): 2.37 INTERMEDIATE 150 Tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Intermediate 145. Purity based on LC-MS 67% borinic ester, 12% boronic acid. LRMS (m/z): 694 [M+1]+ LCMS 2 r.t. (min.): 3.77 INTERMEDIATE 151 5-(3,6-Dihydro-2H-pyran-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 a) 5-(3,6-Dihydro-2H-pyran-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 2-(3,6-dihydro-2H-pyran-4- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following the experimental procedure described in Intermediate 139. Purity based on LC-MS 95%. LRMS (m/z): 588 [M+1]+ LCMS 3 r.t. (min.): 1.58 b) 5-(3,6-Dihydro-2H-pyran-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 5-(3,6-Dihydro-2H-pyran-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)- 7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (140 mg, 0.24 mmol) was dissolved in dioxane (3 mL). Water (2 mL) and a 2 M solution of sodium hydroxide (1 mL) were added and the resulting mixture was stirred at 60 ºC for 3 hours. 2 M hydrochloric acid until neutral pH was reached and the product was purified directly by reverse phase chromatography (using water and a mixture of ACN/MeOH as eluents) to give the title compound. Purity based on LC-MS 83%. LRMS (m/z): 434 [M+1]+ LCMS 3 r.t. (min.): 0.94 INTERMEDIATE 152 5-(3,6-Dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-2-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 2-(3,6-dihydro- 2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 84%. LRMS (m/z): 435 [M+1]+ LCMS 3 r.t. (min.): 0.80 INTERMEDIATE 153 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 5-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (300 mg, 1.30 mmol), (6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)methanamine (350 mg, 1.68 mmol) and DIEA (0.7 mL, 4.1 mmol) were heated in ethanol (10 mL) at 90 ºC for 2 h. The volatiles were removed and the residue was redissolved in dichloromethane. The solution was washed with water, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was suspended in hexanes and the insoluble solid was filtered to give the title compound (420 mg, 78% yield) as a solid. Purity based on LC-MS 100%. LRMS (m/z): 416, 418 [M+1]+ LCMS3 r.t. (min.): 1.15 INTERMEDIATE 154 4-Chloro-5-(2,2-difluorocyclopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine a) 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5- carbaldehyde To a cooled (-78 ºC) solution of 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (1.33 g, 3.66 mmol) in 30 mL of Et2O was added dropwise butyllithium (3.43 mL of a 1.6M solution in hexanes, 5.49 mmol) and the resulting yellow suspension was stirred at -78 ºC for 30 min. Anhydrous DMF (0.711 mL, 9.14 mmol) was added dropwise and the reaction mixture was stirred at -78 ºC for 1 h. Aqueous saturated ammonium chloride solution was then added and the reaction mixture was extracted with EtOAc (x3). The combined organic extracts were washed with water (x3) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent was evaporated to yield the title compound (1.1 g, 96% yield) as an orange oil which was used in the next synthetic step without further purification. Purity based on LC-MS 96%. LRMS (m/z): 312 [M+1]+ LCMS 3 r.t. (min.): 1.83 b) 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-7H-pyrrolo[2,3-d]pyrimidine To a cooled (0 ºC) suspension of (methyl)triphenylphosphonium bromide (2.52 g, 7.06 mmol) in 20 mL of anhydrous THF was added dropwise butyllithium (4.4 mL of a 1.6M solution in hexanes, 7.04 mmol) and the resulting yellow suspension was stirred at 0 ºC for 1 h. A solution of 4-chloro- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.1 g, 3.53 mmol) in 10 mL of THF was then added and the resulting mixture was stirred at 0 ºC for 2 h. Water was added and the reaction mixture was extracted with EtOAc (x3). The combined organic extracts were washed with water (x3) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent was evaporated. The residue was purified by reverse phase chromatography (using water and a mixture of ACN/MeOH as eluents) to give the title compound (547 mg, 50% yield) as a yellow solid. Purity based on LC-MS 98%. LRMS (m/z): 310 [M+1]+ LCMS 3 r.t. (min.): 2.07 c) 4-Chloro-5-(2,2-difluorocyclopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine A Schlenk tube containing a mixture of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-7H- pyrrolo[2,3-d]pyrimidine (545 mg, 1.76 mmol), sodium iodide (105 mg, 0.7 mmol) and trimethyl(trifluoromethyl)silane (1.3 mL, 8.79 mmol) in 6 mL of ACN was sealed and heated at 110 ºC for 2 h. After cooling to ambient temperature, water was added and the reaction mixture was extracted with EtOAc (x3). The combined organic extracts were washed with water (x3) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent was evaporated to yield the title compound (624 mg, 98% yield) as a dark oil which was used in the next synthetic step without further purification. Purity based on LC-MS 98%. LRMS (m/z): 360 [M+1]+ LCMS 3 r.t. (min.): 2.02 INTERMEDIATE 155 Tert-butyl 4-(2-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)methyl)pyridin-4-yl)piperidine-1-carboxylate The title compound was prepared from 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine and tert-butyl 4-(2-(aminomethyl)pyridin-4-yl)piperidine-1-carboxylate following the experimental procedure described in Intermediate 84. Purity based on LC-MS 100%. LRMS (m/z): 617-619 [M+1]+
EXAMPLE 1 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 A mixture of 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-amine (49 mg, 0.22 mmol), Pd(dppf)Cl2 (10 mg, 0.013 mmol), and cesium carbonate (137 mg, 0.42 mmol) in 2 mL of a 4:1 mixture of dioxane/water was heated in a sealed tube under inert atmosphere at 120 ºC for 3 hours. Then, 1 mL of water was added and the mixture was heated at 120 ºC for additional 23 hours. The resulting mixture was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (60 mg, 26% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 430 [M+1]+ LCMS 1 r.t. (min.): 0.63 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J = 6.5 Hz, 6H), 2.59 – 2.69 (m, 2H), 3.14 (s, 2H), 3.13 – 3.20 (m, 4H), 4.13 – 4.30 (m, 2H), 4.63 – 4.73 (m, 2H), 6.04 (s, 1H), 6.26 (t, J = 5.3 Hz, 1H), 6.58 (s, 1H), 6.65 (dd, J = 5.3, 1.4 Hz, 1H), 6.71 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.50 – 7.59 (m, 1H), 7.91 (d, J = 5.3 Hz, 1H), 8.18 (s, 1H), 12.00 (d, J = 2.0 Hz, 1H). EXAMPLE 2 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 The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 1. Purity based on LC-MS 99%. LRMS (m/z): 415 [M+1]+ LCMS 1 r.t. (min.): 0.81 1H NMR (400 MHz, Chloroform-d) δ ppm 1.09 (d, J = 6.3 Hz, 6H), 2.20 – 2.35 (m, 2H), 2.81 – 2.95 (m, 2H), 3.79 – 3.91 (m, 2H), 4.71 – 4.83 (m, 2H), 6.14 (t, J = 4.6 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 7.2 Hz, 1H), 7.22 – 7.28 (m, 2H), 7.41 – 7.52 (m, 3H), 8.46 (s, 1H), 8.57 – 8.63 (m, 2H), 11.15 (s, 1H). EXAMPLE 3 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 The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 1. Purity based on LC-MS 100%. LRMS (m/z): 415 [M+1]+ LCMS 1 r.t. (min.): 0.98 1H NMR (400 MHz, Chloroform-d) δ ppm 1.18 (d, J = 6.3 Hz, 6H), 2.27 – 2.53 (m, 2H), 2.87 – 3.13 (m, 2H), 3.90 (dd, J = 12.8, 2.1 Hz, 2H), 4.74 (d, J = 5.1 Hz, 2H), 5.80 (t, J = 4.8 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.30 – 7.38 (m, 1H), 7.43 (dd, J = 8.4, 7.4 Hz, 1H), 7.83 (dt, J = 7.8, 1.9 Hz, 1H), 8.43 (s, 1H), 8.60 (dd, J = 4.8, 1.6 Hz, 1H), 8.80 – 8.87 (m, 1H), 10.52 (s, 1H). EXAMPLE 4 5-(5-Aminopyridin-3-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-3-amine following the experimental procedure described in Example 1. Purity based on LC-MS 99%. LRMS (m/z): 430 [M+1]+ LCMS 1 r.t. (min.): 0.57 1H NMR (400 MHz, Chloroform-d) δ ppm 1.18 (d, J = 6.4 Hz, 6H), 2.33 – 2.58 (m, 2H), 2.94 (dd, J = 10.1, 3.8 Hz, 2H), 3.93 (dd, J = 13.1, 2.2 Hz, 2H), 4.68 (s, 2H), 6.50 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 2.0 Hz, 2H), 7.40 – 7.52 (m, 1H), 8.01 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H). EXAMPLE 5 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(5-(methylamino)pyridin- 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and N-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine following the experimental procedure described in Example 1. Purity based on LC-MS 98%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.77 1H NMR (400 MHz, Chloroform-d) δ ppm 1.17 (d, J = 6.4 Hz, 6H), 2.33 – 2.52 (m, 2H), 2.56 (s, 3H), 2.81 – 3.11 (m, 2H), 3.80 – 4.13 (m, 2H), 4.69 (s, 2H), 6.50 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 6.88 (s, 1H), 7.08 (s, 1H), 7.39 – 7.48 (m, 1H), 7.95 – 8.03 (m, 2H), 8.33 (s, 1H). EXAMPLE 6 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 The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2-methoxypyridin-4- yl)boronic acid following the experimental procedure described in Example 1. Purity based on LC- MS 100%. LRMS (m/z): 445 [M+1]+ LCMS 1 r.t. (min.): 1.41 1H NMR (400 MHz, Chloroform-d) δ ppm 1.25 (d, J = 6.5 Hz, 6H), 2.53 – 2.68 (m, 2H), 3.03 – 3.17 (m, 2H), 3.84 (s, 3H), 3.88 – 4.04 (m, 2H), 4.71 (s, 2H), 6.54 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 6.79 – 6.86 (m, 1H), 7.02 (dd, J = 5.3, 1.4 Hz, 1H), 7.17 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 5.2 Hz, 1H), 8.30 – 8.34 (m, 2H). 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. The mixture was allowed to cool to room temperature and an aqueous 6 M solution of sodium hydroxyde was added until pH = 8 was reached. A precipitate formed, which was washed with water and dried under vacuum to give the title compound. Purity based on LC-MS 97%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.85 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J = 6.2 Hz, 6H), 2.03 – 2.22 (m, 2H), 2.58 – 2.80 (m, 2H), 3.93 – 4.07 (m, 2H), 4.47 – 4.82 (m, 2H), 6.33 – 6.46 (m, 3H), 6.57 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 6.7 Hz, 1H), 7.40 – 7.48 (m, 1H), 7.50 (s, 1H), 8.18 (s, 1H). 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%. LRMS (m/z): 417 [M+1]+ LCMS 1 r.t. (min.): 0.84 1H NMR (400 MHz, Methanol-d4) δ ppm 1.29 (s, 1H), 1.37 – 1.52 (m, 2H), 1.65 – 1.78 (m, 1H), 1.90 – 2.01 (m, 1H), 2.74 – 2.87 (m, 2H), 3.55 – 3.63 (m, 1H), 3.63 – 3.71 (m, 1H), 3.81 – 3.91 (m, 1H), 4.66 (s, 2H), 6.57 – 6.66 (m, 2H), 6.71 (s, 1H), 6.76 (d, J = 5.4 Hz, 1H), 7.29 (s, 1H), 7.42 – 7.50 (m, 1H), 7.89 (d, J = 5.4 Hz, 1H), 8.22 (s, 1H).. EXAMPLE 9 5-(2-Aminopyridin-4-yl)-N-((6-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((2-methoxyethyl)(methyl)amino)pyridin-2- yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 1. Purity based on LC-MS 99%. LRMS (m/z): 405 [M+1]+ LCMS 1 r.t. (min.): 0.83 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (s, 3H), 3.17 (d, J = 5.3 Hz, 2H), 3.30 (s, 3H), 3.45 (t, J = 5.5 Hz, 2H), 4.65 (d, J = 5.1 Hz, 2H), 5.94 (s, 2H), 6.30 (t, J = 5.2 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 6.55 (s, 1H), 6.61 (dd, J = 5.2, 1.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.41 (dd, J = 8.4, 7.3 Hz, 1H), 7.91 (d, J = 5.1 Hz, 1H), 8.19 (s, 1H), 11.95 (s, 1H). EXAMPLE 10 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrimidine following the experimental procedure described in Example 1. Purity based on LC-MS 97%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 1.01 1H NMR (400 MHz, Chloroform-d) δ ppm 1.17 (d, J = 6.4 Hz, 6H), 2.29 – 2.44 (m, 2H), 2.81 – 3.05 (m, 2H), 3.79 – 3.99 (m, 2H), 4.68 (s, 2H), 6.48 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 7.3 Hz, 1H), 7.13 (s, 1H), 7.37 – 7.48 (m, 1H), 8.33 (s, 1H), 8.88 (s, 2H), 9.13 (s, 1H). EXAMPLE 11 5-(6-Aminopyridin-3-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. Purity based on LC-MS 100%. LRMS (m/z): 430 [M+1]+ LCMS 1 r.t. (min.): 0.58 1H NMR (400 MHz, Methanol-d4) δ ppm 1.11 (d, J = 6.4 Hz, 6H), 2.33 (dd, J = 13.1, 11.0 Hz, 2H), 2.80 – 2.97 (m, 2H), 3.96 – 4.07 (m, 2H), 4.63 (s, 2H), 6.57 – 6.72 (m, 3H), 7.11 (s, 1H), 7.49 (dd, J = 8.5, 7.3 Hz, 1H), 7.59 (dd, J = 8.5, 2.4 Hz, 1H), 8.05 – 8.08 (m, 1H), 8.18 (s, 1H). EXAMPLE 12 5-(2,3-Difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2,3- difluorophenyl)boronic acid following the experimental procedure described in Example 1. Purity based on LC-MS 98%. LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.63 1H NMR (400 MHz, Methanol-d4) δ ppm 1.13 (d, J = 6.4 Hz, 6H), 2.29 – 2.44 (m, 2H), 2.84 – 3.00 (m, 2H), 4.00 – 4.13 (m, 2H), 4.64 (s, 2H), 6.66 (t, J = 8.2 Hz, 2H), 7.11 – 7.31 (m, 4H), 7.40 – 7.54 (m, 1H), 8.19 (s, 1H). EXAMPLE 13 5-(2-Amino-3-methylpyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 3-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. Purity based on LC-MS 100%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.48 1H NMR (400 MHz, Methanol-d4) δ ppm 1.19 (d, J = 6.5 Hz, 6H), 2.01 (s, 3H), 2.45 (t, J = 13.3 Hz, 2H), 2.95 – 3.14 (m, 2H), 4.06 – 4.19 (m, 2H), 4.58 (s, 2H), 6.62 (t, J = 6.4 Hz, 2H), 6.71 (d, J = 8.5 Hz, 1H), 7.10 (s, 1H), 7.50 (dd, J = 8.4, 7.3 Hz, 1H), 7.76 (d, J = 5.3 Hz, 1H), 8.19 (s, 1H). EXAMPLE 14 5-(2-Aminopyridin-4-yl)-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. Purity based on LC-MS 99%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.80 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H), 2.33 (q, J = 12 Hz, 2H), 2.81-2.94 (m, 2H), 4.04 (t, J = 14 Hz, 2H), 5.35 (p, J = 6.8 Hz, 1H), 5.96 (s, 2H), 6.04 (d, J = 8 Hz, 1H), 6.53 (s, 1H), 6.59 (dd, J = 5.2 and 1.4 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.47 (dd, J = 8 and 7.2 Hz, 1H), 7.91 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 11.95 (s, 1H). 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)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (33 mg), prepared according to the experimental procedure described in Example 14. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Daicel Chiralpak ID (20mmx250mm, 5µm); Eluent A: heptane, Eluent B: 0.2% DEA in IPA; Flux: 20 mL/min; Run time: 30 min. First eluting peak (Example 15): Obtained as a white solid (27 mg). Purity by LC-MS 100%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.81 Second eluting peak (Example 16): Obtained as a white solid (30 mg). Purity by LC-MS 100%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.81 EXAMPLE 17 N-(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 The title compound was prepared from 5-bromo-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the experimental procedure described in Example 1. Purity based on LC-MS 96%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.15 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J = 5 Hz, 3H), 0.98 (d, J = 5 Hz, 3H), 1.41 (d, J = 6.5 Hz, 3H), 2.11 (q, J = 11 Hz, 2H), 2.65-2.75 (m, 2H), 3.86 (s, 3H), 3.88-3.98 (m, 2H), 5.29 (p, J = 6 Hz, 1H), 6.08 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 7.09 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.77 (s, 1H), 8.13 (s, 1H), 11.68 (s, 1H). 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-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine (29 mg), prepared according to the experimental procedure described in Example 17. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Daicel Chiralpak ID (20mmx250mm, 5µm); Eluent A: heptane, Eluent B: 0.2% DEA in ethanol; Flux: 20 mL/min; Run time: 30 min. First eluting peak (Example 18): Obtained as a white solid (27 mg). Purity by LC-MS 100%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.15 Second eluting peak (Example 19): Obtained as a white solid (30 mg). Purity by LC-MS 96%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.15 EXAMPLE 20 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-4-ylboronic acid following the experimental procedure described in Example 1. Purity based on LC-MS 100%. LRMS (m/z): 429 [M+1]+ LCMS 1 r.t. (min.): 1.05 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 1.42 (d, J = 6.6 Hz, 3H), 2.02-2.15 (m, 2H), 2.64-2.74 (m, 2H), 3.79-3.92 (m, 2H), 5.37 (p, J = 6.6 Hz, 1H), 6.00 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 7.43-7.54 (m, 4H), 8.22 (s, 1H), 8.55 (d, J = 6 Hz, 1H), 12.10 (s, 1H). EXAMPLE 21 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 1. Purity based on LC-MS 99%. LRMS (m/z): 429 [M+1]+ LCMS 1 r.t. (min.): 1.26 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.7 Hz, 3H), 2.57-2.69 (m, 2H), 3.79-3.88 (m, 2H), 5.34 (p, J = 6.7 Hz, 1H), 5.78 (d, J = 7.8 Hz, 1H), 5.97 (s, 2H), 6.59 (d, J = 7.2 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 7.37-7.46 (m, 3H), 7.87 (dt, J = 8 and 2 Hz, 1H), 8.2 (s, 1H), 8.54 (dd, J = 4.8 and 1.2 Hz, 1H), 8.75 (d, J = 2 Hz, 1H), 12.01 (s, 1H). EXAMPLE 22 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-4-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 97%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 1.06 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 8.17 (s, 1H), 7.92 (dt, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 7.8, 4.8 Hz, 1H), 7.41 (s, 1H), 6.56 (d, J = 5.0 Hz, 1H), 6.26 (t, J = 5.5 Hz, 1H), 4.57 (s, 2H), 2.66 (m, 4H), 2.28 (m, 2H), 0.98 (m, 6H). EXAMPLE 23 5-(2-Aminopyridin-4-yl)-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 5-bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-4-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2-aminopyridin-4- yl)boronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 92%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.73 1H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (s, 1H), 8.26 (s, 2H), 7.93 (d, J = 5.2 Hz, 1H), 7.37 (s, 1H), 6.65 (dd, J = 5.2, 1.4 Hz, 1H), 6.60 – 6.54 (m, 2H), 6.32 (t, J = 5.5 Hz, 1H), 5.95 (s, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.41 (m, 2H), 2.70 (m, 2H), 2.40 – 2.26 (m, 2H), 1.02 (m, 6H). EXAMPLE 24 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(2- (trifluoromethyl)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-4-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2- (trifluoromethyl)pyridin-4-yl)boronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 484 [M+1]+ LCMS 1 r.t. (min.): 1.76 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 8.73 (d, J = 5.1 Hz, 1H), 8.26 – 8.17 (m, 2H), 8.00 – 7.95 (m, 1H), 7.82 (dd, J = 5.1, 1.3 Hz, 1H), 7.74 (s, 1H), 6.63 (t, J = 5.6 Hz, 1H), 6.56 (d, J = 5.0 Hz, 1H), 4.56 (d, J = 5.5 Hz, 1H), 4.38 (d, J = 11.9 Hz, 2H), 2.67 – 2.56 (m, 2H), 2.28 – 2.18 (m, 2H), 0.93 (m, 6H). EXAMPLE 25 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(pyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 5-bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-4-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 96%. LRMS (m/z): 415 [M+1]+ LCMS 1 r.t. (min.): 0.79 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (s, 1H), 8.75 (s, 1H), 8.50 (m, 2H), 8.25 (m, 1H), 7.93 – 7.85 (m, 1H), 7.42 (dd, J = 7.8, 4.8 Hz, 1H), 7.35 (m, 2H), 6.60 (m, 1H), 6.18 (m, 2H), 5.51 (t, J = 5.5 Hz, 1H), 4.32 (s, 2H), 2.61 (m, 3H), 2.54 (m, 2H), 2.24 (m, 2H), 0.97 (m, 6H). EXAMPLE 26 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(3-fluoropyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 5-bromo-N-((2-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-4-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (3-fluoropyridin-4- yl)boronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 98%. LRMS (m/z): 433 [M+1]+ LCMS 1 r.t. (min.): 0.91 1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 8.59 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.24 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.53 – 7.44 (m, 2H), 6.58 (d, J = 5.0 Hz, 1H), 6.16 (d, J = 5.5 Hz, 1H), 5.69 (s, 1H), 4.36 – 4.27 (m, 2H), 2.26 – 2.16 (m, 4H), 2.00 (m, 2H), 1.24 - 0.96 (m, 6H). EXAMPLE 27 5-(2-Aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((4-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. Purity based on LC-MS 97%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.30 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H), 1.47-1.58 (m, 1H), 2.38 (s, 3H), 1.62 (t, J = 7 Hz, 2H), 2.20-2.33 (m, 2H), 2.75-2.88 (m, 2H), 3.97-4.07 (m, 2H), 5.35 (q, J = 7.3 Hz, 1H), 5.81 (d, J = 8.8 Hz, 1H), 5.97 (s, 2H), 6.55-6.60 (m, 2H), 6.65 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.43 (dd, J = 8.4 and 7.2 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H), 8.14 (s, 1H), 11.92 (s, 1H). EXAMPLE 28 5-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrazin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. Purity based on LC-MS 99%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.45 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J = 6.3 Hz, 6H), 2.20-2.28 (m, 2H), 2.65- 2.74 (m, 2H), 4.03 (dd, J = 12.5 and 2.2 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 5.92 (s, 2H), 6.22 (t, J = 5.6 Hz, 1H), 6.55 (br s, 1H), 6.62 (dd, J = 5.2 and 1.5 Hz, 1H), 7.35 (s, 1H), 7.78 (s, 1H), 7.90 (d, J = 5.2 Hz, 1H), 8.13 (s, 1H), 8.18 (s, 1H), 11.97 (s, 1H). EXAMPLE 29 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-5-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrazin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 90%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 0.79 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J = 2.0 Hz, 1H), 8.53 (m, 2H), 8.33 (s, 1H), 7.79 (s, 1H), 7.53 – 7.37 (m, 2H), 7.11 (s, 1H), 6.17 (t, J = 5.5 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 2.78 – 2.70 (m, 2H), 2.28 (d, J = 5.4 Hz, 4H), 1.00 (d, J = 6.3 Hz, 6H). EXAMPLE 30 2-((6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol The title compound was prepared from 2-((6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)-4-(trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with diethylether / methanol. Purity based on LC-MS 94%. LRMS (m/z): 459 [M+1]+ LCMS 1 r.t. (min.): 1.53 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90 (s, 3H), 3.44 (s, 4H), 4.62 (s, 1H), 4.70 – 4.74 (m, 2H), 5.93 (s, 2H), 6.35 (t, J = 5.3 Hz, 1H), 6.55 (s, 1H), 6.62 (d, J = 5.2 Hz, 1H), 6.69 (s, 1H), 6.73 (s, 1H), 7.34 (s, 1H), 7.91 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 11.97 (s, 1H). EXAMPLE 31 3-((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-(6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol The title compound was prepared from 3-((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 98%. LRMS (m/z): 474 [M+1]+ LCMS 1 r.t. (min.): 0.64 1H NMR (400 MHz, Methanol-d6) δ ppm 1.23 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.98-2.14 (m, 2H), 2.39 (dd, J = 13.5 and 11.5 Hz, 1H), 2.55 (dd, J = 13.4 and 11.4 Hz, 1H), 3.05-3.17 (m, 2H), 3.54 (t, J = 6.5 Hz, 2H), 4.09-4.15 (m, 1H), 4.15-4.21 (m, 2H), 5.44 (dd, J = 7.2 and 6.4 Hz, 1H), 6.64 (br s, 1H), 6.67 (dd, J = 5.4 and 1.5 Hz, 1H), 6.73 (d, J = 7 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 7.28 (s, 1H), 7.54 (dd, J = 8.5 and 7.3 Hz, 1H), 7.87 (d, J = 5 Hz, 1H), 8.20 (s, 1H). EXAMPLE 32 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(1- methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 97%. LRMS (m/z): 486 [M+1]+ LCMS 1 r.t. (min.): 1.47 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J = 6.2 Hz, 6H), 2.19-2.28 (m, 2H), 2.65- 2.76 (m, 2H), 3.85 (s, 3H), 4.10 (d, J = 12.3 Hz, 2H), 4.70 (d, J = 5.6 Hz, 2H), 6.26 (t, J = 5.8 Hz, 1H), 6.78 (s, 1H), 6.93 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.56 (s, 1H), 7.81 (d, J = 5.2 Hz, 1H), 8.12 (s, 1H), 11.72 (s, 1H). EXAMPLE 33 5-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 100%. LRMS (m/z): 497 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J = 6 Hz, 6H), 2.18-2.28 (m, 2H), 2.64-2.74 (m, 2H), 4.08 (d, J = 12.7 Hz, 2H), 4.72 (d, J = 5.3 Hz, 2H), 5.91 (s, 2H), 6.29 (t, J = 5.1 Hz, 1H), 6.55 (s, 1H), 6.62 (d, J = 5.2 Hz, 1H), 6.79 (s, 1H), 6.92 (s, 1H), 7.36 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 11.98 (s, 1H). EXAMPLE 34 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5- (pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3- ylboronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 98%. LRMS (m/z): 483 [M+1]+ LCMS 1 r.t. (min.): 1.54 1H NMR (400 MHz, Chloroform-d) δ ppm 1.20 (d, J = 6.3 Hz, 6H), 2.50 (t, J = 15.9 Hz, 2H), 2.83 – 3.07 (m, 2H), 3.79 – 4.14 (m, 2H), 4.80 (d, J = 5.3 Hz, 2H), 5.64 (t, J = 5.3 Hz, 1H), 6.64 (s, 1H), 6.76 (s, 1H), 7.15 (s, 1H), 7.35 (dd, J = 7.6, 5.1 Hz, 1H), 7.83 (dt, J = 7.8, 1.9 Hz, 1H), 8.42 (s, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.82 (d, J = 2.3 Hz, 1H), 10.49 (s, 1H). EXAMPLE 35 5-(2-Aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)propyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)propyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 98%. LRMS (m/z): 458 [M+1]+ LCMS 1 r.t. (min.): 0.97 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (t, J = 7.4 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 1.81 (p, J = 7.2 Hz, 2H), 2.35-2.48 (m, 2H), 2.90-3.01 (m, 2H), 4.06 (td, J = 12.4 and 2.4 Hz, 2H), 5.20-5.28 (m, 1H), 5.94-5.98 (m, 3H), 6.54 (s, 1H), 6.59 (dd, J = 5.2 and 1.4 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.48 (dd, J = 8.4 and 7.3 Hz, 1H), 7.92 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 11.94 (s, 1H). EXAMPLE 36 5-(2-Aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-3- methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)-3-methylbutyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 100%. LRMS (m/z): 486 [M+1]+ LCMS 1 r.t. (min.): 1.33 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H), 1.47-1.58 (m, 1H), 2.38 (s, 3H), 1.62 (t, J = 7 Hz, 2H), 2.20-2.33 (m, 2H), 2.75-2.88 (m, 2H), 3.97-4.07 (m, 2H), 5.35 (q, J = 7.3 Hz, 1H), 5.81 (d, J = 8.8 Hz, 1H), 5.97 (s, 2H), 6.55-6.60 (m, 2H), 6.65 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.43 (dd, J = 8.4 and 7.2 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H), 8.14 (s, 1H), 11.92 (s, 1H). EXAMPLE 37 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-2- methyl-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and (3-fluoropyridin-4- yl)boronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 94%. LRMS (m/z): 446 [M+1]+ LCMS 1 r.t. (min.): 1.18 EXAMPLE 38 3-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)propan-1-ol The title compound was prepared from 3-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)propan-1-ol and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 1. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC- MS 100%. LRMS (m/z): 376 [M+1]+ LCMS 1 r.t. (min.): 0.71 1H NMR (400 MHz, Methanol-d4) δ ppm 1.71 – 1.82 (m, 2H), 2.70 – 2.79 (m, 2H), 3.54 (t, J = 6.5 Hz, 2H), 4.58 (s, 1H), 4.79 (s, 2H), 6.73 (s, 1H), 6.79 (dd, J = 5.4, 1.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.92 – 7.95 (m, 1H), 8.22 (s, 1H). EXAMPLE 39 N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.26 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (88 mg, 0.39 mmol), Pd(dppf)Cl2 (19 mg, 0.013 mmol), and cesium carbonate (257 mg, 0.79 mmol) in 2.5 mL of a 4:1 mixture of dioxane/water was heated in a sealed tube under inert atmosphere at 110 ºC for 4 hours until the starting material was consumed. Then, a 2 M aqueous solution of sodium hydroxide (1 mL) was added and the mixture was heated at 80 ºC until no tosyl-protected product was detected (1 hour). The resulting mixture was then diluted with EtOAc, filtered through Celite® dried over magnesium sulfate and the solvents removed under reduced pressure. The crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (35 mg, 31% yield) as a white solid. Purity based on LC-MS 99%. LRMS (m/z): 433 [M+1]+ LCMS 1 r.t. (min.): 1.19 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.57 (t, J = 6.0 Hz, 2H), 7.47 (d, J = 1.4 Hz, 1H), 6.77 (t, J = 8.1 Hz, 2H), 4.70 (s, 2H), 4.27 (d, J = 13.9 Hz, 2H), 3.24 (dt, J = 9.8, 4.9 Hz, 2H), 2.61 (t, J = 12.6 Hz, 2H), 1.27 (d, J = 6.5 Hz, 6H). EXAMPLE 40 5-(2-Amino-6-methylpyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine following the experimental procedure described in Example 39. The crude product was purified by reverse phase chromatography eluting with 100 % water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 96%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.77 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J = 6.3 Hz, 6H), 1.85 – 2.29 (m, 5H), 2.63 – 2.77 (m, 2H), 3.95 (d, J = 14.8 Hz, 2H), 4.62 (d, J = 5.1 Hz, 2H), 5.85 (s, 1H), 6.24 (t, J = 5.3 Hz, 1H), 6.36 (s, 1H), 6.47 (s, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.64 – 6.69 (m, 1H), 7.32 (s, 1H), 7.37 – 7.52 (m, 1H), 8.18 (s, 1H), 8.29 (s, 1H), 11.93 (s, 1H). EXAMPLE 41 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(4-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (4-fluorophenyl)boronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 98%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.66 1H NMR (400 MHz, Chloroform-d) δ ppm 11.19 (s, 1H), 8.44 (s, 1H), 7.48 (ddd, J = 8.3, 5.2, 2.6 Hz, 2H), 7.42 (dd, J = 8.5, 7.3 Hz, 1H), 7.26 (s, 1H), 7.13 – 6.95 (m, 2H), 6.58 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 5.97 (t, J = 4.9 Hz, 1H), 5.30 (s, 1H), 4.73 (d, J = 4.9 Hz, 2H), 3.89 (dd, J = 12.6, 2.3 Hz, 2H), 2.84 (dqd, J = 9.2, 6.3, 3.0 Hz, 2H), 2.21 (dd, J = 12.4, 10.7 Hz, 2H), 1.07 (d, J = 6.3 Hz, 6H). EXAMPLE 42 5-(3,4-Difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (3,4- difluorophenyl)boronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 96%. LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.77 1H NMR (400 MHz, Chloroform-d) δ ppm 9.20 (s, 1H), 8.42 (s, 1H), 7.43 (dd, J = 8.5, 7.3 Hz, 1H), 7.32 (dd, J = 11.1, 7.6 Hz, 1H), 7.23 – 7.12 (m, 2H), 7.02 (s, 1H), 6.59 (d, J = 7.1 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 5.97 (s, 1H), 4.72 (d, J = 4.8 Hz, 2H), 3.94 – 3.81 (m, 2H), 3.49 (s, 1H), 2.83 (s, 2H), 2.30 – 2.14 (m, 2H), 1.07 (d, J = 6.3 Hz, 6H). EXAMPLE 43 and EXAMPLE 44 (S*)-N-((6-(3-(Fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, first eluting peak (R*)-N-((6-(3-(Fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, second eluting peak A racemic mixture of the title compounds was prepared from 5-bromo-N-((6-(3- (fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. following the experimental procedure described in Example 39. A chiral separation of the two enantiomers was done by preparative HPLC. Column: Daicel Chiralpak ID (20mmx250mm, 5µm); Eluent A: heptane, Eluent B: 0.2% DEA in IPA; Flux: 20 mL/min; Run time: 30 min. First eluting peak (Example 43): Purity by LC-MS 98%. LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 1.25 Second eluting peak Example 44): Purity by LC-MS 92%. LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 1.25 EXAMPLE 45 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and pyridin-4-ylboronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 100%. LRMS (m/z): 414 [M+1]+ LCMS 1 r.t. (min.): 0.74 1H NMR (400 MHz, Methanol-d4) δ ppm 8.45 (d, J = 6.2 Hz, 2H), 7.94 (d, J = 5.7 Hz, 1H), 7.59 (dd, J = 4.6, 1.5 Hz, 2H), 7.55 – 7.45 (m, 1H), 7.39 (s, 1H), 6.66 (t, J = 7.3 Hz, 2H), 6.41 (d, J = 5.8 Hz, 1H), 4.41 (s, 2H), 3.91 (d, J = 10.5 Hz, 2H), 2.75 (d, J = 6.5 Hz, 2H), 2.26 – 2.11 (m, 2H), 1.05 (d, J = 6.4 Hz, 6H). EXAMPLE 46 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 39. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 92%. LRMS (m/z): 414 [M+1]+ LCMS 1 r.t. (min.): 0.89 1H NMR (400 MHz, Methanol-d4) δ ppm 8.76 (d, J = 1.5 Hz, 1H), 8.50 (dd, J = 4.9, 1.6 Hz, 1H), 8.35 (s, 3H), 7.98 (dt, J = 7.9, 1.7 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.58 (dd, J = 8.4, 7.4 Hz, 1H), 7.44 (ddd, J = 7.9, 4.9, 0.8 Hz, 1H), 7.30 (s, 1H), 6.79 (t, J = 7.3 Hz, 2H), 6.43 (d, J = 6.0 Hz, 1H), 4.46 (s, 2H), 4.28 (dd, J = 14.0, 2.4 Hz, 2H), 3.27 – 3.17 (m, 2H), 2.61 (dd, J = 14.2, 11.4 Hz, 2H), 1.28 (d, J = 6.6 Hz, 6H). EXAMPLE 47 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and pyrimidin-5-ylboronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 99%. LRMS (m/z): 415 [M+1]+ LCMS 1 r.t. (min.): 0.91 1H NMR (400 MHz, Methanol-d4) δ ppm 9.06 (s, 1H), 8.97 (s, 2H), 7.93 (d, J = 5.7 Hz, 1H), 7.52 – 7.43 (m, 1H), 7.37 (s, 1H), 6.65 (dd, J = 13.5, 7.9 Hz, 2H), 6.39 (d, J = 5.7 Hz, 1H), 4.39 (s, 2H), 3.97 (dd, J = 12.7, 2.2 Hz, 2H), 2.78 (ddd, J = 9.7, 6.5, 3.0 Hz, 2H), 2.26 – 2.16 (m, 2H), 1.08 (d, J = 6.4 Hz, 6H). EXAMPLE 48 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and 3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 39. Purity based on LC-MS 99%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.12 1H NMR (400 MHz, Methanol-d4) δ ppm 8.51 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 4.9 Hz, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.48 – 7.39 (m, 3H), 6.54 (dd, J = 25.8, 7.9 Hz, 2H), 6.37 (d, J = 5.7 Hz, 1H), 4.40 (d, J = 5.0 Hz, 2H), 3.90 (dd, J = 12.6, 2.4 Hz, 2H), 2.84 (ddt, J = 12.7, 9.3, 4.6 Hz, 2H), 2.22 (dd, J = 12.4, 10.7 Hz, 2H), 1.09 (d, J = 6.3 Hz, 6H). EXAMPLE 49 3-(1,3-Dimethyl-1H-pyrazol-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and (1,3-dimethyl-1H-pyrazol-4- yl)boronic acid following the experimental procedure described in Example 39. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 100%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.99 1H NMR (400 MHz, Methanol-d4) δ ppm 7.88 (d, J = 6.1 Hz, 1H), 7.65 – 7.55 (m, 1H), 7.51 (s, 1H), 7.04 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 7.3 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 4.42 (s, 4H), 4.32 (d, J = 11.6 Hz, 2H), 3.78 (s, 3H), 2.68 (dd, J = 14.1, 11.4 Hz, 4H), 2.20 (s, 3H), 1.30 (d, J = 6.5 Hz, 6H). EXAMPLE 50 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H,1'H-[3,5'-bipyrrolo[2,3- b]pyridin]-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine following the experimental procedure described in Example 39. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 453 [M+1]+ LCMS 1 r.t. (min.): 1.21 1H NMR (400 MHz, Methanol-d4) δ ppm 8.38 (s, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 5.9 Hz, 1H), 7.58 – 7.49 (m, 1H), 7.45 (d, J = 3.4 Hz, 1H), 7.21 (s, 1H), 6.71 (s, 2H), 6.43 (t, J = 4.4 Hz, 2H), 4.41 (s, 2H), 4.07 (d, J = 11.7 Hz, 2H), 3.68 – 3.45 (m, 4H), 3.06 (s, 2H), 2.50 – 2.37 (m, 2H), 1.23 (d, J = 6.5 Hz, 6H). EXAMPLE 51 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 95%. LRMS (m/z): 428 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, Methanol-d4) δ ppm 8.77 (dd, J = 2.2, 0.8 Hz, 1H), 8.51 (dd, J = 4.9, 1.6 Hz, 1H), 8.00 (dt, J = 7.9, 1.9 Hz, 1H), 7.83 (d, J = 5.7 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.23 (s, 1H), 6.64 (dd, J = 7.8, 5.9 Hz, 2H), 6.25 (d, J = 5.9 Hz, 1H), 4.70 (q, J = 6.6 Hz, 1H), 4.58 (s, 1H), 4.02 (t, J = 14.2 Hz, 2H), 2.81 (dddd, J = 26.2, 10.4, 6.5, 3.2 Hz, 3H), 2.25 (ddd, J = 23.9, 12.6, 11.0 Hz, 3H), 1.40 (d, J = 6.6 Hz, 3H), 1.09 (dd, J = 12.4, 6.4 Hz, 6H). EXAMPLE 52 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and pyrimidin-5-ylboronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 96%. LRMS (m/z): 429 [M+1]+ LCMS 1 r.t. (min.): 0.91 1H NMR (400 MHz, Methanol-d4) δ ppm 9.10 (s, 1H), 9.01 (s, 2H), 7.87 (d, J = 5.7 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 6.65 (dd, J = 20.2, 7.9 Hz, 2H), 6.33 (d, J = 5.7 Hz, 1H), 4.72 (q, J = 6.4 Hz, 1H), 4.08 – 3.95 (m, 2H), 2.81 (dd, J = 9.9, 7.2 Hz, 2H), 2.24 (dt, J = 23.1, 11.8 Hz, 2H), 1.44 (d, J = 6.6 Hz, 3H), 1.10 (dd, J = 8.3, 6.6 Hz, 6H). EXAMPLE 53 N-((4-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-3-(pyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((4-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyrimidin-2-yl)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 39. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 88%. LRMS (m/z): 415 [M+1]+ LCMS 1 r.t. (min.): 0.63 1H NMR (400 MHz, Methanol-d4) δ ppm 8.76 (s, 1H), 8.52 (d, J = 4.5 Hz, 1H), 8.05 (dd, J = 16.2, 7.0 Hz, 3H), 7.93 (d, J = 5.6 Hz, 1H), 7.64 (dd, J = 12.2, 7.6 Hz, 1H), 7.50 (dd, J = 7.7, 4.9 Hz, 2H), 7.26 (s, 1H), 6.68 (d, J = 6.3 Hz, 1H), 6.34 (d, J = 5.7 Hz, 1H), 4.42 (s, 2H), 4.29 (d, J = 12.7 Hz, 2H), 2.89 (s, 2H), 2.58 – 2.44 (m, 2H), 1.14 (d, J = 6.4 Hz, 6H). EXAMPLE 54 3-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2- methyl-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine and (2-aminopyridin-4- yl)boronic acid following the experimental procedure described in Example 39. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 89%. LRMS (m/z): 443 [M+1]+ LCMS 1 r.t. (min.): 0.62 1H NMR (400 MHz, Chloroform-d) δ ppm 8.69 (s, 1H), 8.06 (d, J = 5.3 Hz, 2H), 7.80 (d, J = 6.3 Hz, 2H), 7.49 – 7.36 (m, 2H), 6.69 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (dd, J = 13.8, 8.1 Hz, 2H), 6.31 (d, J = 6.4 Hz, 1H), 4.38 (d, J = 5.4 Hz, 2H), 2.89 (s, 2H), 2.42 (m, 2H), 1.35 – 1.20 (m, 4H), 0.88 (m, 6H). EXAMPLE 55 N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine a) Tert-butyl 4-(6-(((5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate A mixture of tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate (140 mg, 0.21 mmol), 3- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (70 mg, 0.31 mmol), Pd(dppf)Cl2 (31 mg, 0.042 mmol), and cesium carbonate (204 mg, 0.62 mmol) in 5 mL of a 4:1 mixture of dioxane/water was heated in a sealed tube under inert atmosphere at 120 ºC for 24 hours until the starting material was consumed. Then, a 2 M aqueous solution of sodium hydroxide (1 mL) was added and the mixture was heated at 60 ºC until no tosyl-protected product was detected (4 hours). The resulting mixture was then partitioned between water and EtOAc, the aqueous layer was extracted with more EtOAc (x2). The combined organic solutions were dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by reverse phase chromatography eluting with 100 % water to 100% methanol/acetonitrile (1:1) to give the title compound (11 mg, 10% yield) as a white solid. Purity based on LC-MS 99%. LRMS (m/z): 533 [M+1]+ LCMS 3 r.t. (min.): 1.68 b) N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Tert-butyl 4-(6-(((5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)-2,2-dimethylpiperazine-1-carboxylate (11 mg, 0.021 mmol) was dissolved in 1 mL dichloromethane and trifluoroacetic acid (0.02 mL, 0.26 mmol) was added. The mixture was stirred at room temperature for 1 hour and then the volatiles were removed under reduced pressure. The crude product was purified by reverse phase chromatography eluting with 100 % water to 100% methanol/acetonitrile (1:1) to give the title compound (6 mg, 65% yield) as a white solid. Purity based on LC-MS 91%. LRMS (m/z): 433 [M+1]+ LCMS 1 r.t. (min.): 1.41 1H NMR (400 MHz, Methanol-d4) δ 8.56 – 8.51 (m, 1H), 8.37 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.57 (dd, J = 6.7, 5.0 Hz, 2H), 7.53 – 7.45 (m, 3H), 6.64 (d, J = 7.9 Hz, 2H), 4.69 (s, 2H), 4.58 (bs, 4H), 3.20 (s, 2H), 2.98 – 2.86 (m, 2H), 1.11 (s, 6H). EXAMPLE 56 N-((6-(2-Oxa-5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl 8-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 39. The purification of the title compound was done by preparative LC-MS under basic conditions. Purity based on LC-MS 96%. LRMS (m/z): 447 [M+1]+ LCMS 1 r.t. (min.): 1.11 1H NMR (400 MHz, DMSO-d6) δ ppm 2.63 – 2.71 (m, 2H), 3.17 (d, J = 5.2 Hz, 2H), 3.51 (s, 2H), 4.26 (d, J = 6.1 Hz, 2H), 4.34 (d, J = 6.1 Hz, 2H), 4.61 (d, J = 5.4 Hz, 2H), 6.39 (t, J = 5.6 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 7.44 – 7.51 (m, 2H), 7.53 (dd, J = 6.8, 4.9 Hz, 1H), 8.19 (s, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 12.21 (s, 1H). EXAMPLE 57 N-((6-(3,3-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine The title compound was prepared from tert-butyl 4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate and pyridin-3-ylboronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 84%. LRMS (m/z): 414 [M+1]+ LCMS 1 r.t. (min.): 0.94 1H NMR (400 MHz, Methanol-d4) δ ppm 8.74 (s, 1H), 8.47 (d, J = 4.1 Hz, 1H), 7.99 (dt, J = 7.9, 1.8 Hz, 1H), 7.91 (s, 1H), 7.52 – 7.40 (m, 2H), 7.25 (s, 1H), 6.62 (dd, J = 7.9, 3.5 Hz, 2H), 6.37 (d, J = 5.6 Hz, 1H), 4.38 (s, 2H), 3.28 (d, J = 5.5 Hz, 3H), 3.17 (s, 2H), 2.94 – 2.79 (m, 2H), 1.09 (s, 6H). EXAMPLE 58 N-((6-(3,3-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl 4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)methyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate and 3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 39. Purity based on LC-MS 74%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.13 1H NMR (400 MHz, Methanol-d4) δ ppm 8.49 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 5.7 Hz, 1H), 7.55 (dd, J = 6.8, 5.1 Hz, 1H), 7.48 (dd, J = 8.5, 7.3 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.34 (m, 1H), 6.69 – 6.61 (m, 2H), 6.39 (d, J = 5.8 Hz, 1H), 4.58 (s, 2H), 4.40 (s, 2H), 3.20 (s, 2H), 2.95 – 2.85 (m, 2H), 1.11 (s, 6H). EXAMPLE 59 5-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)-5-methylpyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 94%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.79 EXAMPLE 60 5-(2-Aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-3-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(3-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (2-aminopyridin-4- yl)boronic acid following the experimental procedure described in Example 39. Purity based on LC-MS 99%. LRMS (m/z): 390 [M+1]+ LCMS 1 r.t. (min.): 0.48 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.32 (s, 1H), 6.60 (dd, J = 5.2, 1.5 Hz, 1H), 6.53 (s, 1H), 6.18 (d, J = 2.2 Hz, 1H), 6.10 (s, 1H), 6.02 (t, J = 4.7 Hz, 1H), 4.61 (d, J = 4.6 Hz, 2H), 4.42 – 4.27 (m, 2H), 3.03 – 2.90 (m, 2H), 2.00 (dt, J = 28.2, 11.3 Hz, 4H). EXAMPLE 61 5-(3,4-Difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine a) Tert-butyl 4-(6-(((5-(3,4-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate (110 mg, 0.17 mmol), (3,4- difluorophenyl)boronic acid (30 mg, 0.19 mmol), Pd(dppf)Cl2 (14 mg, 0.017 mmol), and aqueous 2 M solution of cesium carbonate (0.26 mL, 0.52 mmol) in 2 mL of dioxane was heated in a sealed tube under inert atmosphere at 100 ºC for 2 hours until the starting material was consumed. Then, a 2 M aqueous solution of sodium hydroxide (1 mL) was added and the mixture was heated at 80 ºC until no tosyl-protected product was detected (1 hour). The resulting mixture was then partitioned between water and EtOAc, the aqueous layer was extracted with more EtOAc (x2). The combined organic solutions were dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography eluting from 100% hexane to 100% ethyl acetate to give the title compound (50 mg, 56% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 522 [M+1]+ LCMS 3 r.t. (min.): 1.90 b) 5-(3,4-Difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine carboxylate A 4 M solution of hydrochloric acid in dioxane (1.5 mL) was added to a solution of tert-butyl 4-(6- (((5-(3,4-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1- carboxylate (50 mg, 0.096 mmol) in dioxane (1.5 mL). The mixture was stirred at room temperature for 5 hours and then the volatiles were removed under reduced pressure. The residue was redissolved in water, basified with sodium carbonate and the product was extracted with ethyl acetate (x3). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to give the title compound (33 mg, 82% yield) as a pale solid. Purity based on LC-MS 96%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.71 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 – 2.71 (m, 4H), 3.11 – 3.19 (m, 4H), 4.63 (d, J = 5.0 Hz, 2H), 6.22 (t, J = 5.0 Hz, 1H), 6.61 (dd, J = 7.8, 4.9 Hz, 2H), 7.33 (d, J = 2.2 Hz, 2H), 7.43 – 7.59 (m, 4H), 8.20 (s, 1H), 11.96 (s, 1H). EXAMPLE 62 5-(2,3-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 (2,3- difluorophenyl)boronic acid following the experimental procedure described in Example 61. The purification of the title compound was done by trituration of the crude product in diethylether. Purity based on LC-MS 99%. LRMS (m/z): 531 [M+1]+ LCMS 1 r.t. (min.): 1.55 1H NMR (400 MHz, Methanol-d4) δ ppm 8.40 (s, 1H), 7.72 (dd, J = 8.5, 7.5 Hz, 1H), 7.54 (s, 1H), 7.43 – 7.21 (m, 3H), 6.95 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 4.83 (s, 2H), 3.76 – 3.69 (m, 4H), 3.29 – 3.22 (m, 4H). EXAMPLE 63 5-(2-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 and (2-fluorophenyl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 94%. LRMS (m/z): 404 [M+1]+ LCMS 1 r.t. (min.): 1.51 1H NMR (400 MHz, DMSO-d6) δ ppm 2.68 – 2.74 (m, 4H), 3.11 – 3.20 (m, 4H), 4.59 (d, J = 5.2 Hz, 2H), 5.94 (t, J = 5.2 Hz, 1H), 6.59 (dd, J = 14.0, 7.9 Hz, 2H), 7.24 – 7.35 (m, 3H), 7.37 – 7.52 (m, 3H), 8.19 (s, 1H), 11.98 (s, 1H). 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. Purity based on LC-MS 95%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.62 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 – 2.80 (m, 4H), 3.15 – 3.29 (m, 6H), 4.59 (d, J = 5.2 Hz, 3H), 6.01 (t, J = 5.3 Hz, 1H), 6.59 (dd, J = 20.8, 7.9 Hz, 2H), 7.16 (td, J = 8.4, 2.1 Hz, 1H), 7.26 (s, 1H), 7.36 (td, J = 9.9, 2.6 Hz, 1H), 7.41 – 7.56 (m, 2H), 8.67 (s, 1H), 9.80 (s, 1H), 11.98 (s, 1H). 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. Purity based on LC-MS 97%. LRMS (m/z): 404 [M+1]+ LCMS 1 r.t. (min.): 1.61 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 – 2.77 (m, 4H), 3.16 – 3.21 (m, 4H), 4.65 (d, J = 4.9 Hz, 2H), 6.19 (t, J = 5.0 Hz, 1H), 6.60 – 6.66 (m, 2H), 7.16 (t, J = 8.6 Hz, 1H), 7.31 – 7.38 (m, 3H), 7.43 – 7.50 (m, 2H), 8.21 (s, 1H), 11.97 (s, 1H). 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%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.72 1H NMR (400 MHz, Chloroform-d) δ ppm 9.44 (s, 1H), 8.43 (s, 1H), 7.43 (dd, J = 8.4, 7.3 Hz, 1H), 7.14 – 7.01 (m, 3H), 6.79 (tt, J = 8.9, 2.3 Hz, 1H), 6.62 (d, J = 7.2 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.18 (t, J = 4.7 Hz, 1H), 4.79 (d, J = 4.7 Hz, 2H), 3.35 – 3.09 (m, 4H), 2.99 – 2.77 (m, 4H). EXAMPLE 67 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 (2,5-difluorophenyl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 83%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.57 1H NMR (400 MHz, Chloroform-d) δ ppm 10.68 (s, 1H), 8.43 (s, 1H), 7.43 (dd, J = 8.4, 7.4 Hz, 1H), 7.24 – 7.08 (m, 3H), 7.05 – 6.95 (m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.99 (t, J = 4.7 Hz, 1H), 4.78 (t, J = 4.7 Hz, 2H), 3.30 – 3.20 (m, 4H), 2.94 – 2.84 (m, 4H). EXAMPLE 68 5-(4-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 and (4-fluorophenyl)boronic acid following the experimental procedure described in Example 61. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 99%. LRMS (m/z): 404 [M+1]+ LCMS 1 r.t. (min.): 1.48 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 – 2.72 (m, 4H), 3.11 – 3.17 (m, 4H), 4.63 (d, J = 5.0 Hz, 2H), 6.08 (t, J = 5.0 Hz, 1H), 6.61 (t, J = 8.1 Hz, 2H), 7.23 – 7.30 (m, 3H), 7.46 (dd, J = 8.5, 7.3 Hz, 1H), 7.50 – 7.57 (m, 2H), 8.20 (s, 1H), 11.88 (s, 1H). EXAMPLE 69 5-(4-Chlorophenyl)-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 (4-chlorophenyl)boronic acid following the experimental procedure described in Example 61. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 95%. LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 1.72 1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 – 2.76 (m, 4H), 3.13 – 3.22 (m, 4H), 4.64 (d, J = 5.1 Hz, 2H), 6.14 (t, J = 5.1 Hz, 1H), 6.59 – 6.66 (m, 2H), 7.31 (d, J = 2.2 Hz, 1H), 7.43 – 7.56 (m, 5H), 8.20 (s, 1H), 11.94 (s, 1H). EXAMPLE 70 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(6-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (6- methylpyridin-3-yl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 99%. LRMS (m/z): 428 [M+1]+ LCMS 1 r.t. (min.): 0.96 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J = 6.5 Hz, 5H), 2.79 (s, 3H), 3.05 – 3.18 (m, 2H), 4.25 (d, J = 12.5 Hz, 2H), 4.60 (d, J = 5.8 Hz, 2H), 6.65 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 7.41 – 7.53 (m, 1H), 7.57 – 7.64 (m, 1H), 7.70 (d, J = 2.6 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 7.0 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 9.32 (s, 1H), 9.71 (s, 1H), 13.00 (s, 1H), 14.51 (s, 1H). EXAMPLE 71 N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(5-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (5- methylpyridin-3-yl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 100%. LRMS (m/z): 428 [M+1]+ LCMS 1 r.t. (min.): 1.05 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J = 6.5 Hz, 6H), 2.75 – 2.86 (m, 2H), 3.08 – 3.14 (m, 2H), 4.19 – 4.26 (m, 2H), 4.62 (d, J = 5.8 Hz, 3H), 6.73 (t, J = 7.7 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 7.42 – 7.49 (m, 1H), 7.58 – 7.65 (m, 1H), 7.73 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 7.1 Hz, 1H), 8.37 (s, 1H), 8.79 (s, 1H), 8.85 (s, 1H), 13.02 (s, 1H). EXAMPLE 72 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-methylpyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (3- methylpyridin-4-yl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 91%. LRMS (m/z): 428 [M+1]+ LCMS 1 r.t. (min.): 0.83 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J = 6.5 Hz, 6H), 2.73 – 2.83 (m, 2H), 3.06 – 3.20 (m, 2H), 4.23 (d, J = 12.4 Hz, 3H), 4.54 (d, J = 5.9 Hz, 2H), 6.66 (dd, J = 7.2, 2.3 Hz, 2H), 6.86 (d, J = 8.5 Hz, 1H), 7.14 – 7.22 (m, 1H), 7.54 – 7.62 (m, 1H), 7.73 (s, 1H), 7.81 (d, J = 5.6 Hz, 1H), 8.10 (d, J = 7.1 Hz, 1H), 8.76 (d, J = 5.8 Hz, 1H), 8.90 (s, 1H), 13.13 (s, 1H). EXAMPLE 73 3-(3,4-Difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-amine The title compound was prepared from tert-butyl 4-(6-(((3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate and (3,4-difluorophenyl)boronic acid following the experimental procedure described in Example 61. The purification of the title compound was done by preparative LC-MS under neutral conditions. Purity based on LC-MS 93%. LRMS (m/z): 421 [M+1]+ LCMS 1 r.t. (min.): 1.42 1H NMR (400 MHz, DMSO-d6) δ ppm 2.49 – 2.51 (m, 2H), 2.73 – 2.77 (m, 2H), 3.19 – 3.24 (m, 4H), 4.33 (d, J = 5.0 Hz, 2H), 5.53 – 5.60 (m, 1H), 6.26 (d, J = 5.6 Hz, 1H), 6.66 (d, J = 7.8 Hz, 2H), 7.28 (s, 1H), 7.40 – 7.54 (m, 4H), 7.90 (d, J = 5.4 Hz, 1H), 8.20 (s, 1H), 11.59 (s, 1H). EXAMPLE 74 5-(2,3-Difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(4-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)piperazine-1-carboxylate and (2,3- difluorophenyl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 97%. LRMS (m/z): 423 [M+1]+ LCMS 1 r.t. (min.): 1.52 1H NMR (400 MHz, Methanol-d4) δ ppm 8.44 – 8.31 (m, 2H), 7.55 (s, 1H), 7.45 – 7.22 (m, 3H), 6.75 (d, J = 5.1 Hz, 1H), 4.79 (s, 2H), 4.03 – 3.81 (m, 4H), 3.25 – 3.18 (m, 4H). EXAMPLE 75 5-(2,3-Difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[3,4- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(4-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)piperazine-1-carboxylate and (3,4- difluorophenyl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 95%. LRMS (m/z): 423 [M+1]+ LCMS 1 r.t. (min.): 1.72 1H NMR (400 MHz, Methanol-d4) δ ppm 8.43 (s, 1H), 8.39 (d, J = 5.4 Hz, 1H), 7.58 – 7.32 (m, 4H), 6.92 (d, J = 5.4 Hz, 1H), 4.91 (s, 2H), 4.02 – 3.94 (m, 4H), 3.33 – 3.24 (m, 4H). EXAMPLE 76 5-(2-Aminopyridin-4-yl)-N-((3-cyclopropyl-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)-5-cyclopropylpyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 61. Purity based on LC-MS 94%. LRMS (m/z): 470 [M+1]+ LCMS 1 r.t. (min.): 1.04 EXAMPLE 77 5-(2-Aminopyridin-4-yl)-N-(3-(piperazin-1-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) Tert-butyl 4-(3-(((5-(2-aminopyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)phenyl)piperazine-1-carboxylate A mixture of tert-butyl 4-(3-(((5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)phenyl)piperazine-1-carboxylate (227 mg, 0.33 mmol), (2-aminopyridin-4- yl)boronic acid (59 mg, 0.43 mmol), Pd(dppf)Cl2 (11 mg, 0.013 mmol) and sodium carbonate (70 mg, 0.66 mmol) in a mixture of 1,2-dimethoxyethane (9 mL) and water (3 mL) was stirred at 100 ºC under nitrogen atmosphere until the starting material was consumed (5 hours). The mixture was then allowed to reach room temperature and it was partitioned between water and ethyl acetate. The aqueous layer was extracted with more EtOAc (x2) and the combined organic solutions were dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography eluting with 100% hexanes to 100% ethyl acetate to give the title compound (44 mg, 20% yield) as a white solid. LRMS (m/z): 655 [M+1]+ LCMS 3 r.t. (min.): 1.74 b) 5-(2-Aminopyridin-4-yl)-N-(3-(piperazin-1-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl 4-(3-(((5-(2-aminopyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)phenyl)piperazine-1-carboxylate (44 mg, 0.067 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1.5 hours and the volatiles were removed under reduced pressure. Then, a 7 M solution of ammonia in methanol (4 mL) was added. The resulting solution was stirred at room temperature for 4 hours and the solvents were removed. The crude product was purified by preparative HPLC to give the title compound (7 mg, 26% yield) as a white solid. Purity based on LC-MS 94%. LRMS (m/z): 401 [M+1]+ LCMS 1 r.t. (min.): 0.63 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (s, 2H), 8.20 (s, 1H), 7.88 (d, J = 5.2 Hz, 1H), 7.32 (s, 1H), 7.21 – 7.06 (m, 1H), 6.88 (s, 1H), 6.77 (dd, J = 13.9, 7.7 Hz, 1H), 6.57 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (s, 2H), 5.93 (d, J = 10.0 Hz, 3H), 4.64 (d, J = 5.4 Hz, 2H), 3.11 – 2.93 (m, 4H), 2.93 – 2.80 (m, 4H). EXAMPLE 78 5-(3,5-Difluoro-2-methoxyphenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) Tert-butyl (2R,6S)-4-(6-(((5-(3,5-difluoro-2-methoxyphenyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)- 2,6-dimethylpiperazine-1-carboxylate To a mixture of tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (120 mg, 0.19 mmol), (3,5-difluoro-2-methoxy-phenyl)boronic acid (52 mg, 0.28 mmol), Pd(dppf)Cl2 (13 mg, 0.017 mmol) in dioxane (2 mL), a solution of cesium carbonate (181 mg, 0.56 mmol) in water (0.5 mL) was added. The mixture was stirred at 100 ºC under nitrogen atmosphere until the starting material was consumed (3 hours). The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate, filtered through Celite® and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% hexane to 100% ethyl ether to give the title compound (73 mg, 55% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 710 [M+1]+ LCMS 3 r.t. (min.): 2.36 b) 5-(3,5-Difluoro-2-methoxyphenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl (2R,6S)-4-(6-(((5-(3,5-difluoro-2-methoxyphenyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate (73 mg, 0.10 mmol) in dichloromethane (0.9 mL) was added trifluoroacetic acid (0.9 mL). The mixture was stirred at room temperature for 1 hour and the volatiles were removed under reduced pressure. Cyclohexane was added and evaporated three times to remove completely all traces of trifluoroacetic acid and then a 7 M solution of ammonia in methanol (1 mL) was added. The resulting solution was stirred at room temperature for 1 hour and the solvents were removed. The residue was redissolved in ethyl acetate and the resulting solution was washed with a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate, filtered and the solvent was removed to give the title compound (39 mg, 79% yield) as a white solid. Purity based on LC-MS 94%. LRMS (m/z): 480 [M+1]+ LCMS 1 r.t. (min.): 1.92 1H NMR (400 MHz, Chloroform-d) δ ppm 12.01 (s, 1H), 8.46 (s, 1H), 7.50 – 7.41 (m, 1H), 7.25 (s, 1H), 6.98 – 6.81 (m, 2H), 6.65 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 6.02 (t, J = 5.2 Hz, 1H), 4.78 (d, J = 5.3 Hz, 2H), 4.13 – 4.03 (m, 2H), 3.71 (d, J = 0.9 Hz, 3H), 2.96 (ddd, J = 9.7, 6.4, 3.0 Hz, 2H), 2.46 – 2.34 (m, 2H), 1.17 (d, J = 6.3 Hz, 6H). EXAMPLE 79 5-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,4,5-trimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 100%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.65 1H NMR (400 MHz, Methanol-d4) δ ppm 1.33 (d, J = 6.4 Hz, 6H), 2.74 – 2.80 (m, 2H), 2.82 (s, 3H), 3.12 – 3.22 (m, 2H), 4.14 – 4.21 (m, 2H), 6.79 (t, J = 7.8 Hz, 3H), 6.84 (dd, J = 5.7, 1.4 Hz, 1H), 7.41 (s, 1H), 7.59 (dd, J = 8.4, 7.4 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 8.24 (s, 1H), 8.39 (s, 2H). EXAMPLE 80 5-(2-Aminopyridin-4-yl)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2- aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. . Purity based on LC-MS 100%. LRMS (m/z): 434 [M+1]+ LCMS 1 r.t. (min.): 0.58 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (d, J = 8.8 Hz, 2H), 2.80 – 2.95 (m, 3H), 3.76 – 3.82 (m, 1H), 3.87 – 3.94 (m, 1H), 4.23 – 4.32 (m, 2H), 4.36 – 4.44 (m, 2H), 4.66 (d, J = 5.1 Hz, 2H), 5.94 (s, 1H), 6.28 (t, J = 5.1 Hz, 1H), 6.55 (s, 1H), 6.59 – 6.67 (m, 3H), 7.34 (s, 1H), 7.47 (dd, J = 8.4, 7.3 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 11.96 (s, 1H). EXAMPLE 81 N-((6-(3-(Fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and pyridin-3- ylboronic acid following the experimental procedure described in Example 78.. Purity based on LC-MS 100%. LRMS (m/z): 419 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 – 2.43 (m, 1H), 2.54 – 2.60 (m, 2H), 2.78 – 2.93 (m, 2H), 3.68 – 3.77 (m, 1H), 3.87 – 3.95 (m, 1H), 4.23 – 4.33 (m, 1H), 4.34 – 4.45 (m, 1H), 4.62 (d, J = 5.2 Hz, 2H), 6.15 (t, J = 5.2 Hz, 1H), 6.63 (dd, J = 10.5, 7.9 Hz, 2H), 7.40 (d, J = 2.3 Hz, 1H), 7.41 – 7.49 (m, 2H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H), 8.21 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 12.02 (s, 1H). EXAMPLE 82 N-((6-(3-(Fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole following the experimental procedure described in Example 78. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 100%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 1.06 1H NMR (400 MHz, Methanol-d4) δ ppm 8.52 (s, 1H), 8.15 (s, 1H), 7.61 – 7.51 (m, 1H), 7.48 (s, 1H), 7.00 (s, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 7.3 Hz, 2H), 4.60 (d, J = 15.0 Hz, 4H), 4.27 (d, J = 11.5 Hz, 2H), 3.78 (s, 3H), 2.64 – 2.54 (m, 2H), 2.15 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). EXAMPLE 83 5-(3-Fluoropyridin-4-yl)-N-((6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (1-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)azetidin- 3-yl)(methyl)carbamate and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 78. Purity based on LC-MS 100%. LRMS (m/z): 405 [M+1]+ LCMS 1 r.t. (min.): 0.99 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 3H), 3.41 (dd, J = 7.9, 5.5 Hz, 2H), 3.46 – 3.53 (m, 1H), 3.80 – 3.88 (m, 2H), 4.58 (d, J = 5.0 Hz, 2H), 6.18 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 6.57 (d, J = 7.1 Hz, 1H), 7.39 – 7.45 (m, 1H), 7.47 – 7.54 (m, 2H), 8.17 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H). EXAMPLE 84 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-isopropyl-1H-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole following the experimental procedure described in Example 78. The purification of the title compound was done by preparative LC-MS under neutral conditions. Purity based on LC-MS 99%. LRMS (m/z): 449 [M+1]+ LCMS 1 r.t. (min.): 1.42 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.85 (s, 1H), 7.58 (s, 1H), 7.45 (dd, J = 8.4, 7.3 Hz, 1H), 7.13 (s, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.13 – 6.06 (m, 1H), 4.59 (d, J = 5.3 Hz, 2H), 4.46 (dt, J = 13.3, 6.7 Hz, 2H), 3.97 (dd, J = 12.4, 2.3 Hz, 2H), 2.70 (ddd, J = 9.9, 6.5, 3.2 Hz, 2H), 2.20 – 2.07 (m, 3H), 1.37 (d, J = 6.7 Hz, 6H), 0.98 (d, J = 6.3 Hz, 6H). EXAMPLE 85 5-(3-Chloropyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and (3-chloropyridin-4-yl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 98%. LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.42 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J = 6.5 Hz, 6H), 2.58 – 2.67 (m, 2H), 3.21 – 3.28 (m, 2H), 4.30 (d, J = 11.4 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 6.19 (t, J = 5.6 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.50 – 7.56 (m, 1H), 8.17 (s, 1H), 8.51 (d, J = 4.9 Hz, 1H), 8.70 (s, 1H), 12.16 (s, 1H). EXAMPLE 86 N-((6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3,4-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)- 5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (3,4- difluorophenyl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 79%. LRMS (m/z): 448 [M+1]+ LCMS 1 r.t. (min.): 1.91 1H NMR (400 MHz, DMSO-d6) δ ppm 0.30 – 0.42 (m, 4H), 1.23 (s, 2H), 2.66 – 2.75 (m, 2H), 3.17 – 3.23 (m, 2H), 4.61 (d, J = 5.1 Hz, 2H), 6.15 (s, 1H), 6.53 – 6.60 (m, 2H), 7.33 (s, 1H), 7.38 – 7.44 (m, 2H), 7.46 – 7.52 (m, 2H), 8.18 (s, 1H). EXAMPLE 87 N-((6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)- 5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 78. Purity based on LC-MS 83%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 1.32 1H NMR (400 MHz, DMSO-d6) δ ppm 0.33 – 0.41 (m, 4H), 2.70 – 2.76 (m, 2H), 3.13 (s, 2H), 3.20 – 3.25 (m, 2H), 4.59 (d, J = 5.4 Hz, 2H), 6.29 (t, J = 5.3 Hz, 1H), 6.53 – 6.59 (m, 2H), 7.39 – 7.44 (m, 1H), 7.48 – 7.52 (m, 2H), 8.18 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H). EXAMPLE 88 5-(3,4-Difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(6-(1-((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine- 1-carboxylate and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 78. Purity based on LC-MS 89%. LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.94 1H NMR (400 MHz, Chloroform-d) δ ppm 8.40 – 8.32 (m, 1H), 7.42 (t, J = 6.9 Hz, 1H), 7.32 (s, 1H), 7.25 – 7.18 (m, 2H), 7.02 (d, J = 12.3 Hz, 1H), 6.63 – 6.57 (m, 1H), 6.56 – 6.47 (m, 1H), 5.68 (ddd, J = 17.9, 13.9, 10.7 Hz, 1H), 5.57 – 5.46 (m, 1H), 3.29 (d, J = 14.8 Hz, 3H), 3.12 – 2.97 (m, 2H), 2.57 (d, J = 16.3 Hz, 3H), 1.56 – 1.49 (m, 3H), 0.91 – 0.75 (m, 2H). 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. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Daicel Chiralpak ID (20mmx250mm, 5µm); Eluent A: heptane, Eluent B: 0.2% DEA in IPA; Flux: 20 mL/min; Run time: 30 min. First eluting peak (Example 89): Obtained as a white solid (3 mg). Purity by LC-MS 100%. LRMS (m/z): 435 [M+1]+ LCMS 1 r.t. (min.): 1.93 Second eluting peak (Ecample 90): Obtained as a white solid (2 mg). Purity by LC-MS 100%. LRMS (m/z): 435 [M+1]+ LCMS 1 r.t. (min.): 1.93 EXAMPLE 91 3-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 95%. LRMS (m/z): 429 [M+1]+ LCMS 1 r.t. (min.): 0.49 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J = 6.3 Hz, 6H), 2.11 – 2.22 (m, 2H), 2.71 (s, 2H), 4.00 (d, J = 12.5 Hz, 2H), 4.33 (d, J = 5.3 Hz, 2H), 5.60 – 5.68 (m, 1H), 5.86 (s, 2H), 6.24 (d, J = 6.8 Hz, 1H), 6.55 (s, 1H), 6.64 (dd, J = 17.7, 8.1 Hz, 3H), 7.27 (s, 1H), 7.40 – 7.52 (m, 1H), 7.90 (s, 2H), 11.57 (s, 1H). EXAMPLE 92 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the experimental procedure described in Example 78. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 417 [M+1]+ LCMS 1 r.t. (min.): 0.91 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J = 6.3 Hz, 6H), 2.09 – 2.20 (m, 2H), 2.64 – 2.78 (m, 1H), 3.82 (s, 3H), 3.97 (d, J = 11.3 Hz, 2H), 4.30 (d, J = 5.2 Hz, 2H), 5.73 (t, J = 5.4 Hz, 1H), 6.17 (d, J = 5.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H), 7.05 (s, 1H), 7.42 – 7.49 (m, 1H), 7.51 (s, 1H), 7.72 (s, 1H), 7.84 (d, J = 5.3 Hz, 1H), 11.31 (s, 1H). EXAMPLE 93 3-(2-Aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine and (2- aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 83%. LRMS (m/z): 469 [M+1]+ LCMS 1 r.t. (min.): 0.88 1H NMR (400 MHz, Methanol-d4) δ ppm 8.43 (s, 1H), 8.39 (d, J = 5.4 Hz, 1H), 7.58 – 7.32 (m, 4H), 6.92 (d, J = 5.4 Hz, 1H), 4.91 (s, 2H), 4.02 – 3.94 (m, 4H), 3.33 – 3.24 (m, 4H). EXAMPLE 94 N-((6-((1S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3-(2-aminopyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from N-((6-((1S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2- yl)methyl)-3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine and (2- aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 87%. LRMS (m/z): 427 [M+1]+ LCMS 1 r.t. (min.): 0.51 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (d, J = 6.2 Hz, 6H), 2.03 – 2.14 (m, 2H), 2.59 – 2.70 (m, 2H), 3.91 – 3.98 (m, 2H), 4.62 (d, J = 5.2 Hz, 2H), 6.10 (t, J = 5.3 Hz, 1H), 6.58 – 6.66 (m, 2H), 7.13 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 4.6 Hz, 1H), 7.38 – 7.49 (m, 2H), 7.87 – 7.93 (m, 1H), 8.03 (dd, J = 4.6, 1.3 Hz, 1H), 8.19 – 8.25 (m, 1H), 8.50 (dd, J = 4.8, 1.5 Hz, 1H), 8.76 (d, J = 1.7 Hz, 1H), 8.89 (d, J = 2.5 Hz, 1H), 9.04 (s, 1H), 11.56 (s, 1H). EXAMPLE 95 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-carboxylate following the experimental procedure described in Example 78. Purity based on LC-MS 97%. LRMS (m/z): 403 [M+1]+ LCMS 1 r.t. (min.): 0.89 1H NMR (400 MHz, ethanol-d4) δ ppm 7.98 (d, J = 7.1 Hz, 1H), 7.79 (s, 2H), 7.61 (dd, J = 8.5, 7.4 Hz, 1H), 7.25 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.69 (d, J = 7.1 Hz, 1H), 4.60 (s, 2H), 4.26 (dd, J = 14.1, 2.5 Hz, 2H), 3.31 (dt, J = 3.3, 1.6 Hz, 6H), 2.69 (dd, J = 14.1, 11.5 Hz, 2H), 1.33 (s, 3H), 1.32 (s, 3H). EXAMPLE 96 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(imidazo[1,2-a]pyridin-7- yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)imidazo[1,2-a]pyridine following the experimental procedure described in Example 78. Purity based on LC-MS 96%. LRMS (m/z): 453 [M+1]+ LCMS 1 r.t. (min.): 0.59 1H NMR (400 MHz, Methanol-d4) δ ppm 8.75 (d, J = 6.6 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.02 (d, J = 7.0 Hz, 1H), 7.94 – 7.88 (m, 2H), 7.65 (s, 1H), 7.59 (dd, J = 8.4, 7.5 Hz, 1H), 7.52 (dd, J = 7.0, 1.6 Hz, 1H), 6.85 – 6.68 (m, 3H), 4.65 (s, 2H), 4.25 (dd, J = 14.0, 2.4 Hz, 2H), 3.17 (ddd, J = 10.0, 6.6, 3.3 Hz, 2H), 2.60 (dd, J = 14.1, 11.5 Hz, 2H), 1.26 (s, 3H), 1.25 (s, 3H). EXAMPLE 97 5-(3,4-Difluorophenyl)-N-(1-(2-(piperazin-1-yl)pyrimidin-4-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(4-(1-((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyrimidin-2- yl)piperazine-1-carboxylate and (3,4-difluorophenyl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 95%. LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 1.93 1H NMR (400 MHz, Chloroform-d) δ ppm 8.34 (q, J = 3.5, 2.8 Hz, 1H), 8.23 (dt, J = 5.0, 2.6 Hz, 1H), 7.42 – 7.32 (m, 1H), 7.10 – 7.02 (m, 1H), 6.54 – 6.42 (m, 1H), 5.79 – 5.70 (m, 1H), 5.66 (dd, J = 10.9, 2.3 Hz, 1H), 5.50 – 5.39 (m, 1H), 3.63 (d, J = 40.2 Hz, 4H), 2.98 (d, J = 33.5 Hz, 2H), 2.50 (d, J = 13.2 Hz, 3H), 1.52 (d, J = 6.6 Hz, 3H), 0.92 – 0.75 (m, 2H). EXAMPLE 98 3-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-amine and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 100%. LRMS (m/z): 497 [M+1]+ LCMS 1 r.t. (min.): 0.60 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J = 6.4 Hz, 6H), 2.59 (t, J = 12.2 Hz, 2H), 4.29 (d, J = 13.8 Hz, 2H), 4.45 – 4.49 (m, 2H), 5.71 (t, J = 5.8 Hz, 1H), 5.89 (s, 2H), 6.19 – 6.26 (m, 1H), 6.53 (s, 1H), 6.61 (d, J = 6.9 Hz, 1H), 6.97 (s, 1H), 7.09 (s, 1H), 7.30 (s, 1H), 7.87 (dd, J = 12.6, 5.3 Hz, 2H), 8.12 (s, 1H), 11.62 (s, 1H). EXAMPLE 99 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the experimental procedure described in Example 78. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 98%. LRMS (m/z): 485 [M+1]+ LCMS 1 r.t. (min.): 1.07 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 – 1.01 (m, 6H), 2.18 – 2.29 (m, 2H), 2.66 – 2.76 (m, 2H), 3.83 (s, 3H), 4.09 (d, J = 15.4 Hz, 2H), 4.42 (d, J = 5.9 Hz, 2H), 5.75 (t, J = 6.1 Hz, 1H), 6.16 (d, J = 5.4 Hz, 1H), 6.83 (s, 1H), 6.96 (s, 1H), 7.06 (s, 1H), 7.51 (s, 1H), 7.74 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 8.28 (s, 2H), 11.34 (s, 1H). EXAMPLE 100 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3- (pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-amine and pyridin-3-ylboronic acid following the experimental procedure described in Example 78. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 99%. LRMS (m/z): 482 [M+1]+ LCMS 1 r.t. (min.): 1.08 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J = 6.3 Hz, 6H), 2.14 – 2.30 (m, 2H), 2.68 – 2.78 (m, 2H), 4.09 (d, J = 13.0 Hz, 2H), 4.40 (d, J = 5.4 Hz, 2H), 5.48 (t, J = 5.8 Hz, 1H), 6.25 (d, J = 5.5 Hz, 1H), 6.86 (s, 1H), 6.96 (s, 1H), 7.34 (s, 1H), 7.36 – 7.41 (m, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 8.19 (s, 1H), 8.49 (d, J = 6.3 Hz, 1H), 8.73 – 8.77 (m, 1H), 11.67 (s, 1H). EXAMPLE 101 2-((6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)oxy)ethan-1-ol The title compound was prepared from 2-((6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)oxy)ethan-1-ol and (2-aminopyridin-4- yl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 96%. LRMS (m/z): 378 [M+1]+ LCMS 1 r.t. (min.): 0.91 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 – 3.67 (m, 2H), 3.95 – 4.02 (m, 2H), 4.73 (d, J = 5.2 Hz, 2H), 5.96 (s, 2H), 6.34 (t, J = 5.2 Hz, 1H), 6.56 (s, 1H), 6.62 – 6.66 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 7.34 (s, 1H), 7.63 (dd, J = 8.1, 7.4 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 11.97 (s, 1H). EXAMPLE 102 N1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)-N1,N2-dimethylethane-1,2-diamine The title compound was prepared from tert-butyl (2-((6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)(methyl)amino)ethyl)(methyl)carbamate and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 78. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC- MS 98%. LRMS (m/z): 404 [M+1]+ LCMS 1 r.t. (min.): 0.64 1H NMR (400 MHz, Chloroform-d) δ ppm 2.28 (s, 3H), 2.62 (t, J = 6.3 Hz, 2H), 2.82 (s, 3H), 3.35 – 3.48 (m, 2H), 4.64 (d, J = 4.8 Hz, 2H), 5.94 (s, 2H), 6.26 – 6.33 (m, 1H), 6.46 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.55 (s, 1H), 6.62 (d, J = 5.1 Hz, 1H), 7.33 (s, 1H), 7.38 – 7.46 (m, 1H), 7.90 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.32 (s, 1H). EXAMPLE 103 2-(Ethyl(6-(((5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin- 2-yl)amino)ethan-1-ol The title compound was prepared from 2-((6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)(ethyl)amino)ethan-1-ol and 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 78. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 99%. LRMS (m/z): 408 [M+1]+ LCMS 1 r.t. (min.): 1.24 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, J = 7.0 Hz, 3H), 3.26 – 3.32 (m, 4H), 3.43 (t, J = 6.1 Hz, 3H), 4.57 (d, J = 5.2 Hz, 2H), 6.20 (s, 1H), 6.42 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 7.2 Hz, 1H), 7.38 (dd, J = 8.4, 7.3 Hz, 1H), 7.45 – 7.51 (m, 2H), 8.16 (s, 1H), 8.38 (d, J = 4.9 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H). EXAMPLE 104 5-(3,4-Difluorophenyl)-2-methyl-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-iodo-2-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate and (3,4-difluorophenyl)boronic acid following the experimental procedure described in Example 78. Purity based on LC-MS 98%. LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.63 1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 2.97 – 3.05 (m, 2H), 3.21 – 3.27 (m, 2H), 3.31 – 3.34 (m, 2H), 3.39 – 3.49 (m, 2H), 4.65 (d, J = 4.9 Hz, 2H), 6.07 – 6.19 (m, 1H), 6.65 – 6.70 (m, 1H), 6.70 – 6.76 (m, 1H), 7.24 (dd, J = 4.1, 2.5 Hz, 1H), 7.29 – 7.35 (m, 1H), 7.39 – 7.58 (m, 3H), 11.73 (s, 1H). EXAMPLE 105 1-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)azetidin-3-ol a) 1-(6-(((5-(2-Aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)azetidin-3-ol To a mixture of 1-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)azetidin-3-ol (40 mg, 0.079 mmol), (2-aminopyridin-4-yl)boronic acid (12 mg, 0.087 mmol), Pd(dppf)Cl2 (6.5 mg, 0.008 mmol) in 1,2-dimethoxyethane (0.45 mL), a solution of sodium carbonate (17 mg, 0.16 mmol) in water (0.15 mL) was added. The mixture was stirred at 100 ºC under nitrogen atmosphere until the starting material was consumed (2 hours). The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate, filtered through Celite® and the solvents were evaporated under reduced pressure. The crude product was purified by reverse phase chromatography to give the title compound (20 mg, 49% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 519 [M+1]+ LCMS 3 r.t. (min.): 1.20 b) 1-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)azetidin-3-ol To a solution of 1-(6-(((5-(2-aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)azetidin-3-ol (18 mg, 0.035 mmol) in dichloromethane (0.4 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at room temperature for 1.5 hours and the volatiles were removed under reduced pressure. Then, a 7 M solution of ammonia in methanol (0.4 mL) was added. The resulting solution was stirred at room temperature for 75 minutes and the solvents were removed. The residue was suspended in water and solid was filtered to give the title compound (7 mg, 52% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 389 [M+1]+ LCMS 1 r.t. (min.): 0.60 1H NMR (400 MHz, DMSO-d6) δ 3.53 (dd, J = 8.9, 4.7 Hz, 1H), 3.92 – 4.03 (m, 2H), 4.45 – 4.56 (m, 1H), 4.63 (d, J = 5.4 Hz, 2H), 5.55 (d, J = 5.4 Hz, 1H), 5.92 (s, 2H), 6.20 (d, J = 7.6 Hz, 1H), 6.30 (t, J = 5.2 Hz, 1H), 6.55 (s, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.64 (dd, J = 5.2, 1.5 Hz, 1H), 7.33 (s, 1H), 7.40 – 7.46 (m, 1H), 7.92 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 11.95 (s, 1H). EXAMPLE 106 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the experimental procedure described in Example 105. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 418 [M+1]+ LCMS 1 r.t. (min.): 0.94 1H NMR (400 MHz, methanol-d4) δ ppm 1.06 (d, J = 6.39 Hz, 6H), 2.20-2.25 (m, 2H), 2.76- 2.81 (m, 2H), 3.88 (s, 3H), 3.93-3.97 (dd, J = 12.68, 2.98 Hz, 2H), 4.64 (s, 2H), 6.63-6.68 (t, J = 7.83 Hz, 2H), 7.10 (s, 1H), 7.48-7.52 (t, J = 7.94 Hz, 1H), 7.61 (s, 1H), 7.70 (s, 1H), 8.15 (s, 1H). EXAMPLE 107 5-(2-Aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2- aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 105. Purity based on LC-MS 99%. LRMS (m/z): 470 [M+1]+ LCMS 1 r.t. (min.): 1.12 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 – 2.70 (m, 1H), 2.75 – 2.97 (m, 5H), 3.66 – 3.76 (m, 1H), 4.00 – 4.09 (m, 1H), 4.66 (d, J = 5.2 Hz, 2H), 5.92 (s, 2H), 6.27 (t, J = 5.3 Hz, 1H), 6.54 (s, 1H), 6.61 (dd, J = 5.2, 1.5 Hz, 1H), 6.65 (d, J = 7.3 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.4, 7.4 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 11.95 (s, 1H). EXAMPLE 108 5-(2-Aminopyridin-4-yl)-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-(4-methylpiperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2- aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 105. Purity based on LC-MS 99%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 0.57 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H), 2.27 – 2.33 (m, 4H), 3.20 – 3.26 (m, 4H), 4.68 (d, J = 5.0 Hz, 2H), 5.96 (s, 1H), 6.33 (t, J = 5.1 Hz, 1H), 6.55 (s, 1H), 6.59 – 6.65 (m, 2H), 7.33 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 8.4, 7.3 Hz, 1H), 7.92 (d, J = 5.1 Hz, 1H), 8.20 (s, 1H), 11.96 (s, 1H). EXAMPLE 109 1-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)pyrrolidin-3-ol The title compound was prepared from 1-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)pyrrolidin-3-ol and (2-aminopyridin-4- yl)boronic acid following the experimental procedure described in Example 105. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 74%. LRMS (m/z): 403 [M+1]+ LCMS 1 r.t. (min.): 0.64 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 – 2.00 (m, 4H), 3.06 (d, J = 10.8 Hz, 1H), 3.14 – 3.19 (m, 2H), 4.29 – 4.36 (m, 1H), 4.63 (d, J = 4.8 Hz, 2H), 5.95 (s, 2H), 6.23 (d, J = 8.4 Hz, 1H), 6.45 (t, J = 4.8 Hz, 1H), 6.50 (d, J = 7.1 Hz, 1H), 6.56 (s, 1H), 6.63 (dd, J = 5.2, 1.4 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.37 – 7.44 (m, 1H), 7.90 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 11.95 (s, 1H). 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. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 403 [M+1]+ LCMS 1 r.t. (min.): 0.52 EXAMPLE 111 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-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidine-1-carboxylate and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 105. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 401 [M+1]+ LCMS 1 r.t. (min.): 0.55 1H NMR (400 MHz, methanol-d4) δ ppm 1.57 (qd, J = 12.76, 3.91 Hz, 2H), 1.80 (brd, J = 13.08 Hz, 2H), 2.69-2.89 (m, 3H), 3.22 (br d, J = 12.47 Hz, 2H), 4.82 (s, 2H), 6.75 (s, 1H), 6.81 (dd, J = 5.50, 1.47 Hz, 1H), 7.15 (d, J = 7.70 Hz, 1H), 7.22 (d, J = 7.70 Hz, 1H), 7.31 (s, 1H), 7.69 (t, J = 7.70 Hz, 1H), 7.96 (d, J = 5.38 Hz, 1H), 8.24 (s, 1H). EXAMPLE 112 5-(1-Methyl-1H-pyrazol-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-(6-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidine-1-carboxylate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole following the experimental procedure described in Example 105. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC- MS 98%. LRMS (m/z): 389 [M+1]+ LCMS 1 r.t. (min.): 0.86 1H NMR (400 MHz, methanol-d4) δ ppm 1.63-1.78 (m, 2H), 1.87 (br d, J = 10.64 Hz, 2H), 2.79-2.91 (m, 3H), 3.23 (br d, J = 12.84 Hz, 2H), 3.94 (s, 3H), 4.81 (br s, 2H), 7.09 (s, 1H), 7.17 (d, J = 7.70 Hz, 1H), 7.22 (d, J = 7.46 Hz, 1H), 7.67-7.72 (m, 2H), 7.77 (s, 1H), 8.17 (s, 1H). EXAMPLE 113 5-(2-Aminopyridin-4-yl)-N-((4-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(2-(((5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-4- yl)piperidine-1-carboxylate and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 105. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 100%. LRMS (m/z): 401 [M+1]+ LCMS 1 r.t. (min.): 0.45 1H NMR (400 MHz, methanol-d4) δ ppm 1.97 - 2.10 (m, 2 H) 2.12 - 2.21 (m, 2 H) 3.18 (br d, J = 1.47 Hz, 3 H) 3.54 (br d, J = 12.10 Hz, 2 H) 5.18 (s, 2 H) 7.17 (dd, J = 6.72, 1.34 Hz, 1 H) 7.24 (s, 1 H) 7.80 (s, 1 H) 7.84 (br d, J = 5.75 Hz, 1 H) 7.93 (d, J = 6.60 Hz, 1 H) 8.07 (s, 1 H) 8.46 (s, 1 H) 8.67 (br d, J = 5.99 Hz, 1 H). EXAMPLE 114 5-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-5-iodo-2-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 105. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 100%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.72 1H NMR (400 MHz, methanol-d4) δ ppm 8.48 (s, 1H), 7.85 (s, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.29 (s, 1H), 6.78 (dd, J = 17.7, 9.7 Hz, 3H), 4.72 (s, 2H), 4.24 (d, J = 13.3 Hz, 2H), 2.71 – 2.54 (m, 2H), 2.53 (s, 3H), 1.29 (m, 6H). EXAMPLE 115 2-((6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)(methyl)amino)ethan-1-ol a) 2-((6-(((5-(2-Aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)(methyl)amino)ethan-1-ol To a mixture of 2-((6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)(methyl)amino)ethan-1-ol (200 mg, 0.39 mmol), (2-aminopyridin-4- yl)boronic acid (70 mg, 0.51 mmol), Pd(dppf)Cl2 (32 mg, 0.039 mmol) in dioxane (3 mL), a 2 M aqueous solution of sodium carbonate (0.6 mL, 1.2 mmol) was added. The mixture was stirred at 100 ºC under inert atmosphere for 18 hours. The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate and filtered through Celite®. The filtrates were dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting from 100% dichloromethane to 10% methanol in dichloromethane to give the title compound (88 mg, 43% yield) as a white solid. Purity based on LC-MS 89%. LRMS (m/z): 521 [M+1]+ LCMS 3 r.t. (min.): 1.22 b) 2-((6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)(methyl)amino)ethan-1-ol To a solution of 2-((6-(((5-(2-aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)(methyl)amino)ethan-1-ol (88 mg, 0.17 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 3 hours and the volatiles were removed under reduced pressure. Then, a 7 M solution of ammonia in methanol (1 mL) was added. The resulting solution was stirred at room temperature for 1 hour and the solvents were removed. The residue was suspended in water and solid was filtered to give the title compound (52 mg, 79% yield) as a white solid. Purity based on LC-MS 98%. LRMS (m/z): 391 [M+1]+ LCMS 1 r.t. (min.): 0.59 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.20 (s, 1H), 7.91 (d, J = 5.5 Hz, 1H), 7.48 – 7.32 (m, 2H), 6.71 (d, J = 4.5 Hz, 1H), 6.63 (s, 1H), 6.47 (dd, J = 17.9, 7.8 Hz, 2H), 6.38 (s, 2H), 4.63 (m, 3H), 3.41 (dd, J = 16.1, 5.0 Hz, 4H), 2.85 (s, 3H). EXAMPLE 116 4-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazin-2-one The title compound was prepared from 4-(6-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazin-2-one and (2-aminopyridin-4- yl)boronic acid following the experimental procedure described in Example 115. Purity based on LC-MS 97%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 0.86 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.93 (d, J = 5.5 Hz, 1H), 7.56 – 7.47 (m, 1H), 7.43 (bs, 1H), 6.72 (d, J = 5.1 Hz, 1H), 6.70 – 6.56 (m, 3H), 6.39 (m, 3H), 4.68 (d, J = 5.0 Hz, 2H), 3.87 (s, 2H), 3.56 – 3.46 (m, 2H), 3.21 (m, 2H). EXAMPLE 117 2-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-6-((3R,5S)-3,5- dimethylpiperazin-1-yl)-N,N-dimethylnicotinamide The title compound was prepared from 2-(((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N,N- dimethylnicotinamide and (2-aminopyridin-4-yl)boronic acid following the experimental procedure described in Example 115. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 95%. LRMS (m/z): 501 [M+1]+ LCMS 1 r.t. (min.): 0.49 1H NMR (400 MHz, Methanol-d4) δ ppm 8.90 (s, 1H), 8.26 (s, 1H), 7.84 (d, J = 6.7 Hz, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 6.8, 1.6 Hz, 1H), 7.06 (d, J = 1.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.39 (d, J = 13.8 Hz, 2H), 3.73 (dt, J = 13.2, 6.6 Hz, 2H), 3.27 – 3.17 (m, 4H), 3.00 (s, 3H), 2.87 (s, 3H), 2.80 – 2.69 (m, 3H), 1.27 (d, J = 6.5 Hz, 6H). EXAMPLE 118 3-(3,4-Difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin- 4-amine a) Tert-butyl 4-(6-(1-((3-(3,4-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(6-(1-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate (204 mg, 0.32 mmol), (3,4- difluorophenyl)boronic acid (67 mg, 0.42 mmol), Pd(dppf)Cl2 (24 mg, 0.033 mmol) and potassium phosphate (206 mg, 0.97 mmol) in a mixture of dioxane (5 mL) and water (1.5 mL) was heated at 80 ºC for 1 hour using microwave irradiation until all the starting material was consumed. The mixture was then partitioned between dichloromethane and water and the aqueous layer was further extracted with dichloromethane (x2). The combined organic layers were dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting from 100% hexanes to 100% diethylether to give the title compound (79 mg, 37% yield) as a white solid. Purity based on LC-MS 83%. LRMS (m/z): 665 [M+1]+ LCMS 3 r.t. (min.): 2.28 b) 3-(3,4-Difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3- b]pyridin-4-amine To a solution of tert-butyl 4-(6-(1-((3-(3,4-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)ethyl)pyridin-2-yl)piperazine-1-carboxylate (79 mg, 0.12 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature overnight and the volatiles were removed under reduced pressure. Then, a 7 M solution of ammonia in methanol (10 mL) was added. The resulting solution was stirred at room temperature for 4 hours and the solvents were removed. The residue was redissolved in ethyl acetate and the resulting solution was washed with a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate, filtered and the solvent was removed. The crude product was purified by reverse phase chromatography eluting with 100 % water to 100% methanol/acetonitrile (1:1) to give the title compound (24 mg, 46% yield) as a white solid. Purity based on LC-MS 90%. LRMS (m/z): 435 [M+1]+ LCMS 1 r.t. (min.): 1.60 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.86 (d, J = 5.5 Hz, 1H), 7.57 – 7.40 (m, 3H), 7.33 (s, 1H), 7.27 (s, 1H), 6.63 (dd, J = 14.1, 7.8 Hz, 2H), 6.27 (d, J = 5.7 Hz, 1H), 5.29 (d, J = 8.0 Hz, 1H), 4.71 (dt, J = 14.2, 6.4 Hz, 1H), 3.24 – 3.12 (m, 4H), 2.71 (t, J = 4.9 Hz, 4H), 1.36 (d, J = 6.5 Hz, 3H). EXAMPLE 119 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridazin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine A mixture of (4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (56 mg, 0.10 mmol), 4-bromopyridazine (18 mg, 0.11 mmol), Pd(dppf)Cl2 (8 mg, 0.011 mmol) and cesium carbonate (102 mg, 0.31 mmol) in dioxane (1.6 mL), and water (0.4 mL) was stirred under inert atmosphere at 120 ºC for 30 minutes. Then, additional 0.5 mL of water were added and the mixture was heated again at 120 ºC for 2 hours until no tosyl-protected products were detected. The mixture was partitioned between brine and ethyl acetate and the aqueous solution was extracted twice with more ethyl acetate. The combined organic solutions were dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting from DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (21 mg, 45% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 0.96 1H NMR (400 MHz, Chloroform-d) δ 1.12 (d, J = 6.4 Hz, 6H), 2.29 (t, J = 11.7 Hz, 2H), 2.77 – 2.98 (m, 2H), 3.73 – 3.88 (m, 2H), 4.74 (d, J = 4.0 Hz, 2H), 6.53 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 7.2 Hz, 1H), 7.33 (s, 1H), 7.43 – 7.50 (m, 1H), 7.59 (dd, J = 5.4, 2.4 Hz, 1H), 8.44 (s, 1H), 9.07 – 9.15 (m, 1H), 9.34 – 9.46 (m, 1H). EXAMPLE 120 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from (4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid and 4-bromo-2- methylpyridine following the experimental procedure described in Example 119. Purity based on LC-MS 100%. LRMS (m/z): 429 [M+1]+ LCMS 1 r.t. (min.): 0.68 1H NMR (400 MHz, Methanol-d4) δ ppm 1.01 (d, J = 6.4 Hz, 6H), 2.04 – 2.29 (m, 2H), 2.39 (s, 3H), 2.68 – 2.81 (m, 2H), 3.79 – 3.89 (m, 2H), 4.67 (s, 2H), 6.66 (d, J = 1.6 Hz, 1H), 6.68 (s, 1H), 7.42 (d, J = 5.5 Hz, 3H), 7.47 – 7.56 (m, 1H), 8.24 (s, 1H), 8.37 (d, J = 5.7 Hz, 1H). EXAMPLE 121 4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)picolinamide The title compound was prepared from (4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid and 4-bromopicolinamide following the experimental procedure described in Example 119. The crude product was purified first by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1) and, in a second step, by preparative LC-MS under buffered conditions. Purity based on LC- MS 100%. LRMS (m/z): 458 [M+1]+ LCMS 1 r.t. (min.): 1.07 EXAMPLE 122 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine a) Tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(pyrazin-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate A mixture of tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate (85 mg, 0.12 mmol), 2-chloropyrazine (21 mg, 0.18 mmol), Pd(dppf)Cl2 (9 mg, 0.012 mmol) and cesium carbonate (120 mg, 0.37 mmol) in dioxane (1.6 mL), and water (0.4 mL) was stirred under inert atmosphere at 120 ºC for 1 hour. The mixture was partitioned between brine and ethyl acetate and the aqueous solution was extracted twice with more ethyl acetate. The combined organic solutions were dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting from 100% DCM to 5% DCM/MeOH to give the title compound (28 mg, 35% yield) as a pale solid. Purity based on LC-MS 98%. LRMS (m/z): 646 [M+1]+ LCMS 2 r.t. (min.): 3.23 b) N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(pyrazin-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate (28 mg, 0.043 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 30 minutes until no starting material was detected. Then, the volatiles were removed under reduced pressure and a 7 M solution of ammonia in methanol (3 mL) was added. The resulting solution was stirred at room temperature for 1 hour and the solvents were removed. The crude product was purified by flash chromatography eluting from DCM to DCM/MeOH/7N NH3 (90:8.5:1.5) to give the title compound (14 mg, 76% yield) as a pale solid. Purity based on LC-MS 95%. LRMS (m/z): 416 [M+1]+ LCMS 1 r.t. (min.): 1.09 1H NMR (400 MHz, Chloroform-d) δ 1.09 (d, J = 6.4 Hz, 6H), 2.32 – 2.42 (m, 2H), 2.83 – 2.98 (m, 2H), 4.11 – 4.22 (m, 2H), 4.78 (d, J = 5.1 Hz, 2H), 6.54 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H), 7.40 – 7.49 (m, 1H), 7.67 (s, 1H), 8.22 – 8.37 (m, 3H), 9.00 (d, J = 1.4 Hz, 1H), 10.56 (t, J = 5.0 Hz, 1H). EXAMPLE 123 5-(6-Aminopyrazin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate and 6-chloropyrazin-2-amine following the experimental procedure described in Example 122. Purity based on LC-MS 99%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.88 1H NMR (400 MHz, Chloroform-d) δ ppm 1.06 (d, J = 6.4 Hz, 6H), 2.27 – 2.43 (m, 2H), 2.82 – 3.05 (m, 2H), 4.05 – 4.15 (m, 2H), 4.77 (d, J = 5.0 Hz, 2H), 6.53 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 7.42 – 7.51 (m, 1H), 7.55 (s, 1H), 7.63 (s, 1H), 8.19 – 8.32 (m, 2H), 10.58 (t, J = 4.8 Hz, 1H). EXAMPLE 124 5-(4-Aminopyrimidin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate and 2-chloropyrazin-4-amine following the experimental procedure described in Example 122. Purity based on LC-MS 99%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.86 1H NMR (400 MHz, Chloroform-d) δ ppm 1.07 (d, J = 6.4 Hz, 6H), 2.26 – 2.40 (m, 2H), 2.80 – 3.04 (m, 2H), 4.07 – 4.20 (m, 2H), 4.75 – 4.84 (m, 2H), 6.15 (d, J = 5.9 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 7.40 – 7.56 (m, 1H), 7.91 (s, 1H), 8.02 (d, J = 5.8 Hz, 1H), 8.20 (s, 1H), 11.26 (t, J = 4.2 Hz, 1H). EXAMPLE 125 5-(6-Aminopyrimidin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate and 6-bromopyrimidin-4- amine following the experimental procedure described in Example 122. Purity based on LC-MS 98%. LRMS (m/z): 431 [M+1]+ LCMS 1 r.t. (min.): 0.95 1H NMR (400 MHz, Methanol-d4) δ ppm 1.26 (d, J = 6.6 Hz, 6H), 2.70 (dd, J = 14.2, 11.4 Hz, 2H), 3.15 – 3.43 (m, 2H), 4.47 (dd, J = 14.0, 2.6 Hz, 2H), 4.81 (s, 2H), 6.88 (s, 1H), 6.91 (d, J = 2.6 Hz, 1H), 6.97 (d, J = 1.1 Hz, 1H), 7.66 (dd, J = 8.4, 7.4 Hz, 1H), 8.06 (s, 1H), 8.16 (d, J = 1.1 Hz, 1H), 8.20 (s, 1H). EXAMPLE 126 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(6-(methylamino)pyrazin- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate and 6-chloro-N- methylpyrazin-2-amine following the experimental procedure described in Example 122. Purity based on LC-MS 100%. LRMS (m/z): 445 [M+1]+ LCMS 1 r.t. (min.): 1.07 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J = 6.3 Hz, 6H), 2.06 – 2.17 (m, 2H), 2.67 (d, J = 1.8 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 4.06 (dd, J = 12.2, 2.5 Hz, 2H), 4.72 (d, J = 6.2 Hz, 2H), 6.54 (d, J = 7.2 Hz, 1H), 6.61 (s, 1H), 7.12 (d, J = 4.2 Hz, 1H), 7.35 – 7.44 (m, 1H), 7.73 (s, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 10.39 (t, J = 6.6 Hz, 1H), 12.06 (s, 1H). EXAMPLE 127 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) Tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,6S)-4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate (350 mg, 0.54 mmol) in methanol (15 mL), 10% palladium on charcoal (29 mg, 0.03 mmol) was added. The mixture was stirred under hydrogen atmosphere at a pressure of 1 atm. until all the starting material was consumed (2 hours). The catalyst was filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography eluting from 100% hexane to 100% ethyl acetate to give the title compound (281 mg, 80% yield) as a pale solid. Purity based on LC-MS 98%. LRMS (m/z): 652 [M+1]+ LCMS 3 r.t. (min.): 2.22 b) N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl (2R,6S)-2,6-dimethyl-4-(6-(((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazine-1-carboxylate (281 mg, 0.43 mmol) in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature until no starting material was detected (3 hours). Then, the volatiles were removed under reduced pressure and a 7 M solution of ammonia in methanol (4 mL) was added. The resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between water and methylene chloride. The aqueous layer was extracted with more methylene chloride (x2) and the combined organic layers were dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure to give the title compound (178 mg, 98% yield) as a pale solid. Purity based on LC-MS 99%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.07 1H NMR (400 MHz, Methanol-d4) δ ppm 8.04 (s, 1H), 7.60 – 7.52 (m, 2H), 6.97 (s, 1H), 6.76 (t, J = 7.4 Hz, 2H), 4.40 (d, J = 11.7 Hz, 3H), 3.99 (d, J = 8.1 Hz, 3H), 3.64 (t, J = 10.9 Hz, 3H), 2.67 (dd, J = 14.2, 11.4 Hz, 3H), 2.00 (d, J = 13.2 Hz, 3H), 1.82 – 1.65 (m, 3H), 1.25 (s, 3H), 1.23 (s, 3H). EXAMPLE 128 5-(3,6-Dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.087 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (22 mg, 0.10 mmol) ), Pd(dppf)Cl2 (6 mg, 0.008 mmol) and cesium carbonate (85 mg, 0.26 mmol) in dioxane (1.6 mL) and water (0.4 mL) was stirred at 110 ºC under nitrogen atmosphere overnight. The resulting mixture was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by HPLC to give the title compound (12 mg, 33% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 1.09 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 8.12 (s, 1H), 7.46 (dd, J = 8.4, 7.4 Hz, 1H), 7.23 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.39 (t, J = 5.4 Hz, 1H), 5.82 (s, 1H), 4.64 (d, J = 5.3 Hz, 2H), 4.19 – 4.07 (m, 2H), 3.82 (m, 8H), 2.77 (ddd, J = 9.6, 6.3, 3.0 Hz, 2H), 2.29 – 2.19 (m, 2H), 1.01 (d, J = 6.3 Hz, 6H) EXAMPLE 129 N-(1-(6-(Piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(6-(1-((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine- 1-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 86%. LRMS (m/z): 408 [M+1]+ LCMS 1 r.t. (min.): 1.20 1H NMR (400 MHz, Methanol-d4) δ ppm 8.10 (s, 1H), 7.57 – 7.49 (m, 1H), 6.90 (d, J = 0.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 2H), 5.37 (q, J = 6.6 Hz, 1H), 4.12 – 4.01 (m, 1H), 3.97 – 3.88 (m, 1H), 3.69 – 3.48 (m, 8H), 3.35 (s, 1H), 3.10 (tt, J = 11.5, 3.2 Hz, 1H), 2.95 (t, J = 5.1 Hz, 4H), 2.06 (dt, J = 13.4, 2.7 Hz, 1H), 1.93 – 1.85 (m, 1H), 1.79 (qd, J = 11.9, 4.3 Hz, 1H), 1.72 – 1.59 (m, 2H), 1.56 (d, J = 6.6 Hz, 3H). EXAMPLE 130 N-((6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl 7-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 88%. LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 0.98 1H NMR (400 MHz, DMSO-d6) δ ppm 0.37 – 0.46 (m, 4H), 1.07 (s, 2H), 1.54 – 1.66 (m, 2H), 1.90 (d, J = 10.6 Hz, 2H), 2.79 – 2.84 (m, 2H), 3.40 – 3.47 (m, 2H), 3.54 (t, J = 10.9 Hz, 3H), 3.86 – 3.92 (m, 2H), 4.64 (d, J = 5.7 Hz, 2H), 6.49 (d, J = 7.2 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 6.68 (t, J = 5.8 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.36 – 7.44 (m, 1H), 8.01 (s, 1H), 11.36 (s, 1H). EXAMPLE 131 (S)-N-(1-(6-(Piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine The title compound was prepared from tert-butyl (S)-4-(6-(1-((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)piperazine- 1-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 95%. LRMS (m/z): 408 [M+1]+ LCMS 1 r.t. (min.): 1.14 1H NMR (400 MHz, Methanol-d4) δ ppm 8.16 (s, 1H), 7.63 (dd, J = 8.4, 7.5 Hz, 1H), 7.05 – 7.01 (m, 1H), 6.85 (dd, J = 7.9, 2.0 Hz, 2H), 5.39 (q, J = 6.7 Hz, 1H), 4.93 (s, 1H), 4.08 (dd, J = 11.5, 2.3 Hz, 1H), 3.99 – 3.91 (m, 1H), 3.84 (dd, J = 6.4, 4.0 Hz, 4H), 3.63 (td, J = 11.7, 2.1 Hz, 1H), 3.54 (td, J = 11.7, 2.1 Hz, 1H), 3.19 (tt, J = 8.1, 3.7 Hz, 1H), 2.09 – 2.00 (m, 1H), 1.94 – 1.84 (m, 1H), 1.84 – 1.78 (m, 1H), 1.71 (dd, J = 11.8, 4.3 Hz, 1H), 1.64 (d, J = 6.7 Hz, 3H). EXAMPLE 132 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-3- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-(5,6-dihydro-2H-pyran-3-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The purification of the title compound was done by preparative LC-MS under basic conditions. Purity based on LC-MS 99%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.08 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J = 6.2 Hz, 6H), 1.59 – 1.73 (m, 3H), 2.05 – 2.24 (m, 4H), 2.64 – 2.75 (m, 3H), 3.85 (d, J = 11.2 Hz, 1H), 4.02 – 4.15 (m, 3H), 4.52 – 4.75 (m, 3H), 6.53 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.76 (t, J = 5.6 Hz, 1H), 6.95 (s, 1H), 7.39 – 7.46 (m, 1H), 8.03 (s, 1H). EXAMPLE 133 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydrofuran-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((5-(2,5-dihydrofuran-3-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The purification of the title compound was done by preparative LC-MS under basic conditions. Purity based on LC-MS 99%. LRMS (m/z): 408 [M+1]+ LCMS 1 r.t. (min.): 0.94 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J = 6.2 Hz, 6H), 1.91 (s, 3H), 1.94 – 2.03 (m, 1H), 2.28 – 2.39 (m, 2H), 2.65 – 2.75 (m, 2H), 3.61 – 3.68 (m, 1H), 3.74 – 3.85 (m, 2H), 3.87 – 3.95 (m, 1H), 4.04 – 4.14 (m, 2H), 4.56 – 4.71 (m, 2H), 6.53 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 5.6 Hz, 1H), 7.00 (s, 1H), 7.38 – 7.46 (m, 1H), 8.03 (s, 1H). EXAMPLE 134 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(4-(((5-(3,6-dihydro-2H-pyran-4-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. Purity based on LC-MS 95%. LRMS (m/z): 423 [M+1]+ LCMS 1 r.t. (min.): 0.96 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 6H), 1.53 – 1.68 (m, 2H), 1.85 – 1.97 (m, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.23 – 3.30 (m, 2H), 3.57 (t, J = 10.9 Hz, 3H), 3.86 – 3.96 (m, 2H), 4.49 – 4.66 (m, 5H), 6.46 – 6.51 (m, 1H), 6.79 – 6.86 (m, 1H), 6.93 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 8.21 (d, J = 5.0 Hz, 1H), 11.40 (s, 1H). EXAMPLE 135 N-((6-(3,3-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,2- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 91%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.00 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.60 (qd, J = 12.2, 4.2 Hz, 3H), 1.90 (d, J = 12.9 Hz, 2H), 2.79 – 2.88 (m, 2H), 3.41 – 3.48 (m, 3H), 3.54 (t, J = 10.9 Hz, 3H), 3.90 (dd, J = 11.0, 3.0 Hz, 2H), 4.65 (d, J = 5.7 Hz, 2H), 6.48 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.69 (t, J = 5.9 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.4, 7.4 Hz, 1H), 8.02 (s, 1H), 11.37 (s, 1H). EXAMPLE 136 N-((6-((3S,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2S,6S)-4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 92%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.03 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J = 6.6 Hz, 6H), 1.52 – 1.67 (m, 2H), 1.86 – 1.95 (m, 2H), 3.39 – 3.44 (m, 2H), 3.49 – 3.58 (m, 3H), 3.70 – 3.77 (m, 2H), 3.86 – 3.94 (m, 2H), 4.63 – 4.70 (m, 2H), 6.57 (d, J = 7.3 Hz, 1H), 6.71 – 6.79 (m, 2H), 6.92 (d, J = 2.1 Hz, 1H), 7.45 – 7.52 (m, 1H), 8.01 (s, 1H), 11.38 (s, 1H). EXAMPLE 137 N-((2-(3,3-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl 4-(4-(((5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrimidin-2-yl)-2,2- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 95%. LRMS (m/z): 423 [M+1]+ LCMS 1 r.t. (min.): 1.01 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (s, 6H), 1.61 (qd, J = 12.4, 4.2 Hz, 2H), 1.91 (d, J = 13.0 Hz, 2H), 2.73 – 2.77 (m, 2H), 3.22 – 3.28 (m, 1H), 3.43 (s, 2H), 3.56 (t, J = 10.9 Hz, 2H), 3.60 – 3.65 (m, 2H), 3.90 (dd, J = 11.2, 3.2 Hz, 2H), 4.61 (d, J = 5.9 Hz, 2H), 6.42 (d, J = 5.0 Hz, 1H), 6.77 (t, J = 5.9 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 8.17 (d, J = 5.0 Hz, 1H), 11.40 (s, 1H). 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. The purification of the title compound was done first by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) and in a second step by preparative LC-MS under basic conditions. Purity based on LC-MS 100%. LRMS (m/z): 457 [M+1]+ LCMS 1 r.t. (min.): 1.55 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J = 6.2 Hz, 6H), 1.54 – 1.65 (m, 2H), 2.02 – 2.14 (m, 5H), 2.23 – 2.31 (m, 2H), 2.58 – 2.66 (m, 2H), 3.16 – 3.25 (m, 2H), 4.49 (d, J = 10.5 Hz, 2H), 4.61 (d, J = 5.9 Hz, 2H), 6.45 (d, J = 5.0 Hz, 1H), 6.84 (t, J = 6.1 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 8.01 (s, 1H), 8.19 (d, J = 5.0 Hz, 1H), 11.40 (s, 1H). EXAMPLE 139 N-((6-((3R,5R)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6R)-4-(6-(((5-(3,6-dihydro-2H-pyran-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 99%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J = 6.6 Hz, 6H), 1.53 – 1.68 (m, 3H), 1.89 (d, J = 11.4 Hz, 2H), 3.41 – 3.49 (m, 3H), 3.51 – 3.62 (m, 4H), 3.72 – 3.80 (m, 2H), 3.86 – 3.93 (m, 2H), 4.65 – 4.71 (m, 2H), 6.58 (d, J = 7.3 Hz, 1H), 6.71 – 6.79 (m, 2H), 6.92 (d, J = 2.1 Hz, 1H), 7.44 – 7.54 (m, 1H), 8.00 (s, 1H), 11.38 (s, 1H). EXAMPLE 140 N-((S)-1-(2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)ethyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(4-((S)-1-((5-(3,6-dihydro-2H-pyran- 4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyrimidin-2- yl)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The crude product was purified by reverse phase chromatography eluting with 100% water to 100% methanol/acetonitrile (1:1). Purity based on LC-MS 90%. LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 1.32 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (s, 1H), 8.25 (d, J = 5.0 Hz, 1H), 8.05 (s, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 5.0 Hz, 1H), 6.15 (d, J = 7.8 Hz, 1H), 5.30 (p, J = 7.0 Hz, 1H), 4.53 (d, J = 13.9 Hz, 2H), 3.92 (t, J = 11.4 Hz, 2H), 3.61 – 3.46 (m, 2H), 2.75 – 2.60 (m, 2H), 2.39 – 2.27 (m, 3H), 1.98 – 1.85 (m, 2H), 1.69 – 1.56 (m, 2H), 1.52 (d, J = 6.9 Hz, 3H), 1.00 (dd, J = 12.2, 6.2 Hz, 6H). EXAMPLE 141 N-((6-(3,3-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl 4-(6-(((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,2- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 95%. LRMS (m/z): 421 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (s, 6H), 1.54 – 1.67 (m, 2H), 1.94 (d, J = 12.7 Hz, 3H), 2.87 – 2.94 (m, 2H), 3.17 (d, J = 5.2 Hz, 2H), 3.21 – 3.27 (m, 1H), 3.48 – 3.58 (m, 4H), 3.90 (dd, J = 11.0, 3.1 Hz, 2H), 4.37 (d, J = 5.7 Hz, 2H), 6.04 (d, J = 5.5 Hz, 1H), 6.07 (t, J = 5.8 Hz, 1H), 6.59 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 7.41 – 7.49 (m, 1H), 7.72 (d, J = 5.4 Hz, 1H), 10.96 (s, 1H). EXAMPLE 142 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(4-(((3-(3,6-dihydro-2H-pyran-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)pyrimidin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 92%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 0.88 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J = 6.2 Hz, 6H), 1.61 (s, 2H), 1.95 (d, J = 12.6 Hz, 2H), 2.27 – 2.37 (m, 3H), 2.63 – 2.71 (m, 2H), 3.52 – 3.61 (m, 2H), 3.91 (d, J = 8.3 Hz, 2H), 4.36 (d, J = 5.9 Hz, 2H), 4.54 (d, J = 10.4 Hz, 3H), 5.95 (d, J = 5.5 Hz, 1H), 6.12 – 6.19 (m, 1H), 6.54 (d, J = 5.0 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 5.0 Hz, 1H), 10.99 (s, 1H). EXAMPLE 143 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-(3,6-dihydro-2H-pyran-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)- 2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. Purity based on LC-MS 89%. LRMS (m/z): 423 [M+1]+ LCMS 1 r.t. (min.): 1.12 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J = 5.9 Hz, 6H), 1.74 – 1.94 (m, 4H), 2.15 – 2.29 (m, 2H), 2.71 – 2.85 (m, 2H), 3.52 – 3.61 (m, 3H), 3.88 – 3.97 (m, 2H), 4.07 – 4.17 (m, 2H), 4.69 (d, J = 6.0 Hz, 2H), 6.51 (d, J = 7.2 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 7.40 – 7.46 (m, 2H), 8.13 (s, 1H), 13.12 (s, 1H). EXAMPLE 144 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrazolo[3,4-b]pyridin-4-amine The title compound was prepared from tert-butyl (2R,6S)-4-(6-(((3-(3,6-dihydro-2H-pyran-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)methyl)pyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate following the experimental procedure described in Example 127. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 99%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 0.83 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J = 4.2 Hz, 6H), 1.77 – 1.96 (m, 4H), 2.81 – 3.04 (m, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.50 – 3.64 (m, 4H), 3.88 – 3.97 (m, 2H), 4.19 – 4.34 (m, 2H), 4.44 (d, J = 5.8 Hz, 2H), 5.99 (d, J = 5.6 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 6.66 – 6.76 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.89 (d, J = 5.5 Hz, 1H), 12.74 (s, 1H). EXAMPLE 145 N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of 5-(3,6-dihydro-2H-pyran-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 (37 mg, 0.085 mmol) in methanol (15 mL), 10% palladium on charcoal (10 mg, 0.094 mmol) was added. The mixture was stirred under hydrogen atmosphere at a pressure of 3 atm until all the starting material was consumed (4 days). The catalyst was filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography from 100% water to 100% methanol/acetonitrile (1:1) mixture to give the title compound (7 mg, 18% yield) as a pale solid. Purity based on LC-MS 94%. LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.25 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.08 (s, 1H), 7.46 (dd, J = 8.4, 7.3 Hz, 1H), 6.91 (s, 1H), 6.66 (dd, J = 14.6, 7.9 Hz, 2H), 6.09 (d, J = 8.0 Hz, 1H), 5.36 (dt, J = 14.4, 6.9 Hz, 1H), 4.22 – 4.09 (m, 1H), 3.95 (d, J = 7.0 Hz, 1H), 3.86 (d, J = 9.4 Hz, 1H), 3.59 – 3.42 (m, 4H), 2.74 (s, 2H), 2.23 (td, J = 11.9, 4.0 Hz, 2H), 1.94 (d, J = 13.7 Hz, 1H), 1.82 (d, J = 13.4 Hz, 1H), 1.72 – 1.52 (m, 2H), 1.49 (d, J = 6.7 Hz, 3H), 1.02 (dd, J = 6.2, 3.3 Hz, 6H). EXAMPLE 146 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine following the experimental procedure described in Example 145. LRMS (m/z): 421 [M+1]+ LCMS 1 r.t. (min.): 0.99 EXAMPLE 147 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine following the experimental procedure described in Example 145. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 91%. LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.01 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J = 6.2 Hz, 6H), 1.58 (qd, J = 12.3, 4.1 Hz, 2H), 1.89 (d, J = 12.8 Hz, 2H), 2.14 – 2.25 (m, 2H), 2.31 (s, 3H), 2.69 – 2.77 (m, 2H), 3.12 – 3.25 (m, 1H), 3.47 – 3.57 (m, 2H), 3.88 (dd, J = 11.2, 2.9 Hz, 2H), 4.08 – 4.16 (m, 2H), 4.65 (d, J = 5.6 Hz, 2H), 6.53 (d, J = 7.4 Hz, 2H), 6.64 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 8.4, 7.4 Hz, 1H), 11.12 (s, 1H). EXAMPLE 148 5-(4,4-Difluorocyclohexyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine a) Tert-butyl 4-(6-(((5-(4,4-difluorocyclohex-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate 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-(4,4-difluorocyclohex- 1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following the experimental procedure described in Intermediate 135. Purity based on LC-MS 100%. LRMS (m/z): 526 [M+1]+ LCMS 3 r.t. (min.): 1.78 b) 5-(4,4-Difluorocyclohexyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine To a solution of tert-butyl 4-(6-(((5-(4,4-difluorocyclohex-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate (62 mg, 0.12 mmol) in methanol (5 mL), 10% palladium on charcoal (7 mg, 0.065 mmol) and two drops of concentrated hydrochloric acid were added. The mixture was stirred under hydrogen atmosphere at a pressure of 1 atm overnight. The catalyst was filtered and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (18 mg, 36% yield) as a pale solid. Purity based on LC-MS 89%. LRMS (m/z): 428 [M+1]+ LCMS 1 r.t. (min.): 1.48 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 – 1.67 (m, 3H), 2.00 – 2.15 (m, 5H), 2.71 – 2.78 (m, 1H), 3.14 – 3.29 (m, 8H), 4.66 (d, J = 5.7 Hz, 2H), 6.52 (d, J = 7.3 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.74 – 6.81 (m, 1H), 6.95 (s, 1H), 7.39 – 7.46 (m, 1H), 8.02 (s, 1H). EXAMPLE 149 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(6-(methylamino)pyridin- 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(6-fluoropyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (120 mg, 0.21 mmol), (6-fluoro-3-pyridyl)boronic acid (45 mg, 0.32 mmol), Pd(dppf)Cl2 (15 mg, 0.020 mmol) and cesium carbonate (206 mg, 0.63 mmol) in dioxane (1.6 mL) and water (0.4 mL) were stirred at 120 ºC under nitrogen atmosphere for 2 hours until the starting material was consumed. Then, 1 mL of water was added and the mixture was heated at 120 ºC until complete deprotection of the tosyl group was observed (4 hours). The resulting mixture was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (54 mg, 59% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 432 [M+1]+ LCMS 2 r.t. (min.): 1.27 b) N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(6- (methylamino)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(6-fluoropyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (54 mg, 0.12 mmol) was added a 33% solution of methylamine in ethanol (1 mL). The mixture was heated in a sealed tube for 8 hours at 100 ºC until no starting material was detected. The volatiles were removed under reduced pressure and the crude product was suspended in diethylether and the solvents evaporated. The co-evaporation step was repeated twice and the title compound was obtained (34 mg, 61% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.68 1H NMR (400 MHz, Methanol-d4) δ 1.05 (d, J = 6.4 Hz, 6H), 2.11 – 2.35 (m, 2H), 2.73 – 2.82 (m, 2H), 2.87 (s, 3H), 3.93 (dd, J = 12.9, 2.4 Hz, 2H), 4.62 (s, 2H), 6.53 (dd, J = 8.6, 0.6 Hz, 1H), 6.62 (t, J = 7.8 Hz, 2H), 7.09 (s, 1H), 7.47 (dd, J = 8.5, 7.3 Hz, 1H), 7.58 (dd, J = 8.6, 2.4 Hz, 1H), 8.09 (d, J = 3.0 Hz, 1H), 8.17 (s, 1H). EXAMPLE 150 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-(methylamino)pyridin- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2-fluoropyridin-4- yl)boronic acid following the experimental procedure described in Example 149. Purity based on LC-MS 98%. LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 0.70 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J = 6.3 Hz, 6H), 2.21 (t, J = 12 Hz, 2H), 2.69 (d, J = 5 Hz, 3H), 2.72-2.80 (m, 2H), 3.97 (dd, J = 12 and 1.6 Hz, 2H), 4.63 (d, J = 5 Hz, 2H), 6.28 (t, J = 5 Hz, 1H), 6.41 (q, J = 5 Hz, 1H), 6.49 (s, 1H), 6.61 (d, J = 7.3 Hz, 1H), 6.63 (dd, J = 5 and 1.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 7.37 (s, 1H), 7.46 (dd, J = 8.4 and 7.6 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 11.97 (s, 1H). EXAMPLE 151 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(2- (methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine The title compound was prepared from 5-bromo-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)ethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (2-fluoropyridin-4-yl)boronic acid following the experimental procedure described in Example 149. Purity based on LC-MS 100%. LRMS (m/z): 458 [M+1]+ LCMS 1 r.t. (min.): 0.87 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H), 2.02-2.18 (m, 2H), 2.61-2.76 (m, 5H), 3.84-3.98 (m, 2H), 5.34 (p, J = 6.6 Hz, 1H), 6.13 (d, J = 7.8 Hz, 1H), 6.42 (q, J = 4.8 Hz, 1H), 6.45 (s, 1H), 6.60 (d, J = 6 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 5 Hz, 1H), 8.18 (s, 1H), 11.95 (s, 1H). EXAMPLE 152 5-(2-(Methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) 5-(2-Fluoropyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a mixture of 5-bromo-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (170 mg, 0.29 mmol), 2-fluoro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (79 mg, 0.35 mmol), Pd(dppf)Cl2 (24 mg, 0.029 mmol) in dioxane (1.8 mL), a 2 M aqueous solution of sodium carbonate (0.44 mL, 0.87 mmol) was added. The mixture was stirred at 110 ºC under inert atmosphere for 75 minutes. The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate and filtered through Celite®. The filtrates were dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting from 100% hexane to 100% ethyl acetate to give the title compound (95 mg, 54% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 603 [M+1]+ LCMS 3 r.t. (min.): 2.04 b) 5-(2-(Methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To of 5-(2-fluoropyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (92 mg, 0.15 mmol) was added a 33% solution of methylamine in ethanol (2 mL). The mixture was heated in a sealed tube at 100 ºC for 20 hours until no starting material was detected. The volatiles were removed under reduced pressure and the crude product was suspended in diethylether and the solvents evaporated. The crude product was purified by flash chromatography eluting with 100% DCM to 100% DCM/MeOH/7N NH3 (40:9:1) to give the title compound (53 mg, 57% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 614 [M+1]+ LCMS 3 r.t. (min.): 1.67 c) 5-(2-(Methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of 5-(2-(methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (53 mg, 0.086 mmol) in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 hour. Then, the volatiles were removed under reduced pressure and the residue was treated with a 7 M solution of ammonia in methanol (0.6 mL) at room temperature for 1 hour. A white precipitate formed and was filtered and washed with cold methanol to give the title compound (21 mg, 50% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 484 [M+1]+ LCMS 1 r.t. (min.): 1.21 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 – 2.68 (m, 1H), 2.71 (d, J = 4.8 Hz, 3H), 2.75 – 2.95 (m, 3H), 3.17 (d, J = 5.3 Hz, 1H), 3.64 – 3.72 (m, 1H), 3.99 – 4.06 (m, 1H), 4.66 (d, J = 5.1 Hz, 2H), 6.32 (t, J = 5.2 Hz, 1H), 6.44 (d, J = 5.0 Hz, 1H), 6.49 (s, 1H), 6.62 (dd, J = 5.2, 1.4 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.50 (dd, J = 8.4, 7.4 Hz, 1H), 7.97 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 11.96 (s, 1H). EXAMPLE 153 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(2-(methylamino)pyridin- 4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1- yl)pyridin-2-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 152. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 91%. LRMS (m/z): 443 [M+1]+ LCMS 1 r.t. (min.): 0.55 1H NMR (400 MHz, Methanol-d4) δ ppm 8.53 (s, 2H), 7.94 (d, J = 5.4 Hz, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.64 – 7.55 (m, 1H), 7.33 (s, 1H), 6.85 – 6.75 (m, 3H), 6.59 (s, 1H), 6.40 (d, J = 5.8 Hz, 1H), 4.45 (s, 2H), 4.18 (dd, J = 13.8, 2.5 Hz, 2H), 3.25 – 3.11 (m, 3H), 2.65 (s, 3H), 2.53 (dd, J = 13.9, 11.4 Hz, 3H), 1.26 (s, 3H), 1.24 (s, 3H). EXAMPLE 154 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(2- (methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine The title compound was prepared from 3-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-amine and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following the experimental procedure described in Example 152. The purification of the title compound was done by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1). Purity based on LC-MS 98%. LRMS (m/z): 511 [M+1]+ LCMS 1 r.t. (min.): 0.74 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, J = 6 Hz, 6H), under DMSO (2H), 2.68 (d, J = 4.7 Hz, 3H), 2.95-3.05 (m, 2H), 4.23 (d, J = 13 Hz, 2H), 4.48 (d, J = 5.4 Hz, 2H), 5.76 (t, J = 5.5 Hz, 1H), 6.24 (d, J = 5.5 Hz, 1H), 6.34–6.41 (m, 1H), 6.47 (s, 1H), 6.63 (dd, J = 5.2 and 1.2 Hz, 1H), 6.95 (s, 1H), 7.08 (s, 1H), 7.33 (s, 1H), 7.90 (d, J = 5 Hz, 1H),7.94 (d, J = 5 Hz, 1H), 11.63 (s, 1H). EXAMPLE 155 5-(2-Amino-3-fluoropyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) 5-(2,3-Difluoropyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of (4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (54 mg, 0.10 mmol), 2,3-difluoro-4-iodo-pyridine (20 mg, 0.082 mmol), Pd(dppf)Cl2 (6 mg, 0.008 mmol) and cesium carbonate (81 mg, 0.25 mmol) in dioxane (1.6 mL), and water (0.4 mL) was stirred under inert atmosphere at 120 ºC for 15 minutes. The resulting mixture was partitioned between brine and ethyl acetate and the aqueous solution was extracted twice with more ethyl acetate. The combined organic solutions were dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting from DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (28 mg, 56% yield) as a pale solid. Purity based on LC-MS 99%. LRMS (m/z): 605 [M+1]+ LCMS 2 r.t. (min.): 2.13 b) 5-(2-Amino-3-fluoropyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5-(2,3-Difluoropyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (28 mg, 0.046 mmol) was suspended in 7 M solution of ammonia in methanol and heated in a sealed vessel at 80 ºC for 24 hours and then at 120 ºC for additional 18 hours until all the starting material was consumed. The solvents were then removed under reduced pressure and the crude product was purified by flash chromatography eluting from DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (6 mg, 29% yield) as a solid. Purity based on LC-MS 99%. LRMS (m/z): 448 [M+1]+ LCMS 1 r.t. (min.): 0.94 1H NMR (400 MHz, Chloroform-d) δ 1.05 (d, J = 6.4 Hz, 6H), 2.26 (t, J = 12.1 Hz, 2H), 2.68 – 3.00 (m, 2H), 3.77 – 4.01 (m, 2H), 4.59 (s, 2H), 6.44 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 5.2 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.33 – 7.40 (m, 1H), 7.59 (d, J = 5.3 Hz, 1H), 8.20 (s, 1H). EXAMPLE 156 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- (methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine a) N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- fluoropyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 5-bromo-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (86 mg, 0.13 mmol), (2-fluoro-4- pyridyl)boronic acid (29 mg, 0.21 mmol), Pd(dppf)Cl2 (10 mg, 0.010 mmol) and cesium carbonate (132 mg, 0.41 mmol) in a 4:1 mixture of dioxane and water (2.5 mL) were stirred at 120 ºC under nitrogen atmosphere for 15 minutes. The resulting mixture was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) to give the title compound (53 mg, 60% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 655 [M+1]+ LCMS 2 r.t. (min.): 2.33 b) N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- (methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To solid N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- fluoropyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (53 mg, 0.081 mmol) was added a 33% solution of methylamine in ethanol (2 mL). The mixture was heated in a sealed tube for 5 hours at 100 ºC until no starting material was detected. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with DCM to DCM/MeOH/7N NH3 (90:9:1) to give title compound as a white solid (36 mg, 86% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 512 [M+1]+ LCMS 1 r.t. (min.): 1.11 1H NMR (400 MHz, Methanol-d4) δ ppm 0.95 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H), 2.02-2.18 (m, 2H), 2.61-2.76 (m, 5H), 3.84-3.98 (m, 2H), 5.34 (p, J = 6.6 Hz, 1H), 6.13 (d, J = 7.8 Hz, 1H), 6.42 (q, J = 4.8 Hz, 1H), 6.45 (s, 1H), 6.60 (d, J = 6 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 5 Hz, 1H), 8.18 (s, 1H), 11.95 (s, 1H) EXAMPLE 157 5-(2-Aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 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 (300 mg, 0.72 mmol), (2-aminopyridin-4-yl)boronic acid (129 mg, 0.94 mmol), Pd(dppf)Cl2 (25 mg, 0.030 mmol) and cesium carbonate (160 mg, 0.49 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 100 ºC under nitrogen atmosphere until the starting material was consumed (2 hours). The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate, filtered through Celite® and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with 100% dichloromethane to 100% dichloromethane/methanol/7M ammonia (90:10:1) to give the title compound (129 mg, 61% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 430 [M+1]+ LCMS 1 r.t. (min.): 0.95 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 2.7 Hz, 1H), 7.45 (dd, J = 8.4, 7.3 Hz, 1H), 6.82 (t, J = 5.4 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.68 – 6.53 (m, 2H), 5.99 (s, 1H), 4.63 (d, J = 5.4 Hz, 2H), 3.95 (dd, J = 12.3, 2.1 Hz, 4H), 2.70 – 2.62 (m, 2H), 2.18 – 2.07 (m, 2H), 0.96 (d, J = 6.3 Hz, 6H). EXAMPLE 158 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4- yl)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 (3-fluoropyridin-4-yl)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. Purity based on LC-MS 100%. LRMS (m/z): 433 [M+1]+ LCMS 1 r.t. (min.): 1.93 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.53 (dd, J = 6.7, 4.9 Hz, 1H), 7.46 (dd, J = 8.4, 7.4 Hz, 1H), 7.02 (t, J = 5.6 Hz, 1H), 6.86 (dd, J = 2.7, 1.3 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 4.58 (d, J = 5.4 Hz, 2H), 4.00 (dd, J = 12.4, 2.2 Hz, 2H), 2.72 (ddd, J = 9.6, 6.4, 3.0 Hz, 2H), 2.22 – 2.12 (m, 2H), 0.99 (d, J = 6.3 Hz, 6H). EXAMPLE 159 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-4-yl)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 pyridin-4-ylboronic acid following the experimental procedure described in Example 157. The purification of the title compound was done by preparative LC-MS under buffered conditions. Purity based on LC-MS 99%. LRMS (m/z): 415 [M+1]+ LCMS 1 r.t. (min.): 1.50 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 – 8.54 (m, 2H), 8.22 (s, 1H), 8.00 (s, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.56 – 7.51 (m, 2H), 7.47 (dd, J = 8.5, 7.3 Hz, 1H), 6.90 (q, J = 3.8 Hz, 2H), 6.66 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 7.2 Hz, 1H), 4.63 (d, J = 5.2 Hz, 2H), 3.95 – 3.88 (m, 2H), 2.88 – 2.61 (m, 4H), 2.16 – 2.06 (m, 2H), 0.95 (d, J = 6.3 Hz, 6H). 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. Purity based on LC-MS 100%. LRMS (m/z): 432 [M+1]+ LCMS 1 r.t. (min.): 2.37 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.54 (dd, J = 8.5, 5.6 Hz, 2H), 7.49 – 7.40 (m, 1H), 7.24 (t, J = 8.8 Hz, 2H), 6.73 (d, J = 2.7 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 7.2 Hz, 2H), 4.58 (d, J = 4.8 Hz, 2H), 3.88 (d, J = 11.4 Hz, 2H), 2.62 (d, J = 3.1 Hz, 2H), 2.14 – 1.97 (m, 2H), 0.94 (d, J = 6.2 Hz, 6H). EXAMPLE 161 5-(3,6-Dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 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 (80 mg, 0.19 mmol), 3,6-dihydro-2H-pyran-4-ylboronic acid (32 mg, 0.25 mmol), Pd(dppf)Cl2 (15 mg, 0.018 mmol) and cesium carbonate (180 mg, 0.5 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 110 ºC under nitrogen atmosphere until the starting material was consumed (3 hours). The mixture was then allowed to reach room temperature, it was diluted with ethyl acetate, filtered through Celite® and the solvents were evaporated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (30 mg, 37% yield) as a white solid. Purity based on LC-MS 100%. LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 1.89 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.5, 7.3 Hz, 1H), 6.99 (t, J = 5.6 Hz, 1H), 6.72 – 6.65 (m, 2H), 6.57 (d, J = 7.2 Hz, 1H), 5.84 (s, 1H), 4.66 (d, J = 5.5 Hz, 2H), 4.14 (d, J = 2.6 Hz, 2H), 4.07 (d, J = 9.9 Hz, 3H), 3.83 (t, J = 5.4 Hz, 3H), 2.69 (s, 2H), 2.22 – 2.12 (m, 2H), 0.97 (d, J = 6.3 Hz, 6H). EXAMPLE 162 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine To a solution of 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin- 2-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (10 mg, 0.024 mmol) in methanol (2 mL), 10% palladium on charcoal (5 mg, 0.018 mmol) was added. The mixture was stirred under hydrogen atmosphere at a pressure of 1 atm until all the starting material was consumed (1 hour). The catalyst was filtered and the solvent was removed under reduced pressure to give the title compound (7 mg, 73% yield) as a solid. Purity based on LC-MS 90%. LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.76 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (d, J = 2.8 Hz, 1H), 7.47 – 7.39 (m, 2H), 6.67 – 6.58 (m, 2H), 6.49 (d, J = 7.3 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 4.08 (d, J = 10.1 Hz, 2H), 3.90 (d, J = 11.5 Hz, 4H), 3.55 (dd, J = 20.6, 9.1 Hz, 4H), 2.21 – 2.11 (m, 3H), 1.71 (d, J = 8.4 Hz, 2H), 0.96 (d, J = 6.3 Hz, 6H). EXAMPLE 163 5-(2,2-Difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine a) Tert-butyl 4-(6-(((5-(2,2-difluorocyclopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate A mixture of 4-chloro-5-(2,2-difluorocyclopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (52 mg, 0.14 mmol), tert-butyl 4-(6-(aminomethyl)pyridin-2-yl)piperazine- 1-carboxylate (44 mg, 0.15 mmol) and DIEA (0.075 mL, 0.43 mmol) in DMSO (0.5 mL) was heated at 130 ºC overnight. The mixture was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (28 mg, 31% yield) as a pale oil solid. Purity based on LC-MS 100%. LRMS (m/z): 616 [M+1]+ LCMS 3 r.t. (min.): 2.26 b) 5-(2,2-Difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine To a solution of tert-butyl 4-(6-(((5-(2,2-difluorocyclopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)piperazine-1-carboxylate (28 mg, 0.045 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 1.5 hours and the volatiles were removed under reduced pressure. Then, a 7 M solution of ammonia in methanol (0.8 mL) was added. The resulting solution was stirred at room temperature overnight and the solvents were removed. The residue was redissolved in ethyl acetate and the resulting solution was washed with a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate, filtered and the solvent was removed to give the title compound (14 mg, 80% yield) as a white solid. Purity based on LC-MS 99%. LRMS (m/z): 386 [M+1]+ LCMS 1 r.t. (min.): 1.11 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (s, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.52 – 7.42 (m, 1H), 7.03 (s, 1H), 6.90 (t, J = 4.8 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 6.62 (dd, J = 7.1, 5.4 Hz, 1H), 4.77 – 4.57 (m, 2H), 3.57 – 3.43 (m, 4H), 3.39 – 3.21 (m, 2H), 2.94 – 2.83 (m, 2H), 2.58 – 2.48 (m, 2H), 2.07 – 1.92 (m, 1H), 1.84 – 1.68 (m, 1H). 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. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Daicel Chiralpak ID (20mmx250mm, 5µm); Eluent A: heptane, Eluent B: 0.2% DEA in ethanol; Flux: 18 mL/min; Run time: 30 min. First eluting peak (Example 164): Obtained as a white solid (27 mg). Purity by LC-MS 99%. LRMS (m/z): 386 [M+1]+ LCMS 1 r.t. (min.): 1.11 Second eluting peak (Example 165): Obtained as a white solid (30 mg). Purity by LC-MS 99%. LRMS (m/z): 386 [M+1]+ LCMS 1 r.t. (min.): 1.11 EXAMPLE 166 5-(2,2-Difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine a) 5-(2,2-Difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 4-chloro-5-(2,2-difluorocyclopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (50 mg, 0.14 mmol), (6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methanamine (32 mg, 0.15 mmol) and DIEA (0.073 mL, 0.42 mmol) in DMSO (0.5 mL) was heated at 130 ºC for 9 hours. The mixture was then partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product (74 mg, 98% yield) was used directly in the next step. Purity based on LC-MS 86%. LRMS (m/z): 544 [M+1]+ LCMS 3 r.t. (min.): 1.72 b) 5-(2,2-Difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of 5-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (74 mg, 0.14 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour and the volatiles were removed under reduced pressure. Then, a 7 M solution of ammonia in methanol (2 mL) was added. The resulting solution was stirred at room temperature overnight and the solvents were removed. The crude product was purified by preparative HPLC to give title compound (24 mg, 42% yield) as a pale solid. Purity based on LC- MS 90%. LRMS (m/z): 414 [M+1]+ LCMS 1 r.t. (min.): 1.18 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 8.07 (s, 1H), 7.43 (dd, J = 8.4, 7.4 Hz, 1H), 7.03 (s, 1H), 6.85 (t, J = 5.7 Hz, 1H), 6.63 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 7.4 Hz, 1H), 4.73 – 4.54 (m, 2H), 4.11 (d, J = 12.2 Hz, 2H), 3.32 – 3.18 (m, 3H), 2.77 – 2.62 (m, 2H), 2.17 (t, J = 11.3 Hz, 2H), 2.04 – 1.90 (m, 1H), 1.86 – 1.70 (m, 1H), 0.99 (d, J = 6.2 Hz, 6H). The following examples were prepared following the same experimental procedures to those described in the previous examples, using the suitable starting materials and reactants for each specific example: EXAMPLE 167 5-(2-Aminopyridin-4-yl)-N-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)-2-fluorobenzyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 98% LRMS (m/z): 447 [M+1]+ LCMS 1 r.t. (min.): 0.79 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J = 6.3 Hz, 6H), 2.28 (t, J = 11 Hz, 2H), 2.95-3.05 (m, 2H), 3.21 (d, J = 10 Hz, 2H), 4.72 (d, J = 5.6 Hz, 2H), 5.92 (s, 2H), 6.01 (t, J = 6 Hz, 1H), 6.53 (s, 1H), 6.57 (dd, J = 5.2 and 1.4 Hz, 1H), 6.87-6.96 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 7.33 (s, 1H), 7.89 (d, J = 5 Hz, 1H), 8.18 (s, 1H), 11.96 (s, 1H) EXAMPLE 168 5-(2-Aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 430 [M+1]+ LCMS 1 r.t. (min.): 0.21 1H NMR (400 MHz, Methanol-d4) δ ppm 1.13 (d, J = 6.4 Hz, 6H), 2.39 (t, J = 11.2 Hz, 2H), 2.86 (m, 2H), 3.79 (d, J = 11.6 Hz, 2H), 4.67 (s, 2H), 6.74 (m, 3H), 6.86 (s, 1H), 7.28 (s, 1H), 7.90 (d, J = 5.6 Hz, 1H), 8.07 (d, J = 6 Hz, 1H), 8.22 (s, 1H). EXAMPLE 169 N-((4-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 418 [M+1]+ LCMS 1 r.t. (min.): 0.50 1H NMR (400 MHz, Methanol-d4) δ ppm 1.14 (d, J = 6.0 Hz, 6H), 2.40 (t, J = 11.6 Hz, 2H), 2.86 (m, 2H), 3.81 (d, J = 11.6 Hz, 2H), 3.93 (s, 3H), 4.65 (s, 2H), 6.75 (t, J = 5.6 Hz, 1H), 6.85 (s, 1H), 7.07 (s, 1H), 7.60 (s, 1H), 7.76 (s, 1H), 8.08 (d, J = 6 Hz, 1H), 8.17 (s, 1H). EXAMPLE 170 5-(1-Methyl-1H-pyrazol-4-yl)-N-((4-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 389 [M+1]+ LCMS 1 r.t. (min.): 0.68 1H NMR (400 MHz, Methanol-d4) δ ppm 1.66 (m, 2H), 1.82 (m, 2H), 2.69 – 2.77 (m, 3H), 3.15 (d, J = 12.4 Hz, 2H), 3.95 (s, 3H), 4.77 (s, 2H), 7.08 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.28 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.15 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H). EXAMPLE 171 N-(3-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-2-fluorobenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 97% LRMS (m/z): 435 [M+1]+ LCMS 1 r.t. (min.): 1.11 1H NMR (400 MHz, Chloroform-d) δ 1.21 (d, J = 7 Hz, 6H), 2.39-2.50 (m, 2H),3.14-3.23 (m, 2H), 3.33 (d, J = 11.6 Hz, 2H), 3.94 (s, 3H), 4.81 (d, J = 5.6 Hz, 2H), 5.56 (t, J = 5.9 Hz, 2H), 6.88 (td, J = 8 and 2.3 Hz, 1H), 6.94 (s, 1H), 6.95-7.03 (m, 2H), 7.42 (s, 1H), 7.56 (s, 1H), 8.37 (s, 1H), 9.70 (br s, 1H). EXAMPLE 172 1-(6-(((5-(2-Aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-4-ol Purity based on LC-MS: 99% LRMS (m/z): 417 [M+1]+ LCMS 1 r.t. (min.): 0.84 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 – 1.33 (m, 2H), 1.63 – 1.77 (m, 2H), 2.76 – 2.90 (m, 2H), 3.56 – 3.66 (m, 1H), 3.73 – 3.87 (m, 2H), 4.60 (d, J = 4.4 Hz, 1H), 4.65 (d, J = 5.1 Hz, 2H), 5.93 (s, 2H), 6.30 (t, J = 5.2 Hz, 1H), 6.56 (d, J = 7.0 Hz, 2H), 6.60 – 6.67 (m, 2H), 7.33 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 8.4, 7.3 Hz, 1H), 7.91 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 11.95 (s, 1H). EXAMPLE 173 5-(2-Aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-5-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine Purity based on LC-MS: 95% LRMS (m/z): 390 [M+1]+ LCMS 1 r.t. (min.): 0.53 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (s, 2H), 8.25 (s, 1H), 8.14 (s, 2H), 7.98 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 5.3 Hz, 2H), 7.38 (dd, J = 10.0, 1.8 Hz, 4H), 7.30-6.90 (bs, 4H), 6.69 (dd, J = 5.3, 1.6 Hz, 1H), 6.65 (s, 1H), 6.58 (dd, J = 5.3, 1.3 Hz, 2H), 6.53 (s, 1H), 6.18 (d, J = 1.7 Hz, 2H), 6.14 – 5.98 (m, 5H), 4.77 (d, J = 5.5 Hz, 3H), 4.75 – 4.66 (m, 4H), 3.10 – 2.97 (m, 4H), 2.28 – 2.09 (m, 4H), 1.98 (d, J = 11.1 Hz, 4H). EXAMPLE 174 2-(Methyl(6-(((5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)- 4-(trifluoromethyl)pyridin-2-yl)amino)ethan-1-ol Purity based on LC-MS: 98% LRMS (m/z): 447 [M+1]+ LCMS 1 r.t. (min.): 1.88 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (s, 3H), 3.44 – 3.50 (m, 4H), 3.85 (s, 3H), 4.62 – 4.66 (m, 1H), 4.68 – 4.71 (m, 2H), 6.31 (t, J = 5.5 Hz, 1H), 6.67 – 6.74 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 7.55 (s, 1H), 7.81 (s, 1H), 8.14 (s, 1H), 11.72 (s, 1H). EXAMPLE 175 2-(Methyl(6-(((5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)amino)ethan-1-ol Purity based on LC-MS: 100% LRMS (m/z): 444 [M+1]+ LCMS 1 r.t. (min.): 1.96 1H NMR (400 MHz, DMSO-d6) δ 2.89 (s, 3H), 3.44 (d, J = 2.6 Hz, 4H), 4.62 – 4.66 (m, 1H), 4.68 (d, J = 5.4 Hz, 2H), 6.26 (t, J = 5.4 Hz, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.44 (dd, J = 8.2, 5.2 Hz, 1H), 7.87 – 7.94 (m, 1H), 8.20 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 8.75 (s, 1H), 12.03 (s, 1H). EXAMPLE 176 5-(2-Aminopyridin-4-yl)-N-(3-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine Purity based on LC-MS: 98% LRMS (m/z): 429 [M+1]+ LCMS 1 r.t. (min.): 0.78 EXAMPLE 177 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-5-(pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 96% LRMS (m/z): 417 [M+1]+ LCMS 1 r.t. (min.): 0.81 1H NMR (400 MHz, DMSO-d6) δ 0.98 (d, J = 6.2 Hz, 6H), 2.11 – 2.27 (m, 2H), 2.67 (m, 2H), 4.09 (d, J = 10.2 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H), 6.60 (t, J = 5.6 Hz, 1H), 7.52 (s, 1H), 7.77 (s, 1H), 8.12 (s, 1H), 8.19 (s, 1H), 8.94 (s, 1H), 9.12 (s, 1H), 12.15 (s, 1H). EXAMPLE 178 N-((2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 91% LRMS (m/z): 417 [M+1]+ LCMS 1 r.t. (min.): 1.05 1H NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.3 Hz, 6H), 2.36 (d, J = 11.1 Hz, 2H), 4.52 (dd, J = 16.8, 8.6 Hz, 4H), 6.59 (d, J = 5.0 Hz, 1H), 6.65 (t, J = 5.6 Hz, 2H), 7.11 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 8.18 (d, J = 5.4 Hz, 2H), 8.23 (d, J = 5.0 Hz, 1H), 8.95 (s, 1H), 9.13 (s, 1H). EXAMPLE 179 N-((6-(Dimethylamino)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine Purity based on LC-MS: 99% LRMS (m/z): 346 [M+1]+ LCMS 1 r.t. (min.): 0.94 1H NMR (400 MHz, DMSO-d6) δ 2.75 (s, 6H), 4.62 (d, J = 4.9 Hz, 2H), 6.24 (t, J = 4.9 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 7.36 – 7.48 (m, 3H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H), 8.22 (s, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H), 8.75 (dd, J = 2.3, 0.7 Hz, 1H), 12.02 (s, 1H). EXAMPLE 180 5-(2-Aminopyridin-4-yl)-N-((6-(dimethylamino)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 361 [M+1]+ LCMS 1 r.t. (min.): 0.74 1H NMR (400 MHz, DMSO-d6) δ 2.81 (s, 6H), 4.65 (d, J = 4.9 Hz, 2H), 5.95 (s, 1H), 6.40 (t, J = 4.9 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.54 (s, 2H), 6.62 (dd, J = 5.2, 1.4 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 8.4, 7.3 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 11.95 (s, 1H). EXAMPLE 181 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyrimidin-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 430 [M+1]+ LCMS 1 r.t. (min.): 1.14 1H NMR (400 MHz, DMSO-d6) δ 0.95 (d, J = 6.2 Hz, 6H), 2.05 – 2.11 (m, 2H), 3.29 (s, 3H), 3.96 (d, J = 9.9 Hz, 2H), 4.57 (d, J = 5.4 Hz, 2H), 6.43 – 6.48 (m, 1H), 6.56 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 8.18 (s, 1H), 8.81 (s, 2H). EXAMPLE 182 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2,2-dimethyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 89% LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.31 1H NMR (400 MHz, DMSO-d6) δ 0.99 (d, J = 6.2 Hz, 6H), 1.15 (s, 3H), 1.24 (s, 3H), 1.31 – 1.51 (m, 3H), 1.77 – 1.95 (m, 3H), 2.17 (t, J = 11.3 Hz, 2H), 2.64 – 2.75 (m, 2H), 3.62 (dd, J = 11.7, 3.6 Hz, 1H), 3.80 (t, J = 11.2 Hz, 1H), 4.02 – 4.15 (m, 3H), 4.65 (d, J = 5.8 Hz, 2H), 6.52 (d, J = 7.3 Hz, 1H), 6.58 (t, J = 5.8 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 7.38 – 7.47 (m, 1H), 8.03 (s, 1H), 11.34 (s, 1H). EXAMPLE 183 N-((6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 419 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, DMSO-d6) δ 0.44 (s, 4H), 1.54 – 1.69 (m, 2H), 1.90 – 1.99 (m, 2H), 2.77 – 2.87 (m, 2H), 3.44 – 3.59 (m, 5H), 3.91 (d, J = 7.8 Hz, 2H), 4.36 (d, J = 5.7 Hz, 2H), 6.03 (d, J = 5.6 Hz, 1H), 6.05 – 6.10 (m, 1H), 6.55 – 6.65 (m, 2H), 6.89 (s, 1H), 7.38 – 7.48 (m, 1H), 7.73 (d, J = 5.5 Hz, 1H), 8.46 (s, 2H). EXAMPLE 184 N-((4-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 423 [M+1]+ LCMS 1 r.t. (min.): 0.70 1H NMR (400 MHz, DMSO-d6) δ 0.94 (d, J = 6.1 Hz, 6H), 1.56 – 1.71 (m, 2H), 1.97 (d, J = 13.9 Hz, 2H), 2.19 – 2.30 (m, 2H), 2.52 – 2.63 (m, 3H), 3.57 (t, J = 11.0 Hz, 2H), 3.94 (d, J = 7.9 Hz, 2H), 4.61 (d, J = 5.0 Hz, 2H), 6.70 (d, J = 6.4 Hz, 1H), 6.71 – 6.75 (m, 1H), 6.91 (s, 1H), 8.05 (s, 1H), 8.14 (d, J = 6.3 Hz, 1H), 11.35 (s, 1H). EXAMPLE 185 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(tetrahydro-2H-pyran- 4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine Purity based on LC-MS: 85% LRMS (m/z): 435 [M+1]+ LCMS 1 r.t. (min.): 1.17 1H NMR (400 MHz, Methanol-d4) δ 8.48 (bs, 1H), 7.73 (s, 1H), 7.64 – 7.55 (m, 1H), 6.96 (s, 1H), 6.83 (dd, J = 15.9, 7.9 Hz, 2H), 6.21 (s, 1H), 4.49 (d, J = 13.7 Hz, 2H), 4.13 – 4.03 (m, 1H), 3.99 (d, J = 11.4 Hz, 1H), 3.62 (dtd, J = 23.5, 11.8, 1.9 Hz, 3H), 3.27 – 3.12 (m, 2H), 2.72 (dd, J = 17.5, 7.5 Hz, 2H), 2.07 (dd, J = 22.3, 13.9 Hz, 2H), 1.88 – 1.66 (m, 4H), 1.63 (d, J = 6.7 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H). EXAMPLE 186 4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 100% LRMS (m/z): 446 [M+1]+ LCMS 1 r.t. (min.): 1.58 1H NMR (400 MHz, DMSO-d6) δ 0.92 (d, J = 6.2 Hz, 6H), 1.50 – 1.65 (m, 2H), 1.82 (d, J = 12.3 Hz, 2H), 2.12 (t, J = 11.4 Hz, 2H), 2.59 – 2.72 (m, 2H), 3.37 – 3.49 (m, 3H), 3.82 (d, J = 8.1 Hz, 2H), 3.99 (d, J = 10.6 Hz, 2H), 4.90 (d, J = 6.1 Hz, 2H), 6.38 (t, J = 6.2 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.45 – 7.53 (m, 1H), 8.02 (s, 1H), 11.66 (s, 1H). EXAMPLE 187 3-(2,2-Difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3- b]pyridin-4-amine Purity based on LC-MS: 94% LRMS (m/z): 385 [M+1]+ LCMS 1 r.t. (min.): 1.01 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 11.14 (m, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.47 (m, 1H), 7.00 (s, 1H), 6.65 (m, 2H), 6.26 (t, J = 5.5 Hz, 1H), 6.09 (d, J = 5.5 Hz, 1H), 4.37 (d, J = 5.5 Hz, 2H), 3.47 – 3.35 (m, 4H), 3.22 (m, 1H), 2.82 – 2.66 (m, 4H), 1.97 (m, 1H), 1.74 (m, 1H). EXAMPLE 188 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.53 EXAMPLE 189 N-((2-(3,3-Dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine Purity based on LC-MS: 87% LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 0.88 1H NMR (400 MHz, DMSO-d6) δ 0.99 (s, 6H), 1.24 (s, 2H), 1.50 – 1.69 (m, 3H), 1.88 – 2.01 (m, 2H), 2.76 – 2.84 (m, 2H), 3.56 (t, J = 10.9 Hz, 2H), 3.64 – 3.72 (m, 2H), 3.91 (d, J = 10.6 Hz, 3H), 4.36 (d, J = 5.9 Hz, 2H), 5.97 (d, J = 5.5 Hz, 1H), 6.14 (t, J = 6.3 Hz, 1H), 6.52 (d, J = 5.0 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 5.0 Hz, 1H), 10.99 (s, 1H). EXAMPLE 190 (1R,4r)-4-(4-(((6-((R)-3-Methylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol Purity based on LC-MS: 94% LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 0.89 1H NMR (400 MHz, DMSO-d6) δ 0.99 (d, J = 6.2 Hz, 6H), 1.36 – 1.42 (m, 2H), 1.86 (d, J = 9.3 Hz, 2H), 2.00 (d, J = 10.7 Hz, 2H), 2.15 – 2.23 (m, 2H), 2.68 – 2.77 (m, 2H), 2.84 – 2.98 (m, 2H), 3.39 – 3.48 (m, 1H), 4.08 – 4.15 (m, 2H), 4.54 (d, J = 4.0 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 6.52 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 7.39 – 7.46 (m, 1H), 8.02 (s, 1H), 11.28 (s, 1H). EXAMPLE 191 (1S,4s)-4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)cyclohexan-1-ol Purity based on LC-MS: 93% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 0.99 1H NMR (400 MHz, DMSO-d6) δ 0.99 (d, J = 6.2 Hz, 6H), 1.36 – 1.42 (m, 2H), 1.86 (d, J = 9.3 Hz, 2H), 2.00 (d, J = 10.7 Hz, 2H), 2.15 – 2.23 (m, 2H), 2.68 – 2.77 (m, 2H), 2.84 – 2.98 (m, 2H), 3.39 – 3.48 (m, 1H), 4.08 – 4.15 (m, 2H), 4.54 (d, J = 4.0 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 6.52 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 7.39 – 7.46 (m, 1H), 8.02 (s, 1H), 11.28 (s, 1H). EXAMPLE 192 N-((6-(Piperidin-4-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine Purity based on LC-MS: 96% LRMS (m/z): 392 [M+1]+ LCMS 1 r.t. (min.): 0.87 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.77 (d, J = 5.4 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.19 (dd, J = 13.5, 7.6 Hz, 2H), 6.91 (d, J = 2.1 Hz, 1H), 6.34 (s, 2H), 6.10 (d, J = 5.5 Hz, 1H), 4.53 (d, J = 5.1 Hz, 2H), 4.00 – 3.88 (m, 2H), 3.58 (t, J = 10.9 Hz, 2H), 3.06 (d, J = 11.7 Hz, 2H), 2.81 (t, J = 12.1 Hz, 2H), 2.71 – 2.56 (m, 2H), 1.98 (d, J = 11.2 Hz, 2H), 1.80 (d, J = 10.2 Hz, 2H), 1.71 – 1.55 (m, 4H). EXAMPLE 193 5-(Tetrahydro-2H-pyran-4-yl)-N-((6-(3,3,5,5-tetramethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 93% LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.12 1H NMR (400 MHz, DMSO-d6) δ 1.02 (s, 12H), 1.09 (t, J = 7.0 Hz, 2H), 1.52 – 1.67 (m, 2H), 1.90 (d, J = 11.5 Hz, 2H), 3.34 – 3.42 (m, 3H), 3.55 (t, J = 11.0 Hz, 2H), 3.89 (dd, J = 10.8, 3.0 Hz, 2H), 4.65 (d, J = 5.8 Hz, 2H), 6.43 (d, J = 7.3 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 6.66 (t, J = 6.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 8.01 (s, 1H), 11.35 (s, 1H). EXAMPLE 194 N-((6-(Piperidin-4-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine Purity based on LC-MS: 93% LRMS (m/z): 393 [M+1]+ LCMS 1 r.t. (min.): 0.89 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.11 (dd, J = 17.5, 7.6 Hz, 2H), 6.91 (dd, J = 11.7, 6.1 Hz, 1H), 6.40 (s, 2H), 4.81 (d, J = 5.5 Hz, 2H), 3.92 (dd, J = 11.3, 2.9 Hz, 4H), 2.97 – 2.84 (m, 4H), 2.03 – 1.79 (m, 6H), 1.63 (dq, J = 20.9, 7.9, 6.2 Hz, 2H). EXAMPLE 195 N-((6-(3,3-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 422 [M+1]+ LCMS 1 r.t. (min.): 1.64 1H NMR (400 MHz, DMSO-d6) δ 1.19 (s, 6H), 1.66 – 1.83 (m, 4H), 3.11 – 3.22 (m, 2H), 3.55 – 3.62 (m, 4H), 3.64 – 3.73 (m, 4H), 3.90 (d, J = 10.8 Hz, 3H), 4.75 (d, J = 5.8 Hz, 2H), 6.63 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 7.51 – 7.57 (m, 1H), 7.66 (s, 1H), 7.79 (s, 1H), 9.03 (s, 2H). EXAMPLE 196 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((1s,4S)-4- fluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 97% LRMS (m/z): 438 [M+1]+ LCMS 1 r.t. (min.): 1.35 1H NMR (400 MHz, DMSO-d6) δ 0.99 (d, J = 6.2 Hz, 6H), 1.57 – 1.76 (m, 4H), 1.81 – 1.92 (m, 3H), 1.97 (d, J = 10.1 Hz, 2H), 2.11 – 2.23 (m, 2H), 2.63 – 2.77 (m, 2H), 3.08 (t, J = 11.4 Hz, 1H), 4.10 (d, J = 11.9 Hz, 2H), 4.65 (d, J = 5.7 Hz, 2H), 6.51 (d, J = 7.3 Hz, 1H), 6.60 – 6.67 (m, 2H), 6.90 (d, J = 2.1 Hz, 1H), 7.38 – 7.45 (m, 1H), 8.02 (s, 1H), 11.32 (s, 1H). EXAMPLE 197 N-((6-((3S,5R)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(4-methoxycyclohexyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.44 EXAMPLE 198 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1H-indol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 453 [M+1]+ LCMS 1 r.t. (min.): 1.29 1H NMR (400 MHz, DMSO-d6) δ 0.89 (d, J = 6.2 Hz, 6H), 1.95 – 2.08 (m, 3H), 2.53 – 2.64 (m, 2H), 3.85 (d, J = 10.0 Hz, 2H), 4.49 (d, J = 5.5 Hz, 2H), 5.85 (t, J = 5.6 Hz, 1H), 6.40 – 6.44 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 6.4 Hz, 1H), 7.08 – 7.13 (m, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.32 – 7.41 (m, 3H), 8.18 (s, 1H), 11.22 (s, 1H), 11.84 (s, 1H). EXAMPLE 199 5-(Tetrahydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 92% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 0.97 1H NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.1 Hz, 6H), 1.52 – 1.68 (m, 2H), 1.90 (d, J = 11.6 Hz, 2H), 2.05 – 2.13 (m, 2H), 2.16 (s, 3H), 2.40 – 2.47 (m, 2H), 3.21 – 3.28 (m, 1H), 3.54 (t, J = 10.9 Hz, 2H), 3.89 (dd, J = 11.2, 3.0 Hz, 2H), 4.08 (d, J = 12.1 Hz, 2H), 4.65 (d, J = 5.8 Hz, 2H), 6.51 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.70 (t, J = 5.8 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 7.4 Hz, 1H), 8.02 (s, 1H), 11.36 (s, 1H). EXAMPLE 200 N-((6-(3-Aminoazetidin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 92% LRMS (m/z): 380 [M+1]+ LCMS 1 r.t. (min.): 0.80 1H NMR (400 MHz, DMSO-d6) δ 1.18 – 1.30 (m, 2H), 1.54 – 1.69 (m, 3H), 1.92 (d, J = 14.2 Hz, 2H), 3.56 (t, J = 10.9 Hz, 2H), 3.67 (dd, J = 8.4, 5.4 Hz, 2H), 3.87 – 3.96 (m, 3H), 4.14 (t, J = 7.8 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 6.25 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 6.76 (t, J = 5.6 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 7.39 – 7.46 (m, 1H), 8.03 (s, 1H), 11.37 (s, 1H). EXAMPLE 201 5-(3,6-Dihydro-2H-pyran-4-yl)-4-((5-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-3- yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine Purity based on LC-MS: 97% LRMS (m/z): 421 [M+1]+ LCMS 1 r.t. (min.): 1.11 1H NMR (400 MHz, Methanol-d4) δ 1.17 – 1.47 (m, 6H), 2.06 (s, 2H), 2.40 – 2.71 (m, 4H), 3.87 (q, J = 4.8 Hz, 2H), 4.01 – 4.27 (m, 2H), 5.65 (s, 2H), 6.19 – 6.37 (m, 1H), 7.30 (s, 1H), 7.65 (s, 1H), 8.22 (d, J = 1.4 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H). EXAMPLE 202 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 490 [M+1]+ LCMS 1 r.t. (min.): 1.55 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.02 (s, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.89 (s, 1H), 6.83 (t, J = 5.9 Hz, 1H), 6.69 (s, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.19 (d, J = 10.4 Hz, 2H), 3.89 (dd, J = 11.2, 3.1 Hz, 2H), 3.56 (t, J = 10.9 Hz, 2H), 2.74 – 2.60 (m, 2H), 2.28 – 2.17 (m, 2H), 1.90 (d, J = 13.7 Hz, 2H), 1.60 (qd, J = 12.3, 4.1 Hz, 4H), 0.97 (d, J = 6.2 Hz, 6H). EXAMPLE 203 3-(2,2-Difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-amine Purity based on LC-MS: 95% LRMS (m/z): 413 [M+1]+ LCMS 1 r.t. (min.): 1.12 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.49 – 7.40 (m, 1H), 7.00 (s, 1H), 6.65 (t, J = 7.5 Hz, 2H), 6.24 (t, J = 5.6 Hz, 1H), 6.10 (d, J = 5.5 Hz, 1H), 4.37 (d, J = 5.6 Hz, 2H), 4.14 (d, J = 12.1 Hz, 2H), 3.28 – 3.16 (m, 1H), 2.79 – 2.62 (m, 2H), 2.19 (t, J = 11.3 Hz, 2H), 2.03 – 1.85 (m, 1H), 1.81 – 1.62 (m, 1H), 1.01 (d, J = 6.2 Hz, 6H). EXAMPLE 204 N-((6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 94% LRMS (m/z): 406 [M+1]+ LCMS 1 r.t. (min.): 0.90 1H NMR (400 MHz, DMSO-d6) δ 1.55 – 1.71 (m, 3H), 1.79 (d, J = 9.4 Hz, 1H), 1.88 – 1.95 (m, 2H), 2.79 (d, J = 9.6 Hz, 1H), 2.90 (d, J = 8.2 Hz, 1H), 3.43 – 3.47 (m, 1H), 3.52 (d, J = 11.7 Hz, 2H), 3.76 (s, 1H), 3.86 – 3.94 (m, 1H), 4.06 – 4.12 (m, 4H), 4.59 – 4.70 (m, 2H), 6.31 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 6.72 (t, J = 5.6 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 7.34 – 7.43 (m, 1H), 8.03 (s, 1H), 11.37 (s, 1H). EXAMPLE 205 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 92% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.15 1H NMR (400 MHz, DMSO-d6) δ 0.87 (d, J = 6.3 Hz, 6H), 1.52 – 1.69 (m, 2H), 1.90 – 1.98 (m, 2H), 2.01 – 2.10 (m, 2H), 2.20 (s, 3H), 2.58 – 2.65 (m, 2H), 3.52 (t, J = 10.9 Hz, 3H), 3.85 – 3.96 (m, 4H), 4.65 (d, J = 5.0 Hz, 2H), 6.52 (t, J = 5.0 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 11.36 (s, 1H). EXAMPLE 206 5-(3,6-Dihydro-2H-pyran-4-yl)-4-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine Purity based on LC-MS: 100% LRMS (m/z): 421 [M+1]+ LCMS 1 r.t. (min.): 0.72 1H NMR (400 MHz, Methanol-d4) δ 1.36 (d, J = 6.5 Hz, 6H), 2.52 (d, J = 1.7 Hz, 2H), 2.85 (dd, J = 13.9, 11.5 Hz, 4H), 3.82 (t, J = 5.5 Hz, 2H), 4.13 (q, J = 2.6 Hz, 2H), 4.21 (d, J = 13.8 Hz, 2H), 5.57 (s, 4H), 6.19 – 6.36 (m, 2H), 7.03 (dd, J = 6.4, 2.7 Hz, 2H), 7.24 (d, J = 2.6 Hz, 1H), 7.28 (s, 1H), 8.24 (d, J = 6.4 Hz, 1H), 8.36 (s, 1H). EXAMPLE 207 N-((6-(2,5-Diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 95% LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 0.98 1H NMR (400 MHz, DMSO-d6) δ 1.55 – 1.94 (m, 4H), 3.50 – 3.60 (m, 5H), 3.84 – 3.95 (m, 4H), 4.21 – 4.27 (m, 2H), 4.64 (d, J = 5.8 Hz, 3H), 6.27 (s, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 6.91 (s, 1H), 7.32 – 7.41 (m, 1H), 8.03 (s, 1H), 11.37 (s, 1H). EXAMPLE 208 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran- 4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Purity based on LC-MS: 95% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.91 1H NMR (400 MHz, DMSO-d6) δ 1.00 (d, J = 3.9 Hz, 3H), 1.02 (d, J = 3.9 Hz, 3H), 1.53 (d, J = 6.7 Hz, 3H), 1.61 – 1.91 (m, 4H), 2.16 – 2.28 (m, 2H), 2.65 – 2.80 (m, 2H), 3.41 – 3.58 (m, 3H), 3.65 – 3.74 (m, 1H), 3.82 – 3.88 (m, 1H), 3.93 – 3.99 (m, 1H), 4.15 (t, J = 13.4 Hz, 2H), 5.37 (p, J = 6.7 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.66 (d, J = 7.3 Hz, 2H), 6.71 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 8.4, 7.3 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.81 (s, 1H). EXAMPLE 209 N-((6-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 94% LRMS (m/z): 406 [M+1]+ LCMS 1 r.t. (min.): 0.90 1H NMR (400 MHz, DMSO-d6) δ 1.07 (s, 6H), 1.57 – 1.69 (m, 3H), 1.75 (d, J = 8.8 Hz, 1H), 1.91 (d, J = 12.5 Hz, 2H), 2.76 (d, J = 9.5 Hz, 1H), 2.87 (d, J = 8.0 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 3.44 (dd, J = 9.3, 2.0 Hz, 1H), 3.54 (t, J = 11.7 Hz, 2H), 3.68 (s, 1H), 3.85 – 3.92 (m, 2H), 4.61 – 4.70 (m, 3H), 6.30 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 6.71 (t, J = 5.7 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 7.34 – 7.41 (m, 1H), 8.03 (s, 1H), 11.37 (s, 1H). EXAMPLE 210 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 490 [M+1]+ LCMS 1 r.t. (min.): 1.67 1H NMR (400 MHz, DMSO-d6) δ 0.73 (d, J = 6.0 Hz, 6H), 1.61 (qd, J = 12.4, 4.2 Hz, 2H), 1.92 (d, J = 10.9 Hz, 2H), 2.04 – 2.16 (m, 2H), 3.17 (d, J = 4.4 Hz, 1H), 3.23 (d, J = 11.5 Hz, 1H), 3.54 (t, J = 10.9 Hz, 2H), 3.89 (dd, J = 11.2, 3.1 Hz, 2H), 3.95 (d, J = 12.1 Hz, 2H), 4.09 (d, J = 5.1 Hz, 1H), 4.89 (d, J = 5.4 Hz, 2H), 6.52 (t, J = 6.0 Hz, 1H), 6.71 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.98 (s, 1H), 11.34 (s, 1H). EXAMPLE 211 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine Purity based on LC-MS: 97% LRMS (m/z): 489 [M+1]+ LCMS 1 r.t. (min.): 1.47 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, J = 6.2 Hz, 6H), 1.60 (qd, J = 12.4, 4.1 Hz, 2H), 1.88 – 2.02 (m, 2H), 2.25 – 2.37 (m, 2H), 2.57 – 2.69 (m, 2H), 3.52 (t, J = 10.9 Hz, 3H), 3.89 (dd, J = 11.2, 2.9 Hz, 2H), 4.12 (d, J = 12.3 Hz, 2H), 4.61 (d, J = 5.7 Hz, 2H), 5.96 (d, J = 6.1 Hz, 1H), 6.00 (d, J = 5.6 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.89 (s, 1H), 7.72 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 10.97 (s, 1H). EXAMPLE 212 4-(((6-(3,3-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 94% LRMS (m/z): 446 [M+1]+ LCMS 1 r.t. (min.): 1.63 1H NMR (400 MHz, DMSO-d6) δ 1.00 (s, 6H), 1.56 (q, J = 12.0 Hz, 2H), 1.81 (d, J = 11.7 Hz, 2H), 2.95 (s, 2H), 3.18 – 3.26 (m, 2H), 3.41 – 3.50 (m, 4H), 3.82 (d, J = 8.1 Hz, 2H), 4.93 (d, J = 6.4 Hz, 2H), 6.39 (t, J = 6.5 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.49 – 7.56 (m, 1H), 8.01 (s, 1H), 11.68 (s, 1H). EXAMPLE 213 N-((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 1.16 1H NMR (400 MHz, DMSO-d6) δ 11.29 - 11.55 (m, 1 H), 8.17 (s, 1 H), 8.07 (s, 1 H), 7.86 (s, 1 H), 6.92 (d, J=1.72 Hz, 1 H), 5.97 - 6.11 (m, 1 H), 5.38 - 5.51 (m, 1 H), 4.13 - 4.30 (m, 2 H), 3.84 - 3.99 (m, 2 H), 3.43 - 3.60 (m, 2 H), 3.12 - 3.26 (m, 1 H), 2.65 - 2.81 (m, 2 H), 2.23 - 2.38 (m, 3 H), 1.81 - 1.97 (m, 2 H), 1.47 - 1.72 (m, 5 H), 0.93 - 1.09 (m, 6 H). EXAMPLE 214 4-(4-(((6-((3S,5R)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol Purity based on LC-MS: 100% LRMS (m/z): 438 [M+1]+ LCMS 1 r.t. (min.): 0.86 1H NMR (400 MHz, DMSO-d6) δ 11.78 – 10.97 (m, 1H), 8.66 (t, J = 5.4 Hz, 1H), 8.08 (s, 1H), 7.45 – 7.34 (m, 1H), 6.98 (s, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 7.3 Hz, 1H), 6.02 (s, 1H), 4.61 (d, J = 5.4 Hz, 2H), 4.19 (d, J = 10.4 Hz, 2H), 3.78 (t, J = 10.5 Hz, 2H), 3.72 – 3.54 (m, 2H), 2.79 – 2.68 (m, 2H), 2.22 – 2.13 (m, 3H), 1.94 (dd, J = 18.9, 10.0 Hz, 2H), 1.82 (d, J = 13.4 Hz, 2H), 1.02 (d, J = 6.2 Hz, 6H). EXAMPLE 215 N-((6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 96% LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 0.98 1H NMR (400 MHz, DMSO-d6) δ 1.57 – 1.74 (m, 6H), 1.91 (d, J = 11.4 Hz, 2H), 2.87 (d, J = 10.2 Hz, 2H), 3.20 – 3.25 (m, 1H), 3.54 (t, J = 10.8 Hz, 2H), 3.60 (s, 2H), 3.82 – 3.94 (m, 4H), 4.65 (d, J = 5.7 Hz, 2H), 6.51 (d, J = 2.2 Hz, 1H), 6.53 (s, 1H), 6.70 (t, J = 5.8 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 7.39 – 7.45 (m, 1H), 8.03 (s, 1H), 11.38 (s, 1H). EXAMPLE 216 4-(((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 98% LRMS (m/z): 460 [M+1]+ LCMS 1 r.t. (min.): 1.82 1H NMR (400 MHz, DMSO-d6) δ 1.02 (t, J = 7.0 Hz, 6H), 1.25 (d, J = 9.4 Hz, 1H), 1.50 (d, J = 6.6 Hz, 3H), 1.60 (d, J = 6.5 Hz, 1H), 2.20 – 2.37 (m, 3H), 2.77 – 2.94 (m, 2H), 3.76 – 3.86 (m, 2H), 4.05 – 4.16 (m, 6H), 5.40 – 5.49 (m, 1H), 5.86 (s, 1H), 6.28 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.48 – 7.56 (m, 1H), 8.07 (s, 1H), 11.98 (s, 1H). EXAMPLE 217 3-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol Purity based on LC-MS: 94% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.01 1H NMR (400 MHz, DMSO-d6) δ 0.99 (d, J = 6.2 Hz, 6H), 1.04 – 1.33 (m, 4H), 1.45 – 1.58 (m, 1H), 1.65 – 1.77 (m, 1H), 1.83 – 2.00 (m, 3H), 2.13 – 2.24 (m, 3H), 2.63 – 2.78 (m, 2H), 2.93 – 3.07 (m, 1H), 3.54 – 3.67 (m, 1H), 4.06 – 4.15 (m, 2H), 4.57 – 4.74 (m, 2H), 6.52 (d, J = 7.3 Hz, 1H), 6.57 (t, J = 5.6 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 8.4, 7.4 Hz, 1H), 8.02 (s, 1H), 11.30 (s, 1H). EXAMPLE 218 3-(3,6-Dihydro-2H-pyran-4-yl)-4-(((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2- yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 97% LRMS (m/z): 445 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, DMSO-d6) δ 0.98 (d, J = 6.2 Hz, 6H), 2.25 – 2.37 (m, 3H), 2.39 – 2.47 (m, 2H), 2.57 – 2.70 (m, 2H), 3.87 (t, J = 5.4 Hz, 2H), 4.14 – 4.27 (m, 2H), 4.83 (d, J = 4.6 Hz, 2H), 5.83 (s, 1H), 6.78 (d, J = 6.4 Hz, 1H), 7.29 (s, 2H), 8.12 (s, 1H), 8.16 (d, J = 6.3 Hz, 1H), 11.92 (s, 1H). EXAMPLE 219 4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorotetrahydro-2H-pyran-4-ol Purity based on LC-MS: 98% LRMS (m/z): 456 [M+1]+ LCMS 1 r.t. (min.): 0.87 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.50 (t, J = 5.3 Hz, 1H), 8.09 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 7.1 Hz, 1H), 6.54 (s, 1H), 4.84 (ddd, J = 46.7, 9.2, 4.9 Hz, 1H), 4.71 – 4.54 (m, 2H), 4.28 (s, 2H), 3.85 – 3.66 (m, 4H), 3.65 – 3.56 (m, 1H), 3.01 – 2.71 (m, 2H), 2.42 – 2.24 (m, 2H), 2.09 – 1.85 (m, 2H), 1.09 (d, J = 3.2 Hz, 6H). EXAMPLE 220 N-((6-(3,8-Diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 87% LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 1.02 EXAMPLE 221 N-((4-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 0.65 1H NMR (400 MHz, DMSO-d6) δ 11.55 – 10.65 (m, 1H), 8.07 (s, 1H), 6.91 (s, 1H), 6.67 (t, J = 4.7 Hz, 1H), 6.60 (s, 1H), 4.63 – 4.51 (m, J = 4.7 Hz, 2H), 4.19 (s, 2H), 3.94 (dd, J = 11.1, 3.1 Hz, 2H), 3.56 (t, J = 11.0 Hz, 2H), 3.18 (t, J = 11.7 Hz, 1H), 2.57 (s, 2H), 2.29 (s, 3H), 2.24 (s, 2H), 2.07 – 1.91 (m, 2H), 1.64 (qd, J = 12.5, 4.1 Hz, 2H), 0.94 (d, J = 6.2 Hz, 6H). EXAMPLE 222 N-((6-((1R*,4R*)-2,5-Diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 0.93 EXAMPLE 223 N-((6-((1S*,4S*)-2,5-Diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 420 [M+1]+ LCMS 1 r.t. (min.): 0.93 EXAMPLE 224 N-((S)-1-(4-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 0.93 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 6.3 Hz, 1H), 8.08 (s, 1H), 6.91 (d, J = 0.8 Hz, 1H), 6.66 (d, J = 6.4 Hz, 1H), 5.22 (q, J = 6.7 Hz, 2H), 4.57 (s, 1H), 4.35 (s, 2H), 4.07 (t, J = 11.4 Hz, 2H), 3.77 – 3.64 (m, 2H), 2.87 – 2.66 (m, 3H), 2.50 – 2.39 (m, 2H), 2.08 (d, J = 12.3 Hz, 2H), 1.80 (ddt, J = 25.4, 13.4, 6.6 Hz, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H). EXAMPLE 225 4-(((S)-1-(6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 91% LRMS (m/z): 461 [M+1]+ LCMS 1 r.t. (min.): 1.50 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.23 (s, J = 10.6 Hz, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.09 (s, 1H), 5.85 – 5.77 (m, 1H), 5.51 (quint, 1H), 4.18 – 4.04 (m, 2H), 3.99 – 3.90 (m, 1H), 3.87 – 3.78 (m, 1H), 3.48 (t, J = 11.3 Hz, 1H), 3.40 – 3.34 (m, 1H), 3.21 – 3.10 (m, 1H), 2.85 – 2.64 (m, 2H), 2.39 – 2.21 (m, 2H), 1.96 – 1.87 (m, 1H), 1.85 – 1.77 (m, 1H), 1.74 – 1.65 (m, 1H), 1.63 (d, J = 6.5 Hz, 3H), 1.58 – 1.49 (m, 1H), 1.02 – 0.92 (m, 6H). EXAMPLE 226 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-3,5-dimethylpyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 97% LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.26 1H NMR (400 MHz, DMSO-d6) δ 0.95 (d, J = 6.3 Hz, 6H), 1.56 – 1.71 (m, 2H), 1.89 – 2.01 (m, 2H), 2.09 (s, 3H), 2.16 (s, 3H), 2.36 – 2.46 (m, 2H), 3.05 – 3.28 (m, 5H), 3.58 (t, J = 11.2 Hz, 2H), 3.84 – 3.96 (m, 2H), 4.70 (d, J = 5.3 Hz, 2H), 6.53 (s, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.31 (s, 1H), 8.01 (s, 1H), 11.33 (s, 1H). EXAMPLE 227 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 93% LRMS (m/z): 450 [M+1]+ LCMS 1 r.t. (min.): 1.24 1H NMR (400 MHz, Chloroform-d) δ 1.15 (d, J = 6.3 Hz, 6H), 1.20 (d, J = 6.2 Hz, 6H), 1.24 – 1.36 (m, 2H), 2.02 (d, J = 13.1 Hz, 2H), 2.38 – 2.48 (m, 2H), 2.90 – 3.01 (m, 2H), 3.07 (t, J = 11.9 Hz, 1H), 3.58 – 3.68 (m, 2H), 4.16 – 4.23 (m, 2H), 4.80 (d, J = 4.7 Hz, 2H), 5.99 – 6.07 (m, 1H), 6.55 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.78 (s, 1H), 7.47 (dd, J = 8.4, 7.4 Hz, 1H), 8.35 (s, 1H), 9.41 (s, 1H). EXAMPLE 228 4-(((4-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Purity based on LC-MS: 98% LRMS (m/z): 461 [M+1]+ LCMS 1 r.t. (min.): 0.94 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br b, 1H), 8.01 (s, 1H), 7.02 (s, 1H), 6.91 (t, J = 4.5 Hz, 1H), 6.63 (s, 1H), 4.77 (d, J = 4.4 Hz, 2H), 4.12 (s, 1H), 3.93 – 3.77 (m, 2H), 3.48 (t, J = 11.1 Hz, 2H), 2.54 (s, 2H), 2.32 (s, 3H), 2.25 (dd, J = 11.5, 9.7 Hz, 4H), 1.89 (d, J = 12.9 Hz, 2H), 1.56 (qd, J = 12.7, 4.0 Hz, 2H), 0.90 (d, J = 6.1 Hz, 6H). EXAMPLE 229 (3S*,4S*)-4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol Purity based on LC-MS: 99% LRMS (m/z): 438 [M+1]+ LCMS 1 r.t. (min.): 0.86 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.02 (s, 1H), 7.55 (t, J = 5.8 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 7.3 Hz, 1H), 5.66 (d, J = 4.7 Hz, 1H), 4.67 – 4.50 (m, 2H), 4.21 (d, J = 11.7 Hz, 2H), 3.92 – 3.76 (m, 2H), 3.48 – 3.34 (m, 2H), 3.09 (t, J = 10.4 Hz, 1H), 2.98 – 2.90 (m, 1H), 2.90 – 2.71 (m, 2H), 2.37 – 2.17 (m, 2H), 1.97 – 1.76 (m, 2H), 1.06 (d, J = 5.9 Hz, 6H). EXAMPLE 230 (3R*,4R*)-4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol Purity based on LC-MS: 99% LRMS (m/z): 438 [M+1]+ LCMS 1 r.t. (min.): 0.86 1H NMR (400 MHz, DMSO-d6) δ 11.60 – 11.16 (m, 1H), 8.03 (s, 1H), 7.54 (t, J = 5.8 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 5.90 – 5.43 (m, 1H), 4.70 – 4.48 (m, 2H), 4.15 (d, J = 11.9 Hz, 2H), 3.94 – 3.75 (m, 2H), 3.40 (dd, J = 13.5, 10.4 Hz, 2H), 3.09 (t, J = 10.4 Hz, 1H), 3.00 – 2.89 (m, 1H), 2.80 – 2.68 (m, 2H), 2.26 – 2.12 (m, J = 11.3 Hz, 3H), 1.96 – 1.74 (m, 2H), 1.02 (d, J = 6.2 Hz, 6H). EXAMPLE 231 (3S*,4R*)-4-(4-(((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol Purity based on LC-MS: 98% LRMS (m/z): 438 [M+1]+ LCMS 1 r.t. (min.): 0.71 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.01 (s, 1H), 7.45 – 7.35 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 4.83 (d, J = 4.8 Hz, 1H), 4.62 (qd, J = 16.4, 5.9 Hz, 2H), 4.22 – 4.10 (m, 2H), 3.93 – 3.87 (m, 1H), 3.78 – 3.70 (m, 2H), 3.63 (d, J = 10.8 Hz, 1H), 3.50 (t, J = 10.9 Hz, 1H), 3.40 – 3.33 (m, 1H), 2.89 – 2.70 (m, 2H), 2.31 – 2.09 (m, 3H), 1.49 (d, J = 13.2 Hz, 1H), 1.10 – 0.98 (m, 6H). EXAMPLE 232 (3R*,4S*)-4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol Purity based on LC-MS: 98% LRMS (m/z): 438 [M+1]+ LCMS 1 r.t. (min.): 0.71 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.02 (s, 1H), 7.48 – 7.33 (m, 2H), 6.95 (d, J = 2.2 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 4.84 (d, J = 5.0 Hz, 1H), 4.63 (qd, J = 16.2, 5.5 Hz, 2H), 4.23 – 4.13 (m, 2H), 3.95 – 3.87 (m, 1H), 3.79 – 3.71 (m, 2H), 3.64 (d, J = 10.5 Hz, 1H), 3.51 (t, J = 10.6 Hz, 1H), 3.35 (s, 1H), 2.85 – 2.73 (m, 2H), 2.34 – 2.13 (m, 3H), 1.50 (d, J = 12.8 Hz, 1H), 1.04 (d, J = 5.4 Hz, 6H). EXAMPLE 233 N-((4-(4,7-Diazaspiro[2.5]octan-7-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 91% LRMS (m/z): 421 [M+1]+ LCMS 1 r.t. (min.): 0.63 EXAMPLE 234 5-(2,2-Difluoro-3-methylcyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 94% LRMS (m/z): 400 [M+1]+ LCMS 1 r.t. (min.): 1.36 1H NMR (400 MHz, Methanol-d4) δ 8.58 – 8.50 (m, 1H), 8.23 (t, J = 4.4 Hz, 1H), 8.09 (s, 1H), 7.22 – 7.15 (m, 1H), 7.00 (s, 1H), 6.67 – 6.56 (m, 2H), 4.73 (s, 2H), 3.93 – 3.83 (m, 2H), 3.83 – 3.72 (m, 2H), 2.95 – 2.87 (m, 2H), 2.87 – 2.81 (m, 2H), 1.40 – 1.32 (m, 3H), 1.30 (d, J = 7.1 Hz, 3H). EXAMPLE 235 N-(1-(4-(3,3-Dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 99% LRMS (m/z): 437 [M+1]+ LCMS 1 r.t. (min.): 0.89 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.28 (s, 1H), 8.17 (d, J = 6.3 Hz, 1H), 8.10 (s, 1H), 6.86 (d, J = 6.5 Hz, 1H), 6.73 (d, J = 6.3 Hz, 1H), 5.21 – 5.03 (m, 1H), 4.06 – 3.92 (m, 2H), 3.63 – 3.51 (m, 4H), 2.78 (t, J = 5.1 Hz, 1H), 2.02 – 1.89 (m, 2H), 1.65 (dd, J = 42.3, 9.0 Hz, 2H), 1.53 (d, J = 6.7 Hz, 3H), 1.00 (s, 3H), 0.97 (s, 3H). EXAMPLE 236 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R*,4R*)-2- methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 95% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, Chloroform-d) δ 1.14 (d, J = 6.1 Hz, 9H), 1.29 – 1.45 (m, 1H), 1.62 (qd, J = 12.5, 4.3 Hz, 1H), 1.81 – 2.00 (m, 2H), 2.77 – 2.98 (m, 3H), 3.08 (s, 2H), 3.49 (dd, J = 13.5, 8.6 Hz, 2H), 4.01 (dd, J = 11.4, 3.3 Hz, 1H), 4.16 (d, J = 13.7 Hz, 2H), 4.80 (d, J = 5.5 Hz, 2H), 5.67 (t, J = 5.3 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.80 (s, 1H), 7.41 – 7.49 (m, 1H), 8.13 (s, 1H), 10.85 (s, 1H). EXAMPLE 237 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2S*,4S*)-2- methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 97% LRMS (m/z): 436 [M+1]+ LCMS 1 r.t. (min.): 1.04 1H NMR (400 MHz, Chloroform-d) δ 1.14 (d, J = 6.1 Hz, 9H), 1.29 – 1.45 (m, 1H), 1.62 (qd, J = 12.5, 4.3 Hz, 1H), 1.81 – 2.00 (m, 2H), 2.77 – 2.98 (m, 3H), 3.08 (s, 2H), 3.49 (dd, J = 13.5, 8.6 Hz, 2H), 4.01 (dd, J = 11.4, 3.3 Hz, 1H), 4.16 (d, J = 13.7 Hz, 2H), 4.80 (d, J = 5.5 Hz, 2H), 5.67 (t, J = 5.3 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.80 (s, 1H), 7.41 – 7.49 (m, 1H), 8.13 (s, 1H), 10.85 (s, 1H). 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. (min.): 2.01 1H NMR (500 MHz, Chloroform-d) δ 9.60 (bs, 1H), 8.23 (s, 1H), 6.96 – 6.90 (m, 1H), 6.84 (s, 1H), 6.75 (s, 1H), 6.01 (s, 1H), 5.04 (d, J = 4.9 Hz, 2H), 4.21 – 4.12 (m, 2H), 3.97 (ddd, J = 11.7, 4.2, 1.9 Hz, 2H), 3.37 (td, J = 11.8, 1.9 Hz, 2H), 3.00 (ddt, J = 11.1, 6.6, 3.2 Hz, 1H), 2.96 – 2.88 (m, 2H), 2.49 (t, J = 11.6 Hz, 2H), 1.93 (ddd, J = 13.3, 3.8, 1.9 Hz, 2H), 1.79 – 1.67 (m, 2H), 1.14 (d, J = 6.3 Hz, 6H). EXAMPLE 239 5-Cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Purity based on LC-MS: 89% LRMS (m/z): 350 [M+1]+ LCMS 1 r.t. (min.): 1.71 1H NMR (400 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.58 – 7.52 (m, 1H), 7.37 (d, J = 2.7 Hz, 1H), 6.74 – 6.67 (m, 2H), 6.43 – 6.40 (m, 1H), 4.73 (s, 2H), 3.53 – 3.46 (m, 4H), 2.93 – 2.85 (m, 4H), 2.21 – 2.09 (m, 1H), 1.04 – 0.97 (m, 2H), 0.78 – 0.70 (m, 2H). EXAMPLE 240 N-((6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5- (tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 490 [M+1]+ LCMS 1 r.t. (min.): 2.17 1H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.53 (d, J = 2.8 Hz, 1H), 6.85 (s, 1H), 6.81 (s, 1H), 6.67 (d, J = 2.8 Hz, 1H), 4.86 (s, 2H), 4.25 – 4.18 (m, 2H), 4.06 – 3.99 (m, 2H), 3.79 – 3.58 (m, 2H), 3.44 – 3.35 (m, 1H), 2.83 – 2.72 (m, 2H), 2.41 – 2.32 (m, 2H), 1.96 – 1.79 (m, 4H), 1.05 (d, J = 6.4 Hz, 6H). EXAMPLE 241 N-((6-(4,7-Diazaspiro[2.5]octan-7-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Purity based on LC-MS: 100% LRMS (m/z): 488 [M+1]+ LCMS 1 r.t. (min.): 1.77 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 7.81 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 8.9 Hz, 1H), 6.31 (t, J = 6.1 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 3.73 (dd, J = 11.4, 4.1 Hz,2H), 3.43 – 3.33 (m, 2H), 3.16 - 3.12 (m, 2H), 3.06 - 3.00 (m, 1H), 2.93 (s, 2H), 2.41 (s, 2H), 2.08 (s, 1H), 1.74 (d, J = 13.0 Hz, 2H), 1.51 - 1.37 (m, 2H), -0.00 (t, J = 3.0 Hz, 2H), -0.38 (s, 2H). EXAMPLE 242 5-Cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine Purity based on LC-MS: 99% LRMS (m/z): 350 [M+1]+ LCMS 1 r.t. (min.): 1.05 1H NMR (400 MHz, Chloroform-d) δ 9.43 (bs, 1H), 8.32 (s, 1H), 7.48 (dd, J = 8.5, 7.3 Hz, 1H), 6.97 (t, J = 4.8 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 4.6 Hz, 2H), 3.58 – 3.49 (m, 4H), 3.22 – 2.94 (m, 3H), 2.63 – 2.57 (m, 1H), 2.07 – 1.97 (m, 1H), 0.96 – 0.86 (m, 2H), 0.73 – 0.66 (m, 2H). PHARMACOLOGICAL ACTIVITY In vitro 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 µM. The degree of ADP formation was detected by luminescence (ADP-Glo Kinase Assay from Promega). IC50s of compounds (a 10-point 5-fold serial dilution in 100% DMSO at 25X final test concentration) were measured in a reaction mixture containing the enzyme, ATP and MBP in Kinase Assay Buffer III + 50 µM DTT. The ATP concentration in the reaction was 25 µM and the final concentration of DMSO was 4%. The enzymatic reaction took place for 60 minutes at room temperature. Then, the 5 µl reaction were stopped with 5 µL of ADP-Glo, incubated for 40 minutes and finally added 10 µl of Kinase Detection Reagent. Incubate for 30 minutes and read luminescence on Luminoskan (Thermo Fisher Luminescence reader) Some of the acronyms used above have the following meaning: 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. In the following table 1, IC50 values are represented by letters according to the value: A: < 100 nM B: 100 – <500 nM C: 500- <1000 nM D: ≥ 1000 nM Example IC50 ITK 1 A 2 A 3 A 4 A 5 A 6 A 7 B 8 B 9 B 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 B 23 A 24 B 25 A 26 A 27 A 28 A 29 B 30 B 31 A 32 A 33 A 34 A 35 A 36 A 37 B 38 B 39 A 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 B 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 B 78 A 79 A 80 A 81 A 82 B 83 B 84 B 85 A 86 A 87 A 88 A 89 B 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A 99 A 100 A 101 B 102 A 103 B 104 B 105 B 106 A 107 A 108 B 109 B 110 A 111 A 112 B 113 B 114 A 115 A 116 A 117 B 118 A 119 B 120 A 121 A 122 A 123 A 124 A 125 A 126 B 127 A 128 A 129 A 130 A 131 A 132 B 133 A 134 A 135 A 136 A 137 A 138 B 139 A 140 A 141 A 142 A 143 B 144 B 145 A 146 A 147 B 148 A 149 A 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 B 159 A 160 B 161 B 162 B 163 A 164 A 165 A 166 A 167 B 168 C 169 D 170 D 171 D 172 C 173 D 174 D 175 D 176 C 177 D 178 D 179 D 180 C 181 D 182 C 183 A 184 A 185 A 186 A 187 A 188 A 189 A 190 A 191 B 192 B 193 A 194 A 195 C 196 A 197 A 198 A 199 C 200 B 201 C 202 A 203 A 204 A 205 A 206 C 207 A 208 A 209 B 210 A 211 A 212 A 213 A 214 C 215 A 216 A 217 A 218 A 219 D 220 B 221 A 222 A 223 A 224 A 225 A 226 B 227 A 228 A 229 D 230 A 231 C 232 A 233 A 234 A 235 A 236 A 237 B 238 A 239 B 240 D 241 A 242 A Table 1 It can be seen from Table 1 that the heterobicyclic derivatives of the present invention are potent inhibitors of ITK kinase. Preferred heterobicyclic derivatives of the invention possess an IC50 value for the inhibition of ITK kinase (determined as defined above) of less than 1 µM (1000 nM), preferably of less than 0.5 µM (500 nM), more preferably of less than 0.1 µM (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. Microwave or radio frequency drying may be used for this purpose. 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. Typically, 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, 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. In a preferred embodiment the heterobicyclic derivatives of the present invention may be used in the treatment of dermatological diseases. In a more preferred embodiment 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. Typically 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 as hydroxichloroquine, chloroquine or quinacrine; f) Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; g) JAK inhibitors, such as baricitinib, upadacitinib or abrocitinib h) TYK2 inhibitors such as deucravacitinib i) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine; j) Fumaric acid esters, such as dimethyl fumarate; k) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; l) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; m) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; n) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC- 11050; o) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061; p) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; q) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab; r) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; s) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab; t) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab; u) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; v) Anti-Interleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab; w) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab; x) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab; y) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept; z) Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI- 551 or MOR-208; aa) Anti-IL-1b antibodies such as canakinumab; bb) Anti-IL-alpha antibodies such as bermekimab; cc) Anti-Interleukin 1 Receptor (IL-1R) antibody dd) Anti-CD6 antibodies such as itolizumab; ee) Anti-IL-36/ IL-36R antibodies such as BI-655130 or ANB019; ff) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR-845; gg) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; hh) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; ii) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine; jj) Histamine 4 (H4) receptor antagonists. kk) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast; ll) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant; or mm) 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. In a preferred embodiment the combinations of the invention may be used in the treatment of dermatological diseases. In a more preferred embodiment, 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. Preferably at least two, and more preferably all, of the actives would be administered together at the same time. Preferably, at least two, and more preferably all actives would be administered as an admixture. 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. 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. 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. 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca, comprising administering a therapeutically effective amount of a combination of the heterobicyclic derivatives of the invention together with one or more other therapeutic agents. 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 pustular psoriasis, palmoplantar pustulosis, urticaria, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo, such as these active compounds recited above. 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 pustulosis, urticaria, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo, such as these active compounds recited above.. PHARMACEUTICAL COMPOSITIONS Pharmaceutical compositions according to the present invention comprise the heterobicyclic derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier. As used herein, the term 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. As used herein, 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. 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. 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo. 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. 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 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention. Pharmaceutical compositions according to the present invention comprise the heterobicyclic derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier. As used herein, the term 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. As used herein, 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. The present invention also provides pharmaceutical 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. Preferably the compositions are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration. In a preferred embodiment, the compositions are made up in a form suitable for oral administration. In another preferred embodiment, 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. Such 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. i) 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. Other means of topical administration 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. ii) Oral Administration The heterobicyclic derivatives of the invention may be administered orally (peroral administration; per os (latin)). 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. 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. iii) Oral mucosal administration The heterobicyclic derivatives of the invention can also be administered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) 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. iv) Inhaled administration 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. v) Nasal mucosal administration The heterobicyclic derivatives of the invention may also be administered via the nasal mucosal. Typical 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. 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. vii) 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. viii) Ocular Administration 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. Preferably, 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.

Claims

CLAIMS 1. A 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 C1-4 haloalkyl group, wherein the C3-7 cycloalkyl group, the C6-14 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, a halogen atom, and a –(CH2)0-4-CONR’R’’ group; • B represents a -NR’- group, a -S- atom or -O- atom, • C represents a C6-14 aryl group or a monocyclic 5- to 7-membered heteroaryl group containing at least one heteroatom selected from N, O and S, wherein the C6-14 aryl group and the monocyclic 5- to 7-membered heteroaryl group are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-NR’R’’ group, a –(CH2)0-4-OR’ group, and a –(CH2)0-4-CONR’R’’ group; • D represents a -(CH2)0-4-NRaRb- group, a -O–(CH2)1-4-NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’; • X1, X2, X3, X4 and X5 each independently represent a nitrogen atom, a carbon atom or a - CRc- group; • Z represents a -CH- group or a -NH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group.
2. A heterobicyclic derivative according to claim 1 wherein the compound of Formula (I) is represented by compound of Formula (II): Formula (II) wherein X3 and X5 each independently represents a nitrogen atom or a -CRc- group.
3. A heterobicyclic derivative according to claim 2, wherein X3 represents a -CRc- group, preferably X3 represents a -CH- group.
4. A heterobicyclic derivative according to claim 2, wherein X5 represents a nitrogen atom.
5. A heterobicyclic derivative according to claim 2, wherein X5 represents a -CRc- group, preferably X5 represents a -CH- group.
6. A heterobicyclic derivative according to any one of the preceding claims, wherein A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group.
7. A heterobicyclic derivative according to any one of the preceding claims, wherein B represents a -NR’- group, preferably B represents a -NH- group.
8. A heterobicyclic derivative according to any one of the preceding claims, wherein 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group.
9. A heterobicyclic derivative according to any one of the preceding claims, wherein D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9- membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4- NR’R’’ group.
10. A heterobicyclic derivative according to claim 1 wherein the compound of Formula (I) is represented by Formula (II): Formula (II) wherein, • A represents a C3-6 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 C3-6 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 C1-4 haloalkyl group, a -NR’R’’ group, a–(CH2)0-4- OR’ group, a halogen atom and a -CONR’R’’ group; • B represents a -NR’- group, preferably B represents a -NH- group; • 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 C1-4 alkyl group, a C3-7 cycloalkyl group, a linear or branched C1-4 haloalkyl group, a -OR’ group and a -CONR’R’’ group; • D represents a -NRaRb group, a -O–(CH2)1-4-OH group, a –(CH2)1-4-OH group, or a 4- to 9-membered heterocyclyl group containing at least one N atom, preferably 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 C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)0-4-OR’ group, an oxo group and a –(CH2)0-4-NR’R’’ group; • X3 represents a nitrogen atom or a -CRc- group, preferably X3 represents a -CRc-group, and more preferably X3 represents a -CH- group; • X5 represents a nitrogen atom or a -CRc- group, preferably X3 represents a nitrogen atom or a -CH- group; • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a –(CH2)1-4-OR’ group ; • Ra and Rb are independently selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group, a –(CH2)1-4- OR’ group and a –(CH2)1-4-NR’R’’ group; • Rc is selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl group, a linear or branched C1-4 haloalkyl group and a -CN group; • R’ and R’’ are independently selected from the group consisting of a hydrogen atom, and a linear or branched C1-4 alkyl group.
11. A heterobicyclic derivative according to claim 1 wherein: • 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 pyridyl group, the pyrazinyl group, the pyrimidinyl group, the pyridazinyl group, the pyrrolopyridyl group, the imidazopyridyl group and the indolyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CF3 group, a -NH2 group, a -NHCH3 group, a –OH group, a –(CH2)0-1-OCH3 group, a fluorine atom, a chlorine atom, and a –CONH2 group; • B represents a -NH- group or a -O- atom; • 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 C1-4 alkyl group, a cyclopropyl group, a -CF3 group, a –OCH3 group, and a -CON(CH3)2 group; • D represents a -N(CH3)2 group, a -NH–(CH2)3-OH group, a -N(CH3)-(CH2)2OH group, a - N(CH2CH3)-(CH2)2OH group, a -N(CH3)-(CH2)2OMe group, a -N(CH3)-(CH2)2N(CH3) group, a -O–(CH2)2-OH group, a –(CH2)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[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, the 4,7-diazaspiro[2.5]octanyl group and the 2-oxa-5,8-diazaspiro[3.5]nonanyl group are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a -CH2F group, a -CHF2 group, a -CF3 group, a -OH group, an oxo group, a –NH2 group and a –NHCH3 group; • X1 and X2 represent a carbon atom, • X3 represents a -CRc- group, X4 represent a carbon atom, X5 represents a nitrogen atom or a -CRc- group and Z represents a -NH- group, or X3 represents a -CH- group, X4 and X5 represent a nitrogen atom and Z represents a - CH- group, or X3 represents a N atom, X4 represents a carbon atom, X5 represents a nitrogen atom or a -CRc- group and Z represents a -NH- group; • R1 represents a hydrogen atom or a methyl group; • R2 represents a hydrogen atom, a methyl group, a ethyl group, an isobutyl group, a - CH2CF3 group or a –(CH2)2-OH group; • Rc is selected from the group consisting of a hydrogen atom, a methyl group or a -CN group.
12. A heterobicyclic derivative according to claims 1 to 11 wherein the compound of Formula (I) is one of: 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)-3,5-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-(5-(methylamino)pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 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, 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, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-3-ol, 5-(2-aminopyridin-4-yl)-N-((6-((2-methoxyethyl)(methyl)amino)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-(pyrimidin-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(6-aminopyridin-3-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,3-difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-amino-3-methylpyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 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, 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, N-(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, 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, 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, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(2-(trifluoromethyl)pyridin-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(2-aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)(methyl)amino)ethan-1-ol, 3-((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-(6-((3R,5S)-3,5- dimethylpiperazin-1-yl)pyridin-2-yl)propan-1-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-3- methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-2-methyl- 1H-pyrrolo[2,3-b]pyridin-4-amine, 3-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)propan- 1-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-amino-6-methylpyridin-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-(4-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,4-difluorophenyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (S*)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (R*)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H,1'H-[3,5'-bipyrrolo[2,3- b]pyridin]-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(pyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-fluoropyridin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 5-(3,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2,3-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(3-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,5-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2,5-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(4-fluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4-chlorophenyl)-N-((6-(piperazin-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)-3-(6-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(5-methylpyridin-3-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-methylpyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(3,4-difluorophenyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, 5-(2,3-difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(3,4-difluorophenyl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((3-cyclopropyl-6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(3-(piperazin-1-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,5-difluoro-2-methoxyphenyl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(3-(fluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3-fluoropyridin-4-yl)-N-((6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-isopropyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3-chloropyridin-4-yl)-N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3,4-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, (R*)-5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, (S*)-5-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 3-(2-aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((1S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3-(2-aminopyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(imidazo[1,2-a]pyridin-7-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, 5-(3,4-difluorophenyl)-N-(1-(2-(piperazin-1-yl)pyrimidin-4-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 3-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(1-methyl-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(pyridin-3-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)oxy)ethan-1-ol, N1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2-yl)- N1,N2-dimethylethane-1,2-diamine, 2-(ethyl(6-(((5-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)amino)ethan-1-ol, 5-(3,4-difluorophenyl)-2-methyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)azetidin-3-ol, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)pyrrolidin-3-ol, 5-(2-aminopyridin-4-yl)-N-((2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(1-methyl-1H-pyrazol-4-yl)-N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 5-(2-aminopyridin-4-yl)-N-((4-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2-((6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)(methyl)amino)ethan-1-ol, 4-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperazin-2-one, 2-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-6-((3R,5S)-3,5- dimethylpiperazin-1-yl)-N,N-dimethylnicotinamide, 3-(3,4-difluorophenyl)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridazin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)picolinamide, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyrazin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(6-aminopyrazin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4-aminopyrimidin-2-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(6-aminopyrimidin-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-(6-(methylamino)pyrazin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, (S)-N-(1-(6-(piperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydrofuran-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 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, N-((6-((3R,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-b]pyridin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methyl-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(4,4-difluorocyclohexyl)-N-((6-(piperazin-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-(6-(methylamino)pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-(methylamino)pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(2-(methylamino)pyridin-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-(methylamino)pyridin-4-yl)-N-((6-(3-(trifluoromethyl)piperazin-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)-3-(2-(methylamino)pyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-3-(2- (methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 5-(2-amino-3-fluoropyridin-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)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(2- (methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(3-fluoropyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(pyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, 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, 5-(3,6-dihydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, 5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, (R*)-5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, (S*)-5-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)-2-fluorobenzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(1-methyl-1H-pyrazol-4-yl)-N-((4-(piperidin-4-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, N-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)-2-fluorobenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 1-(6-(((5-(2-aminopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-2- yl)piperidin-4-ol, 5-(2-aminopyridin-4-yl)-N-((1-(piperidin-4-yl)-1H-pyrazol-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, 2-(methyl(6-(((5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)amino)ethan-1-ol, 2-(methyl(6-(((5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-4- (trifluoromethyl)pyridin-2-yl)amino)ethan-1-ol, 5-(2-aminopyridin-4-yl)-N-(3-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)methyl)-5-(pyrimidin-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-((2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(pyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(dimethylamino)pyridin-2-yl)methyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2-aminopyridin-4-yl)-N-((6-(dimethylamino)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2-methylpyrimidin-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(2,2-dimethyltetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine, 4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 3-(2,2-difluorocyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4- amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)propyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((2-(3,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine, (1R,4r)-4-(4-(((6-((R)-3-methylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, (1S,4s)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- amine, 5-(tetrahydro-2H-pyran-4-yl)-N-((6-(3,3,5,5-tetramethylpiperazin-1-yl)pyridin-2-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(piperidin-4-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine, N-((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((1s,4S)-4-fluorocyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(4-methoxycyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-(1H-indol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(tetrahydro-2H-pyran-4-yl)-N-((6-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-(3-aminoazetidin-1-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-4-((5-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)methoxy)- 7H-pyrrolo[2,3-d]pyrimidine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 3-(2,2-difluorocyclopropyl)-N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine, N-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-methylpyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-(3,6-dihydro-2H-pyran-4-yl)-4-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methoxy)- 7H-pyrrolo[2,3-d]pyrimidine, N-((6-(2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 4-(((6-(3,3-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol, N-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 3-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)cyclohexan-1-ol, 3-(3,6-dihydro-2H-pyran-4-yl)-4-(((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2- yl)methyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3-fluorotetrahydro-2H-pyran-4-ol, N-((6-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((1R*,4R*)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((1S*,4S*)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((S)-1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((S)-1-(6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrazin-2-yl)ethyl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-3,5-dimethylpyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-(((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-2-yl)methyl)amino)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, (3S*,4S*)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3R*,4R*)-4-(4-(((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3S*,4R*)-4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, (3R*,4S*)-4-(4-(((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol, N-((4-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-2-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, 5-(2,2-difluoro-3-methylcyclopropyl)-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine, N-(1-(4-(3,3-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2R*,4R*)-2-methyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)-5-((2S*,4S*)-2-methyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 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, 5-cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro- 2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, N-((6-(4,7-diazaspiro[2.5]octan-7-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-cyclopropyl-N-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt, or solvate, or N-oxide, or tautomer, or stereoisomer, or isotopically labelled derivative thereof.
13. A heterobicyclic derivative as defined in any one of claims 1 to 12, for use in the treatment of the human or animal body by therapy..
14. A heterobicyclic derivative as defined in any one of claims 1 to 12, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Interleukin-2- inducible T-cell kinase.
15. A heterobicyclic derivative according to any one of claims 1 to 12, for use according to claim 14 wherein the treatment is of a pathological condition or disease 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 vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, organ transplantation, GVHD, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca.
16. A heterobicyclic derivative according to any one of claims 1 to 12, for use according to claims 14 and 15 wherein the treatment is of a pathological condition or disease selected from atopic dermatitis, psoriasis, chronic hand eczema, T cell lymphoma, alopecia areata and vitiligo.
17. A pharmaceutical composition comprising a heterobicyclic derivative as defined in any one of claims 1 to 12 in association with a pharmaceutically acceptable diluent or carrier.
18. Use of a heterobicyclic derivative as defined in any one of claims 1 to 12, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claims 14 to 16.
19. A method for treating a subject afflicted with a pathological condition or disease as defined in claims 14 to 16, which comprises administering to said subject a therapeutically effective amount of a heterobicyclic derivative as defined in any one of claims 1 to 12, or a pharmaceutical composition as defined in claim 17.
20. A combination product comprising (i) at least one heterobicyclic derivative as defined in any one of claims 1 to 12, 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 leflunomide, teriflunomide or farudodstat; d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; e) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; f) Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; g) JAK inhibitors, such as baricitinib, upadacitinib or abrocitinib h) TYK2 inhibitors such as deucravacitinib i) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine; j) Fumaric acid esters, such as dimethyl fumarate; k) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; l) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; m) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; n) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC- 11050; o) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061; p) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; q) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab; r) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; s) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab; t) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab; u) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; v) Anti-Interleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab; w) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab; x) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab; y) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept; z) Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI- 551 or MOR-208; aa) Anti-IL-1b antibodies such as canakinumab; bb) Anti-IL-alpha antibodies such as bermekimab; cc) Anti-Interleukin 1 Receptor (IL-1R) antibody dd) Anti-CD6 antibodies such as itolizumab; ee) Anti-IL-36/ IL-36R antibodies such as BI-655130 or ANB019; ff) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR-845; gg) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; hh) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; ii) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine; jj) Histamine 4 (H4) receptor antagonists. kk) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast; ll) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant; or mm) Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.
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