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WO2025181247A1 - Heterobicyclic derivatives as itk inhibitors - Google Patents

Heterobicyclic derivatives as itk inhibitors

Info

Publication number
WO2025181247A1
WO2025181247A1 PCT/EP2025/055361 EP2025055361W WO2025181247A1 WO 2025181247 A1 WO2025181247 A1 WO 2025181247A1 EP 2025055361 W EP2025055361 W EP 2025055361W WO 2025181247 A1 WO2025181247 A1 WO 2025181247A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolo
pyran
tetrahydro
pyrimidin
prop
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/055361
Other languages
French (fr)
Inventor
Angelo Sanzone
Joan Taltavull Moll
Montse ERRA SOLA
Craig DONOGHUE
Cristina Esteve Trias
Steven John HEWISON
Jérôme MENEYROL
Stefania MONTELEONE
Jonathan Philip RICHARDS
Kate Elizabeth SPEAR
Penelope Alice WELHAM
Edward Richard Walker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Almirall SA
Original Assignee
Almirall SA
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Filing date
Publication date
Application filed by Almirall SA filed Critical Almirall SA
Publication of WO2025181247A1 publication Critical patent/WO2025181247A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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

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. 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).
  • TCR T cell receptor
  • 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- ⁇ 1), leading to the generation of phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) that serve as second messengers.
  • ITK 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the ITK inhibitor CPI-818 shows preclinical anti-tumour activity and is currently in clinical trials in patients with relapsed/refractory T cell lymphoma.
  • ITK inhibitor CPI-818 shows preclinical anti-tumour activity and is currently in clinical trials in patients with relapsed/refractory T cell lymphoma.
  • new compounds that modulate ITK pathways and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients.
  • Several companies are developing ITK inhibitors, but many of these also target additional tyrosine kinases.
  • ritlecitinib is a marketed small molecule that covalently and irreversibly inhibits Janus kinase 3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC).
  • ATI-2138 is a dual ITK/JAK3 inhibitor currently in phase II clinical trials for the treatment of autoimmune and inflammatory diseases.
  • VIT-801 is a dual ITK/BTK inhibitor that is expected to begin clinical development soon.
  • a key aspect in the field of ITK inhibitors is finding compounds with the required selectivity to ensure proper safety profile in a clinical setting.
  • the present invention therefore provides a heterobicyclic derivative, which heterobicyclic derivative is a compound of formula (I) or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, wherein • X 1 is N or CR 1 , wherein R 1 is selected from H, halogen, nitrile, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and -C 1-2 alkyl-O-C 1-2 alkyl; • (a) X 2 is C and X 3 is NH or (b) X 2 is N and X 3 is CH, • G 1 is a 5-7 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 3 groups and/or (b) two R
  • 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.
  • 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.
  • a N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • 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.
  • 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.
  • the compounds 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.
  • 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 compounds 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 (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Isotopically-labelled compounds 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.
  • compounds of the invention 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.
  • the configurational descriptors R* or S* in each chiral center are assigned independently from one another.
  • An example of such situation would be 1-((3S,5R)-3-methyl-5-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one, wherein (2R*,4R*) means that both chiral centers at the C2 and at the C4 position of the tetrahydropyrane ring are unknown, being each of them either R or S independently.
  • alkyl is intended to include both branched and linear (straight- chain) saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 alkyl (or alkylene) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups.
  • C 1 -C 3 alkyl (or alkylene), is intended to include C 1 , C 2 and C 3 alkyl groups.
  • C 1 -C 6 alkyl denotes alkyl having 1 to 6 carbon atoms.
  • C 1 -C 3 alkyl denotes alkyl having 1 to 3 carbon atoms.
  • C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl, more preferably C 1 -C 3 alkyl, and is more preferably methyl.
  • alkyl examples include, but are not limited to, methyl, ethyl, propyl (for example n- propyl, i-propyl, preferably i-propyl) and butyl (for example n-butyl, i-butyl, sec-butyl and t-butyl, preferably t-butyl).
  • alkyl moieties may be the same or different.
  • alkenyl refers to a branched or linear (straight-chain) hydrocarbon group comprising one or more double bonds and having the specified number of carbon atoms.
  • alkynyl refers to a branched or linear (straight-chain) hydrocarbon group comprising one or more triple bonds and having the specified number of carbon atoms.
  • examples of C 2-4 alkynyl include -C ⁇ CH, -CH 2 -C ⁇ CH, - C ⁇ C-CH 3 and -C ⁇ C-CH 2 -CH 3 .
  • a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine, more preferably chlorine or fluorine, and most preferably fluorine.
  • the term “haloalkyl” is intended to include both branched and linear (straight-chain) saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, and which contains at least one halogen atom.
  • the halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, fluorine or bromine, more preferably chlorine or fluorine, and most preferably fluorine.
  • C 1 -C 6 haloalkyl is preferably C 1 -C 4 haloalkyl, and more preferably C 1 -C 3 haloalkyl, for example C 1 -C 3 fluoroalkyl.
  • C 1 -C 4 alkoxy refers to a said C 1 -C 4 alkyl group attached to an oxygen atom.
  • spirocyclic group refers to a cyclic or heterocyclic group formed on, and sharing one atom with, a second cyclic or heterocyclic group.
  • a spirocyclic group formed from two alkyl groups bonded to the same carbon atom of a heterocyclic ring corresponds to a cycloalkyl group which together with the heterocyclic ring form a spiro bicyclic moiety.
  • a spirocyclic group formed from two groups bonded to the same carbon atom of a heterocyclic ring corresponds to heterocyclyl group which together with the heterocyclic ring form a spiro bicyclic moiety.
  • heterocyclyl refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic, spirocyclic), non-aromatic, saturated or partially unsaturated ring system whose ring atoms consist of carbon atoms and at least one heteroatom selected from O, S and N.
  • the at least one heteroatom is commonly 1-3 heteroatoms, for instance 1-2 heteroatoms or 1 heteroatom.
  • the at least one heteroatom ring atom is selected from N and O, more preferably N.
  • the heterocyclyl is monocyclic or bicyclic.
  • the heterocyclyl is saturated. In one embodiment, the heterocyclyl is unsaturated.
  • Two rings in a polycyclic heterocyclic may form a bridged bicyclic moiety (three or more atoms shared by the two rings), a fused bicyclic moiety (two adjacent atoms shared by the two rings), or a spiro bicyclic moiety (a single atom shared by the two rings).
  • the term “O-containing heterocyclic ring” refers to a heterocyclic ring comprising at least one oxygen atom as a ring atom and optionally one or more heteroatom ring atom selected from N and S.
  • an O-containing heterocyclic ring comprises one or two heteroatom ring atoms which are O and zero or one heteroatom ring atom which is N.
  • the ring atoms of an O-containing heterocyclic ring may consist of carbon and one or two O atoms.
  • the term “N-containing heterocyclic ring” refers to a heterocyclic ring comprising at least one nitrogen atom as a ring atom and optionally one or more heteroatom ring atom selected from O and S.
  • an N-containing heterocyclic ring comprises one or two heteroatom ring atoms which are N and zero or one heteroatom ring atom which is O.
  • the ring atoms of an N-containing heterocyclic ring may consist of carbon and one or two N atoms.
  • Typical examples of heterocycles include 4- to 10-membered heterocycles, wherein “X-membered” means that the total number of ring atoms in the heterocycle is X.
  • Preferred heterocycles are 5- to 10-membered heterocycles, 9- to 10-membered heterocycles, 4- to 7-membered heterocycles, 4- to 6-membered heterocycles, 4- to 5- membered heterocycles and 5- to 6-membered heterocycles.
  • heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, piperazinyl, pyrazolidinyl, piperadinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, indolinyl and tetrahydropyrazolo[1,5-a]pyrazinyl.
  • Preferred examples of heterocycles include oxetanyl, piperidinyl and pyrrolidinyl.
  • a heterocycle may be substituted by one or more oxo groups, typically one oxo group.
  • heterocycles substituted by one oxo group include pyrrolidinonyl and oxoindolinyl.
  • the compounds of the present invention share a general formula (I), which contains the following core structure: The solid circle within the ring in the left-hand side ring represents the aromaticity of the ring.
  • the solid circle within the ring in the right-hand side represents the different positions that can be adopted by the double rings of the right-hand side ring as shown below:
  • Compounds The invention relates to compounds 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:
  • the heterobicyclic derivative of the invention is a compound as described herein or a pharmaceutically acceptable salt, or a solvate, or a tautomer, or a stereoisomer thereof.
  • X 1 is N or CR 1 and either (a) X 2 is C and X 3 is NH or (b) X 2 is N and X 3 is CH.
  • R 1 is typically H, halogen, nitrile, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.
  • R 1 is H, halogen, nitrile, C1-2 alkyl, C1-2 haloalkyl, or C1-2 alkoxy. More preferably, R1 is H or F, for instance R 1 is H.
  • X 1 is N or CR 1 , wherein R 1 is selected from H and halogen, C 1-2 alkyl, C 1-2 haloalkyl and C 1-2 alkoxy; and (a) X 2 is C and X 3 is NH or (b) X 2 is N and X 3 is CH.
  • R 1 is H.
  • X 2 is C and X 3 is NH.
  • X 1 is N, X 2 is C and X 3 is NH.
  • X 1 is CR 1 , preferably CH, X 2 is C and X 3 is NH.
  • G 1 is a 5-7 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 3 groups and/or (b) two R 3a groups.
  • the O-containing heterocyclic ring may be substituted with: one, two or three R 3 groups and zero R 3a groups; zero R 3 groups and two R 3a groups; or one, two or three R 3 groups and two R 3a groups.
  • Each R 3 group is typically independently selected from C 1-4 alkyl, hydroxy, nitrile, C 1-4 alkoxy, halogen, C 1-4 haloalkyl.
  • Each R 3 group may be methyl or fluoro.
  • Each R 3a group is attached to the same carbon atom of the O-containing heterocyclic ring, and the two R 3a groups together form a 3-to 6-membered spirocyclic group optionally comprising an O atom.
  • the O-containing heterocyclic ring is substituted with two R 3a groups, these are bonded to the same ring carbon atom in the heterocyclic ring and together form a 3-to 6-membered spirocylic ring on the heterocyclic ring.
  • G 1 is tetrahydropyran substituted with two R 3a groups might form spirocyclic groups as follows:
  • G 1 is a 5 or 6 membered O-containing heterocyclic ring, wherein said O- containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 3 groups and/or (b) two R 3a groups.
  • G 1 may be a 5 or 6 membered O-containing heterocyclic ring, wherein said heterocyclic ring is unsubstituted or substituted with one, two or three R 3 groups.
  • G 1 is a 6 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 3 groups and/or (b) two R 3a groups.
  • G 1 may be a 6 membered O-containing heterocyclic ring, wherein said heterocyclic ring is unsubstituted or substituted with one, two or three R 3 groups.
  • G 1 is saturated.
  • R 3 is preferably C 1-4 alkyl, hydroxy, nitrile, C 1-4 alkoxy, or C 1-4 haloalkyl, provided that two hydroxy groups are not attached to the same atom. More preferably R 3 is C 1-3 alkyl, hydroxy, nitrile, C 1-3 alkoxy, or C 1-3 haloalkyl, provided that two hydroxy groups are not attached to the same atom. Yet more preferably, R 3 is C 1-2 alkyl, C 1-2 alkoxy, halogen or C 1-2 haloalkyl. Most preferably, R 3 is methyl, methoxy or fluoro.
  • G 1 is typically substituted by one or two R 3 groups (and zero R 3a groups). If G 1 is substituted with at least one R 3 group and two R 3a groups, G 1 is typically substituted with one or two R 3 groups and two R 3a groups. Preferably G 1 is unsubstituted. G 1 may be selected from oxetane, tetrahydrofuran, tetrahydropyran and oxepane. G 1 is typically tetrahydropyran or tetrahydrofuran. G 1 is preferably tetrahydropyran which is unsubstituted or substituted with one or two groups selected from methyl and fluoro.
  • G 1 is other than 3,6-dihydro-2H-pyranyl, more preferably other than any dihydropyranyl group. Most preferably, G 1 is saturated. G 1 may be bonded to the rest of the compound via any of the carbon ring atoms in the O-containing heterocyclic ring. G 1 may for instance be selected from: Y is selected from -N(R2)-, -O- and -C(HR2a)-. Y is typically -N(R2)- or-O-. Preferably, Y is -N(R 2 )-. R 2 is preferably H or C 1-4 alkyl. More preferably, R 2 is H, or C 1-3 alkyl. Most preferably R 2 is H.
  • R 2a is typically H, halogen or C 1-3 alkyl, preferably H. In another preferred embodiment, Y is -O-. In some embodiments, n is 1. In some embodiments, n is 0. When n is 0, Y is not present and G 2 is directly bonded to the central bicyclic moiety.
  • G 2 is typically a 4-10 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-3 alkyl, halogen, C 1-2 haloalkyl and C 1-2 alkoxy, and wherein the two R 4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R 4a groups together form a 3- to 6-membered spirocyclic group optionally comprising an O atom.
  • G 2 may be an unsubstituted 4-10 membered N- containing monocyclic or bicyclic heterocyclic ring.
  • G 2 is preferably a 5-9 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 4 groups and/or (b) two R 4a groups.
  • G 2 is preferably a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N- containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R 4 groups and/or (b) two R 4a groups, , wherein each R 4 is independently selected from C 1-4 alkyl, halogen, C 1-4 haloalkyl, hydroxy, C 1-4 hydroxyalkyl and C 1-4 alkoxy, and wherein the two R 4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R 4a groups together form a 3-to 6-membered spirocyclic group optionally comprising an O atom.
  • G 2 may be substituted with one or two R 4 groups, where R 4 is C 1-3 alkyl, halogen, C 1-3 haloalkyl or C 1-3 alkoxy.
  • R 4 is C 1-2 alkyl, halogen, C 1-2 alkoxy, or C 1-2 haloalkyl. More preferably, R 4 is methyl or fluoro.
  • G 2 may be unsubstituted or substituted with one or two R 4, wherein each R 4 is independently selected from C 1-2 alkyl, C 1-2 alkoxy, halogen or C 1-2 haloalkyl.
  • G 2 is substituted with two R 4a groups
  • the two R 4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R 4a groups together form a 3- to 6-membered spirocyclic group optionally comprising an O atom.
  • the two R 4a groups together form a 3-, 4-, 5- or 6-membered spirocyclic group.
  • the two R 4a groups together form a 3-membered spirocyclic group (i.e. together form a cyclopropyl group with the G 2 ring carbon atom to which they are bonded).
  • G 2 is substituted with two R 4a groups, wherein the two R 4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R 4a groups together form a 3- to 6-membered spirocyclic group comprising an O atom (i.e. together form an oxetanyl group).
  • G 2 may be (i) unsubstituted or (ii) substituted with (a) one, two or three R 4 groups and/or (b) two R 4a groups.
  • G 2 may be substituted with (a) one, two or three R 4 groups and/or (b) two R4a groups. If G2 is substituted, G2 is preferably substituted by one, or two R 4 groups.
  • Exemplary G 2 groups include:
  • * and ** represent the points of attachment to the rest of the compound.
  • * may be the point of attachment to (Y) n
  • ** may be the point of attachment to G 3
  • ** may be the point of attachment to (Y) n
  • * may be the point of attachment to G 3 .
  • n is 1.
  • Y is preferably -N(H)-.
  • G 2 is preferably selected from: wherein each of p, q, r, r’, s, t and t’ is independently 0, 1, 2 or 3; u is 1, 2 or 3; the point of attachment to Y is obtained by removing a hydrogen atom from one of the carbon atoms in G 2 ; and the N atom in G 2 is bonded to G 3 and wherein G 2 is unsubstituted or substituted as described herein.
  • G2 is unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are bonded to the same carbon atom in G 2 and the two groups together form a spirocyclic cyclopropyl group.
  • G 2 is preferably unsubstituted or substituted with one methyl group.
  • the sum of r, q and s and the sum of t and u are each such that G 2 is at most a 10 membered N-containing bicyclic heterocyclic ring as defined herein (which may be unsubstituted or substituted as defined herein).
  • p is 1 or 2.
  • G 2 is selected from: wherein * represents the point of attachment to Y, and the N atom in G 2 is bonded to G 3 , wherein G 2 is unsubstituted or substituted with one or two substituents selected from methyl and fluoro. More preferably, when n is 1, G 2 is selected from: wherein G 2 is unsubstituted or substituted with one or two substituents selected from methyl and fluoro. For instance, when n is 1, G 2 may be selected from: (i.e.
  • G 2 is typically selected from: wherein: each of p, q, r, r’, s, s’, t, t’, v and v’ is independently 0, 1, 2 or 3; m is 2 or 3; and wherein each of p, q, r, r’, s, s’, t, t’, v’and v’ is independently 0, 1, 2 or 3; m is 2 or 3; and one N is attached to the atom adjacent to X 1 and the other N is attached to G 3 , and wherein G 2 is unsubstituted or substituted as described herein.
  • G 2 is preferably unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are two groups bonded to the same carbon atom in G 2 and the two groups together form a spirocyclic cyclopropyl group.
  • the sum of m and p, the sum of q, r, r’, s and s’ and the sum of t, t’, v and v’ are each such that G 2 is at most a 10 membered N-containing bicyclic heterocyclic ring as defined herein (which may be unsubstituted or substituted as defined herein).
  • G 2 may be: wherein: w is 1, 2 or 3, the dotted double bond is present or absent, the point of attachment to the atom adjacent to X 1 is obtained by removing a hydrogen atom from a ring carbon atom, and the N is attached to G 3 , and wherein G 2 is unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are two groups bonded to the same carbon atom in G 2 and the two groups together form a spirocyclic cyclopropyl group.
  • w is typically 1 or 2.
  • G 2 is typically selected from: wherein, * represents the point of attachment to the atom adjacent to X 1 , and ** represents the point of attachment to G 3 .
  • G 2 may be selected from wherein, * represents the point of attachment to the atom adjacent to X 1 , and ** represents the point of attachment to G 3 .
  • G 2 may be selected from wherein, * represents the point of attachment to the atom adjacent to X 1 , and ** represents the point of attachment to G 3 .
  • said C 2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from methyl, fluoro and N(CH 3 ) 2 .
  • said C 2-4 alkenyl is unsubstituted.
  • said C 2-4 alkynyl is unsubstituted.
  • G 3 is attached to a C-atom in G 2
  • said C 2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, or N(CH 3 ) 2 .
  • said C 2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, or N(R 6 ) 2 .
  • said C 2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C 1-2 haloalkyl, or N(R 6 ) 2 .
  • R 6 is a C 1-2 alkyl. More preferably, R 6 is methyl.
  • said C 2-4 alkenyl is unsubstituted. More preferably said C 2-4 alkynyl is unsubstituted. More Preferably, said C 2-4 alkenyl is unsubstituted. More preferably said C 2-4 alkynyl is unsubstituted.
  • R 5 is H or C 1-2 alkyl. More preferably, R 5 is H or methyl. Most preferably, R 5 is H.
  • G 3 is attached to a N-atom on G 2, and G 3 is selected from: . a on .
  • G 1 is other than 3,6-dihydro-2H-pyranyl, more preferably other than any dihydropyranyl group. In this embodiment, most preferably, G 1 is saturated.
  • the invention also provides a compound which compound is (a) a heterobicyclic derivative of formula (I), wherein Y, X 1 , X 2 , X 3 , G 1 , G 2 , G 3 and n are as defined herein; or (b) a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative of said heterobicyclic derivative, provided that said compound is not 1-(5-((5-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one or any acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer thereof.
  • a pharmaceutically acceptable salt or a solvate, or
  • the heterobicyclic derivative is a compound of formula (Ii) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein X 1 , R 1 , X 2 , X 3 , Y, R 2 , R 2a , n, G 2 , R 4 , R 4a , G 3 , R 5 and R 6 are as defined above for formula (I).
  • X 1 is N or CR 1
  • X 2 is C
  • X 3 is NH
  • Y is -O- or - N(R2)-
  • R2 is H or methyl
  • G3 is attached to a N-atom on G2, and G3 is selected from: .
  • the heterobicyclic derivative is a compound of formula (Iii) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein Y, R 2 , R 2a , n, G 2 , R 4 , R 4a , G 3 , R 5 and R 6 are as defined above for formula (I).
  • the heterobicyclic derivative is a compound of formula (Iiii) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein R 1, Y, R 2 , R 2a , n, G 2 , R 4 , R 4a , G 3 , R 5 and R 6 are as defined above for formula (I).
  • the heterobicyclic derivative is a compound of formula (Iiv) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein Y, R 2 , R 2a , n, G 2 , R 4 , R 4a , G 3 , R 5 and R 6 are as defined above for formula (I).
  • the heterobicyclic derivative is a compound of formula (II) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
  • Y is -NH- or -O-;
  • G 2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-2 alkyl and halogen, and wherein the two R 4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R 4a groups together form a 3- to 4- membered spirocyclic group; and G 3 is , wherein R 7a is H or F and R 7b is H, -CH 3 or -CH 2 -N(CH 3 ) 2 .
  • the heterobicyclic derivative is a compound of formula (IIa) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein: Y is -NH- or -O-; G 2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-2 alkyl and halogen, and wherein the two R 4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R 4a groups together form a 3- to 4- membered spirocyclic group; and G 3 is , wherein R 7a is H or F and R
  • Y is preferably -NH-. In other embodiment, in formula (II) and (IIa), Y is preferably -O-.
  • R 4 is preferably methyl or fluorine. If G 2 is substituted, G 2 is preferably substituted by one R 4 group.
  • R 7a is H.
  • R 7b is H.
  • G 2 is typically selected from: wherein * represents the point of attachment to Y, and the N atom in G 2 is bonded to G 3 , where G 2 is unsubstituted or substituted with one or two substituents selected from methyl and fluoro.
  • the heterobicyclic derivative is a compound of formula (III) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
  • G 2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-2 alkyl and halogen, and wherein the two R 4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- memebered spirocyclic group; and G 3 is , wherein R 7a is H or F and R 7b is H, -CH 3 or -CH 2 -N(
  • R 7a is H.
  • R 7b is H.
  • G 2 may be selected from
  • the heterobicyclic derivative is a compound of formula (IV) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative therof: wherein: G 2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring contains at least two nitrogen atoms, and is (i) unsubstituted or (ii) substituted with (a) one or two R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-2 alkyl and halogen, and wherein the two R 4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R 4a groups together form a 3- to 4- member
  • the heterobicyclic derivative is a compound of formula (IIIa) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
  • G 2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-2 alkyl and halogen, and wherein the two R 4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R 4a groups together form a 3- to 4- memebered spirocyclic group; and , wherein R 7a is H or F and R 7b is H, -CH 3 or -CH 2 -N(CH 3
  • R 7a is H.
  • R 7b is H.
  • G 2 may be selected from
  • the heterobicyclic derivative is a compound of formula (IVa) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative therof: wherein: G 2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring contains at least two nitrogen atoms, and is (i) unsubstituted or (ii) substituted with (a) one or two R 4 groups and/or (b) two R 4a groups, wherein each R 4 is independently selected from C 1-2 alkyl and halogen, and wherein the two R 4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R 4a groups together form a 3- to
  • R 1 is preferably H, F or CN.
  • R 1 is H.
  • Preferred compounds of formula (I) are: • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-
  • the compound of formula (I) is other than: .
  • Heterobicyclic derivatives of the invention as described herein are inhibitors of ITK kinase.
  • the heterobicyclic derivative has an IC 50 against ITK of no more than 10,000 nM, more preferably no more than 1,000 nM, or no more than 100 nM, or no more than 10 nM.
  • the IC 50 may be as measured by a method as defined herein, for instance by the in vitro ITK kinase Assay as defined herein.
  • 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.
  • 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,
  • 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, alopecia areata, hidradenitis suppurativa and vitiligo.
  • the patient or subject treated in the present invention is an animal, preferably a human.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibition 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 the use of a heterobicyclic derivative of the invention, or a pharmaceutical composition of the invention, for the manufacture of a medicament.
  • the invention also provides the use of a heterobicyclic derivative of the invention, or a pharmaceutical composition of the invention, for the manufacture of a medicament for treating a condition or disease selected from cancer, T-cell lymphoma, asthma, inflammatory bowel disease, atopic dermatitis, psoriasis, chronic hand eczema, alopecia areata, hidradenitis suppurativa, vitiligo, and multiple sclerosis.
  • 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 inhibition 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
  • 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 combinations of the invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of ITK, such as the ones previously described. In a preferred embodiment 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, alopecia areata, hidradenitis suppurativa and vitiligo.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibition of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described, comprising administering a therapeutically effective amount of a combination of the heterobicyclic derivatives of the invention together with one or more other therapeutic agents. It is contemplated that all active agents would be administered at the same time, or very close in time.
  • one or two actives could be administered in the morning and the other(s) later in the day.
  • 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.
  • at least two, and more preferably all, of the actives would be administered together at the same time.
  • 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 inhibition of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described.
  • ITK Interleukin-2-inducible T-cell kinase
  • 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 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.
  • 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.
  • INK 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), 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 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 inhibition of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described, 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • General synthetic schemes 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.
  • Scheme 1 As illustrated in Scheme 1, compounds of Formula (I) may be prepared directly from haloderivatives of Formula (IB) by reaction with nucleophiles of Formula (IC) such as an amine or an alcohol, in the presence of a suitable base and in a suitable solvent.
  • Scheme 2 Compounds of Formula (IB) may be prepared as illustrated in Scheme 2 from dihalogenated compounds of Formula (X) by reaction with boronic acids or boronic esters of Formula (XIa) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457).
  • 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 or potassium phosphate, at temperatures ranging from 60-140 oC with or without the use of microwave irradiation to give compounds of Formula (XII).
  • 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 dimethoxye
  • Compounds of Formula (XII) can then be reduced with hydrogen at a pressure between atmospheric pressure and 60 psi in the presence of a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney in a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 oC to give compounds of Formula (IB).
  • a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney
  • a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 oC
  • compounds of Formula (I) may be prepared in a two-step synthesis, as illustrated in Scheme 3, from compounds of Formula (IB).
  • compounds of Formula (IB) may be reacted with amines or alcohols of Formula (IV) in the presence of a suitable base and in a suitable solvent to give compounds of Formula (V).
  • amines of Formula (V) may be reacted with acyl chlorides of Formula (VIa) or with carboxylic acids of Formula (VIb) to give compounds of Formula (I).
  • Scheme 4 As illustrated in Scheme 4, in the particular case where Y is a NR2 group, compounds of Formula (IB) may be treated with amines of Formula (IVa) in the presence of a suitable base such as cesium carbonate or triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile or dimethylsulfoxide or ethanol or butanol or N-N- dimethylacetamide at a temperature ranging from 60-180 oC with or without the use of microwave irradiation to give compounds of Formula (Va).
  • a suitable base such as cesium carbonate or triethylamine or diisopropylethylamine
  • a suitable solvent such as acetonitrile or dimethylsulfoxide or ethanol or butanol or N-N- dimethylacetamide
  • compounds of Formula (IB) may be treated with amines of Formula (IVa) 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 to give compounds of Formula (Va).
  • 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 (Va) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC to give compounds of Formula (Ia).
  • a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC
  • compounds of Formula (Va) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Ia).
  • a suitable coupling agent such as HATU or HBTU or T3P or HOBT
  • compounds of Formula (IB) may be treated with alcohols of Formula (IVb) in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in an appropriate solvent such as 1,4-dioxane or tetrahydrofurane or dimethylsulfoxide to give compounds of Formula (Vb).
  • a suitable base such as sodium hydride or potassium tert-butoxide
  • an appropriate solvent such as 1,4-dioxane or tetrahydrofurane or dimethylsulfoxide
  • Compounds of Formula (Vb) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC to give compounds of Formula (Ib).
  • compounds of Formula (Vb) can be treated with carboxylic acids of Formula (VIb) in the presence of
  • compounds of Formula (IB) may be treated with amines of Formula (IVc) 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 to give compounds of Formula (Vc).
  • 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 (Vc) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC to give compounds of Formula (Ic).
  • a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC
  • compounds of Formula (Vc) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Ic)
  • Scheme 7 Alternatively, as illustrated in Scheme 7, in the particular case where in the formula (Y) n the value of n equals 0, compounds of Formula (IB) may be treated with boronic acids or boronic esters of Formula (IVd) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457).
  • 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 or potassium phosphate, at temperatures ranging from 60-140 oC with or without the use of microwave irradiation to give compounds of Formula (Vd1).
  • 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 dimethoxyethan
  • Compounds of Formula (Vd1) can then be reduced with hydrogen at a pressure between atmospheric pressure and 60 psi in the presence of a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney in a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 oC to give compounds of Formula (Vd2).
  • a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney
  • a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 oC
  • Compounds of Formula (Vd2) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC to give compounds of Formula (Id).
  • a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 oC
  • compounds of Formula (Vd2) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Id).
  • a suitable coupling agent such as HATU or HBTU or T3P or HOBT
  • Scheme 8 Alternatively, compounds of Formula (V) may be prepared as illustrated in Scheme 8 from dihalogenated compounds of Formula (X) by reaction with amines or alcohols of Formula (IV) in the presence of a suitable base and in a suitable solvent to give compounds of Formula (XI).
  • Compounds of Formula (XI) may be reacted with boronic acids or boronic esters of Formula (XIa) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457).
  • 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 or potassium phosphate, at temperatures ranging from 60-140 oC with or without the use of microwave irradiation to give compounds of Formula (XII).
  • 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 dimethoxye
  • Compounds of Formula (XII) can then be reduced with hydrogen at a pressure between atmospheric pressure and 60 psi in the presence of a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney in a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 oC to give compounds of Formula (V).
  • a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney
  • a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 oC
  • compounds of Formula (XI) can be transformed directly into compounds of Formula (V) as illustrated in Scheme 9 using photochemistry by treatment with carboxylic acids of Formula (XIIIa) or carboxylic acid derivatives of Formula (XIIIb) in the presence of a suitable Nickel catalyst such as [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride and a suitable base such as sodium hydrogen carbonate in a suitable solvent such as N,N-dimethylacetamide and under irradiation of visible light at wavelenght typically between 380 nm and 430 nm.
  • a suitable Nickel catalyst such as [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride
  • nickel (II) dichloride nickel (II) dichloride
  • a suitable base such as sodium hydrogen carbonate
  • a suitable solvent such as N,N-dimethylacetamide
  • compounds of Formula (XI) can also be transformed directly into compounds of Formula (V) via a photochemical reaction by treatment with bromides of Formula (XIIIc) in the presence of a suitable catalyst such as [4,4′-Bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride in the presence of a suitable reagent such as bis(trimethylsilyl)silyl- trimethylsilane and a base such as 2,6-dimethylpyridine in a solvent such as 1,2- dimethoxyethane under irradiation of visible light at wavelenght typically between 380 nm and
  • compounds of Formula (X) can also be transformed directly into compounds of Formula (II) via a photochemical reaction by treatment with bromides of Formula (XIIIc) in the presence of a suitable catalyst such as [4,4′-Bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride in the presence of a suitable reagent such as Bis(trimethylsilyl)silyl- trimethylsilane and a base such as 2,6-dimethylpyridine in a solvent such as 1,2- dimethoxyethane under irradiation of visible light at wavelenght between 380 nm and
  • 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. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • these 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.
  • SFC superfluid chromatography
  • mixtures of diastereomers may be obtained during the process of preparation of the compounds of this invention.
  • 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.
  • 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: 6 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.
  • LC-MS method 2 LCMS 2 Apparatus: Agilent 1290 Infinity II; Bin. Pump: 1290 High speed Pump, 1290 Multisampler; 1290 DAD WR; LC/MSD IQ; ESI, pos/neg 100-1000; column: Infinitylab Poroshell 120 EC-C182,1X50mm, 50x2.1mm, 1.9 ⁇ m, Temp column: 50oC, Flow rate: 0.65 mL/min, Gradient: from 4% B to 98% 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 3 Chromatograms were processed at 210 nm.
  • LC-MS method 3 LCMS 3 Apparatus: Agilent 1290 Infinity II; Bin. Pump: 1290 High speed Pump, 1290 Multisampler; 1290 DAD WR; LC/MSD IQ; ESI, pos/neg 100-1000; column: Infinitylab Poroshell 120 EC-C182,1X50mm, 50x2.1mm, 1.9 ⁇ m, Temp column: 50oC, Flow rate: 0.65 mL/min, Gradient: from 4% B to 98% 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).
  • UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.
  • Mass spectra were obtained using a Waters QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.
  • Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.
  • Mass spectra were obtained using a Waters Quattro Premier XE, a QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.
  • 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 Bruker Avance III HD 500 MHz NMR (B114) Bruker Avance III HD 400 MHz NMR (B114) Bruker NEO 400 MHz NMR (B111) 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: Biotage Isolera ® automated purification system equipped with a silica gel (40-63 ⁇ m) 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 or in a Phenomenex Gemini ® purification system equiped with a C18 column.
  • Typical conditions Gradient of water-acetonitrile/MeOH (1:1) from 0% to 100% acetonitrile/MeOH (1:1) in 40 column volumes. If required, 0.1% v/v formic acid or ammonium formate was added in both phases to achieve a better separation. The appropriate fractions were collected, and the solvents were typically evaporated under reduced pressure and/or liofilized.
  • Preparative LC-MS Preparative HPLC Method 1A (P1A): Apparatus: Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector.
  • the reaction mixture was diluted in EtOAc, washed with water, brine, dried over anh. MgSO4, filtered and removed under reduced pressure.
  • the crude was purified by flash column chromatography on silica gel eluting with a gradient of heptanes-EtOAc (100:00 to 85:15) to yield tert-butyl 4-(5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazine-1- carboxylate (0.454 g, 1.18 mmol, 85% yield, 99% purity) as a colourless oil that solidified on standing as a white solid.
  • the tube was sealed and heated at 80 °C for 19 h.
  • the reaction mixture was cooled to r.t. and diluted with ethyl acetate (40 mL), washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo. Purification by column chromatography, 100 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected and the solvent was removed in vacuo to give the title compound (563 mg, 0.985 mmol, 91% yield) as a beige solid.
  • the reaction mixture was sparged with nitrogen for 10 min. before the addition of PdCl 2 (dppf) ⁇ DCM (89 mg, 0.11 mmol, 0.1 eq) and was sparged with nitrogen for a further 10 min.
  • the reaction mixture was heated at 80 °C in a sealed tube for 16 h.
  • the reaction mixture was diluted with water (20 mL) and ethyl acetate (20 mL), the aqueous layer was extracted with EtOAc (2 x 20 mL), the organics combined, washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification by flash column chromatography (0-100% EtOAc in Heptanes).
  • the reaction flask was evacuated and purged with nitrogen 3 times, to which palladium on carbon (72 mg, 0.07 mmol, 10 mass%, 0.1 eq) was added, which was then evacuated and purged with nitrogen 3 times.
  • the suspension was then stirred under an atmosphere of hydrogen at r.t. for 8 days.
  • the reaction mixture was filtered through celite, washed with ethyl acetate (3 x 10 mL) and the solvent was removed in vacuo to give the title compound (300 mg, 0.60 mmol, 87% yield) as a colourless oil.
  • Aqueous solution of potassium carbonate (2 M, 62.2 mL, 3.00 eq) and Pd(dppf)Cl 2 .CH 2 Cl 2 (3.39 g, 4.15 mmol, 0.10 eq) were added at 20 °C under nitrogen and the mixture was stirred at 40 °C for 12 h.
  • the mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • NiBr 2 .dtbbpy (112 mg, 0.23 mmol, 0.1 eq.) was added, the solution was degassed and the mixture irradiated at 390 nm in a Penn PhD PR m2 photoreactor overnight. The reaction was quenched with water (30 ml) and the product extracted with 1:1 Heptane and TBME (3 x 25 ml). The combined organics were washed with 2 M HCl (3 x 20 ml) and concentrated under reduced pressure. The residue was taken up in tert-butyl methyl ether and acetonitrile (1:1), filtered and concentrated under reduced pressure.
  • reaction mixture was added NiBr 2 . dtbbpy (238 mg, 0.49 mmol, 0.1 eq.) and degassed for a further 5 mins under sonication.
  • the reaction mixture was sealed and irradiated under 395 nm light in a Penn PhD PR m2 photoreactor for 20 h.
  • the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL).
  • reaction mixture was added NiBr2.dtbbpy (475 mg, 0.97 mmol, 0.1 eq.) and degassed for a further 5 mins under sonication.
  • the reaction mixture was sealed and irradiated under 395 nm light in a Penn PhD PR m2 photoreactor for 20 h.
  • the reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated, and the organic layer was washed with water (100 mL) and brine (2 x 100 mL) and concentrated in vacuo.
  • the reaction was retreated with DIEA (0.5 mL, 3.0 mmol, 5 eq) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.66 mmol, 1.2 eq) and stirred for a further 3 days at 120 °C.
  • the reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate and the solvent was removed in vauco. Purification by normal-phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane.
  • Step 2 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidine hydrochloride
  • Hydrochloric acid in dioxane was added to a solution of tert- butyl 3-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.52 mmol) in dichloromethane (3 mL) at r.t.
  • Step 3 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one
  • Acryloyl chloride 50 ⁇ L, 0.62 mmol, 1.2 eq
  • 4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (343 mg, 0.50 mmol, 61 mass%, 1 eq) and triethylamine (0.21 mL, 1.5 mmol, 3 eq) in dichloromethane (5 mL) at 0 °C under nitrogen, warmed to r.t.
  • Trifluoroacetic acid (0.8 mL, 10 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2.5 h. Additional trifluoroacetic acid (0.8 mL, 10 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (in methanol) (10 mL, 70 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo. Purification by basic reverse-phase HPLC (Gilson 5). The product tubes were collected, and the solvent was removed in vacuo.
  • reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate and the solvent was removed in vauco. Purification by normal-phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane.
  • Step 2 4-(2, 6-D iazaspiro[3.3]heptan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidine Trifluoroacetic acid (0.65 mL, 8.5 mmol, 20 eq) was added to a solution of tert-butyl 6-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (230 mg, 0.40 mmol) in dichloromethane (5 mL) at r.t.
  • Step 3 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one HATU (153 mg, 0.40 mmol, 1.1 eq) was added to a solution of 4-(2,6-diazaspiro[3.3]heptan- 2-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (115 mg, 0.36 mmol, 1.0 eq) and DIPEA (0.19 mL, 1.1 mmol, 3 eq) in N,N-dimethylformamide (2 mL) at r.t.
  • Step 2 1-(5-(Tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-amine
  • Trifluoroacetic acid (0.65 mL, 8.5 mmol, 20 eq) was added to a solution of tert-butyl (1-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)azetidin-3-yl)carbamate (221 mg, 0.42 mmol, 1.0 eq) in dichloromethane (5 mL) at r.t.
  • Trifluoroacetic acid (0.61 mL, 8.0 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2.5 h. Additional trifluoroacetic acid (0.61 mL, 8.0 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (in methanol) (5 mL, 35 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo. Purification by basic reverse-phase HPLC. The product was collected, and the solvent was removed in vacuo.
  • the reaction mixture was stirred at r.t. for 1 h.
  • the reaction mixture was washed with saturated NaHCO 3 (10 mL), then extracted using first DCM (3 x 5 mL) then nBuOH (5 mL).
  • the combined organic layers were concentrated to dryness.
  • the crude intermediate was then dissolved in ethanol (5 mL) and water (0.5 mL), then potassium carbonate (56 mg, 0.567 mmol, 5 eq.) was added, stirred for one hour, then evaporated to dryness and purified by preparative HPLC (Method P3E).
  • the product tubes were collected, and the solvent was removed in vacuo.
  • EXAMPLE 45 and EXAMPLE 46 1-((4aS,7aS)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one 1-((4aR,7aR)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one
  • the title compounds were separated from a racemic mixture of rac-1-((4aR,7aR)-1-(5- (Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oc
  • EXAMPLE 52 and EXAMPLE 53 1-((3aS,7aR)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one 1-((3aR,7aS)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of rac-1-((3aR,7aS)-1-(5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro
  • EXAMPLE 55 and EXAMPLE 56 1-((3aS,7aS)-4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one 1-((3aR,7aR)-4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of rac-((3aR,7aR)-4-(5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-1
  • EXAMPLE 60 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-1-yl)prop-2-en-1-one
  • the title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate following the experimental procedure described in Synthesis method 4.25 mg of the title compound were obtained.
  • Trifluoroacetic acid (825 ⁇ L, 10.8 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen. Ammonia (in methanol) (5 mL, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen. Purification by preparative HPLC (Method P3E). The product tubes were collected, and the solvent was removed in vacuo.
  • Trifluoroacetic acid (825 ⁇ L, 10.8 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. Additional trifluoroacetic acid (825 ⁇ L, 10.77 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 8 h. The solvent was removed under nitrogen. Ammonia (in methanol) (5 mL, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen. Purification by preparative HPLC (Method P3E). The product tubes were collected, and the solvent was removed in vacuo.
  • EXAMPLE 79 and EXAMPLE 80 (R)-1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 1-yl)prop-2-en-1-one (S)-1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 1-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of 1-(3-(5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-1-yl)prop-2-en-1-one (34 mg), prepared as described in Example 78.
  • Second eluting peak (Example 79): Obtained as a white solid (39 mg). Purity by LCMS 100%. LCMS 5 : RT 1.67 min, m/z 327 [M+H] + , 100% 1 H NMR (400 MHz, d 6 -DMSO) ⁇ 11.96 (s, 1H), 8.68 – 8.62 (m, 1H), 7.41 – 7.35 (m, 1H), 6.71 – 6.57 (m, 1H), 6.21 – 6.12 (m, 1H), 5.73 – 5.62 (m, 1H), 4.16 – 3.64 (m, 7H), 3.60 – 3.47 (m, 2H), 3.22 – 3.12 (m, 1H), 2.41 – 2.13 (m, 2H), 1.93 – 1.81 (m, 2H), 1.77 – 1.62 (m, 2H).
  • the mixture was heated at 110 oC for 1 h under microwave irradiation. Once at room temperature, the mixture was filtered through Celite ® , washed with EtOAc and the solvents evaporated under reduced pressure. The resulting crude was purified by flash column chromatography, 0-100% hexane/EtOAc.
  • Step 4 (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.4]heptan-5-yl)prop-2-en-1-one 7 M ammonia in methanol (1 mL, 7 mmol, 7 mol/L) was added to (S)-1-(7-((7- (hydroxymethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one (39 mg, 0.07 mmol, 1 eq.) and the solution was stirred at room temperature for 5 h.
  • Step 3 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
  • Diisopropylethylamine (0.93 mL, 5.34 mmol, 5 eq.) and T3P (50% in DMF, 0.77 mL, 1.30 mmol. 1.2 eq.) were added to a solution of acrylic acid (85 mg, 1.19 mmol, 1.1 eq.) in dry DMF (3 mL) under nitrogen atmosphere and the mixture was stirred at room temperature for 30 min.
  • Step 2 N-(5-(Tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-azabicyclo[3.1.1]heptan-4-amine 4 M HCl in dioxane (4.0 mL, 16.0 mmol, 15 eq.) was added to a solution of tert-butyl 4-((5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[3.1.1]heptane-2-carboxylate (574 mg, 1.05 mmol, 1 eq.) in DCM (2 mL).
  • the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL), the aqueous phase was extracted with EtOAc (2 x 10 mL), the combined organic layers were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum.
  • the crude was purified by flash chromatography, 0-100%, heptane/EtOAc to afford the title compound (294 mg, 0.42 mmol, 77.42% yield) as a yellow oil.
  • the reaction was degassed with nitrogen for 5 mins and BrettPhos-Pd-G3 (125 mg, 0.13 mmol, 0.1 eq.) was added.
  • the vial was sealed and the reaction stirred at 60 °C overnight.
  • the reaction was cooled to RT and filtered.
  • the filtrate was taken up in EtOAc (20 mL) and washed with water (2 x 10 ml) and brine (5 ml) then concentrated under reduced pressure.
  • the crude product was purified by column chromatography (Biotage Sfär Duo 10g, 40 ml/min) eluting with 0-100% heptane/EtOAc.
  • Step 2 N-((3R,5S)-5-Methylpiperidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine
  • Tert-butyl (3S,5R)-3-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (1.10 g, 1.88 mmol, 1 eq.) was dissolved in TRIFLUOROACETIC ACID (5 mL) and the solution was stirred at room temperature for 2 h.
  • Step 3 1-((3S,5R)-3-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one
  • Acrylic acid 61 ⁇ L, 0.89 mmol, 1 eq.
  • T3P 50% in DMF (0.58 mL, 0.98 mmol, 1.1 eq.) and DIPEA (0.69 mL, 4.01 mmol, 4 eq.) were added to the solution and the mixture was stirred at r.t. for 30 min.
  • reaction mixture was cooled to 0 oC and a solution of N-((3R,5S)-5-methylpiperidin-3-yl)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (500 mg, 0.89 mmol, 1 eq.) and diisopropylethylamine (0.70 mL, 4.01 mmol, 4 eq.) in dry DMF (2 mL) was added. The solution was stirred at room temperature for 16 h under nitrogen atmosphere.
  • the mixture was diluted with EtOAc, washed with water and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • the crude was purified by reverse phase from 72% [25mM NH4HCO3] - 28% [ACN:MeOH (1:1)] to 36% [25mM NH4HCO3] - 64% [ACN:MeOH (1:1)]) to obtain the title compound (30 mg, 0.08 mmol, 9% yield) as a white solid.
  • EXAMPLE 95 and EXAMPLE 96 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
  • the title compounds were separated from the isomeric mixture of 1-((2R,3R)-2-methyl-3- ((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4
  • RuPhosPdG 3 50 mg, 0.06 mmol
  • cesium carbonate 489 mg, 1.50 mmol, 2.5 eq.
  • the tube was sealed and the reaction was stirred at 90 oC for 16 h.
  • the mixture was filtered over a pad of Celite ® , rinsed with EtOAc and the filtrate was concentrated under reduced pressure.
  • the crude was purified by flash chromatography with 0-40% heptane/EtOAc, 0-40% to give the title compound (0.29 g, 0.52 mmol, 88%) as a gum.
  • Step 4 (R)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one
  • a mixture of trifluoroacetic acid (1.0 mL) and (R)-1-(3,3-dimethyl-4-((3-(tetrahydro-2H- pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (245 mg, 0.49 mmol, 1 eq.) was stirred at room temperature for 3 h.
  • Step 3 1-((2R,3R)-2-Methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one
  • N-((2R,3R)-2-methylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (328 mg, 0.70 mmol, 1 eq.) and triethylamine (0.29 mL, 2.11 mmol, 3 eq.) in DCM (10 mL) was bubbled with nitrogen for 5 min.
  • the mixture was further bubbled with nitrogen for 5 min.
  • the reactor was sealed, and the reaction mixture was stirred at 120 °C for 18 h.
  • the crude was filtered over a pad of Celite ® and rinsing with EtOAc. The filtrate was concentrated, and the crude was purified by flash chromatography with heptane/EtOAc, 0-20%.
  • Step 2 (R)-4-((4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile Tert-butyl (R)-4-((5-cyano-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-3,3- dimethylpyrrolidine-1-carboxylate (131 mg, 0.17 mmol, 1 eq.) was dissolved in trifluoroacetic acid (2.72 mL, 35.35 mmol, 200 eq.) and the mixture was stirred at 25 oC for 1 h.
  • reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography with heptane/EtOAc, 0-100% and repurified by reverse phase obtain (R)-4-((1-acryloyl-4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile (17 mg, 42.69 ⁇ mol, 25% yield) as a white solid.
  • the mixture was heated at 80 oC for 16 h. Once at room temperature, the mixture was filtered through Celite ® , washed with EtOAc and the solvents evaporated under reduced pressure. The resulting crude was purified by normal-phase chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to obtain the desired compound (756 mg, 1.32 mmol, 96% yield) as a yellow solid.
  • the oil was purified by flash chromatography, 0-50% ethyl acetate in heptane followed by low pH reverse phase chromatography eluting with a gradient of 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid).
  • the reaction mixture was stirred for 48 h and then concentrated in vacuo to afford a brown oil.
  • the oil was dissolved in ammonia (in methanol) (10 mL, 70 mmol, 7 mol/L) and was stirred at RT for 72 h.
  • the reaction mixture was concentrated in vacuo to afford a yellow solid.
  • the solid was loaded onto an SCX cartridge (20 g column) and the column was washed with MeOH (3 CV) and the product eluted with 7M ammonia in MeOH (3 CV).
  • the reaction mixture was cooled to 0oC and a solution of acryloyl chloride (60 ⁇ L, 0.74 mmol) was added.
  • the reaction mixture was stirred at 0oC for 1 h before analysis by LCMS, which showed less than 50% conversion.
  • the reaction mixture was retreated with acryloyl chloride (60 ⁇ L, 0.74 mmol) and the reaction mixture was stirred at 0oC for a further 1 h.
  • the organics were removed in vacuo and the aqueous phase was diluted with water (3 mL) and ethyl acetate (3 x 5 mL).
  • EXAMPLE 102 and EXAMPLE 103 1-((3S,5R)-3-Methyl-5-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • the title compounds were separated from an isomeric mixture of 1-((3S,5R)-3-methyl-5-((3- (2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-
  • EXAMPLE 104 and EXAMPLE 105 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-2-methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H
  • the mixture was heated at 80oC for 16 h. Once at room temperature, the mixture was filtered through Celite ® , washed with EtOAc and the solvents evaporated under reduced pressure. The resulting crude was purified by normal-phase chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to obtain the desired compound (251 mg, 0.46 mmol, 88% yield).
  • EXAMPLE 106 and EXAMPLE 107 1-((2S,4R)-2-Methyl-4-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 1-((2S,4R)-2-Methyl-4-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2S,4R)-2-methyl-4-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo
  • reaction mixture was degassed for a further 5 minutes before being heated to 80 oC and stirred for 18 h.
  • the reaction mixture was filtered and the solids washed with ethyl acetate (5 mL).
  • the filtrate was concentrated in vacuo to afford an orange oil that was purified by column chromatography using a Biotage Isolera (10 g column) eluting with a gradient of 0-30% ethyl acetate in heptane.
  • the reaction mixture was stirred for 6 h.
  • the reaction mixture was concentrated in vacuo to afford a brown oil.
  • the oil was dissolved in ammonia (in methanol) (1 mL, 7 mmol, 7 mol/L) and was stirred at RT for 18h.
  • the reaction mixture was concentrated in vacuo to afford a yellow solid.
  • the solid was loaded onto an SCX cartridge (10 g column) and the column was washed with MeOH (3 CV) and the product eluted with 7M ammonia in MeOH (3 CV).
  • the reaction mixture was cooled to 0oC and a solution of acryloyl chloride (54 ⁇ L, 0.66 mmol) in THF (5 mL) was added. The reaction mixture was stirred at 0oC for 1 h. The organics were removed in vacuo and the aqueous was diluted with water (3 mL) and ethyl acetate (3 x 5 mL). The combined organics were concentrated in vacuo to afford a brown oil that was purified by preparative HPLC.
  • EXAMPLE 111 and EXAMPLE 112 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)
  • Step 4 1-((2R,3R)-2-Methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
  • Acryloyl chloride 40 ⁇ L, 0.55 mmol, 1.4 eq.
  • 4-(((2R,3R)-2- methylpyrrolidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine 510 mg, 25%, 0.40 mmol, 1 eq.
  • diisopropylethylamine 0.3 mL, 1.72 mmol, 4 eq.
  • reaction mixture was stirred for 2h 45 min.
  • the reaction mixture was concentrated in vacuo to afford an oil, which was dissolved in 7 N ammonia in methanol (5.0 mL, 35 mmol, 70 eq.) and the solution was stirred at r.t. for 18h.
  • the reaction mixture was concentrated in vacuo to afford a crude that was used without further purification.
  • reaction mixture was degassed for a further 5 mins under sonication, sealed and irradiated under 395 nm light for 20 h.
  • the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (2 x 50 mL) and concentrated in vacuo.
  • the reaction mixture was stirred at r.t. for 6 h.
  • the reaction mixture was concentrated in vacuo and dissolved in 7 M ammonia (in methanol) (10 mL, 70.00 mmol, 233 eq.) and was stirred at r.t. for 72 h.
  • the reaction mixture was concentrated in vacuo to afford a yellow solid.
  • the solid was loaded onto an SCX cartridge (10 g column) and the column was washed with MeOH (3 cv.) and the product eluted with 7M ammonia in MeOH (3 cv.).
  • the methanolic ammonia flush was concentrated in vacuo to afford the title compound (150 mg, 0.30 mmol, 100 % yield).
  • EXAMPLE 117 and EXAMPLE 118 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one 4-(((2R,3R)-2-Methylpyrrolidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine (1
  • EXAMPLE 119, EXAMPLE 120, EXAMPLE 121 and EXAMPLE 122 1-((3S,5R)-3-Methyl-5-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((5-((2R*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyr
  • EXAMPLE 242 1-((3aR,6aS)-5-(3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 1 : RT 1.2 min, m/z 381 [M+H] + , 90%; EXAMPLE 243 1-((3aR,6aS)-5-(3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 1 : RT 1.2 min, m/z 381 [M
  • EXAMPLE 280 (E)-4-(Dimethylamino)-1-((1S*,5R*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1-one LCMS 1 : RT 0.77 min, m/z 411 [M+H] + , 99%; EXAMPLE 281 (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)but-2-en-1-one LCMS 1 : RT 1.5 min, m/z 444 [M+H] +
  • ITK kinase Assay Time Dependent Inhibition (TDI) 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 MBP 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 (5 nM), ATP and MBP in Kinase Assay Buffer III without DTT (12.5 ⁇ M DTT is included in normal ADP-Glo assay).
  • the ATP concentration in the reaction was 30 ⁇ M and the final concentration of DMSO was 1%.
  • the enzyme was pre-incubated with the compounds for 0 minutes and 180 minutes to record any shift in potency of the compounds. Following pre- incubation, the enzymatic reaction took place for 40 minutes at room temperature. Then, the enzymatic reaction was stopped with the addition of 5 ⁇ l of ADP-Glo and incubation for 40 minutes.
  • ITK kinase Assay Determination of k inact /K I Kinetic Parameters of ITK inhibition This in-vitro assay was developed to better understand the SAR by assessing the association kinetics of the compounds to the target (K I ) as well as the rate of inactivation of the target (k inact ). This was done by using the PhosphoSens® kinase assay platform which provides a simple, one-step homogeneous, fluorescence-based assay for rapid and sensitive detection of target ITK kinase activity. The test compounds (ITK inhibitors) were spotted into an ARP using the Tecan D300e (start concentration 10 ⁇ M, 1:2 serial dilution to obtain 16-point CRCs).
  • the 1X reaction buffer was freshly prepared by diluting the 10X reaction buffer in ultrapure water.
  • 1.25X ATP (FAC:1mM) and 1.25X substrate-AQT0101 (FAC: 20uM) was added.
  • 5X ITK enzyme (FAC: 5nM) is prepared in 1X enzyme dilution buffer.16 ⁇ L/well of the reaction buffer containing ATP and substrate was carefully added with the ThermoFisher E1-ClipTipTM (16 channel, 2 to 125 ⁇ l), followed by addition of 4 ⁇ L/well of enzyme-buffer mix.
  • the 1X reaction buffer was freshly prepared by diluting the 10X reaction buffer in ultrapure water.
  • 1.25X ATP FAC:1mM
  • 1.25X substrate-AQT0661 FAC: 20uM
  • 5X JAK3 enzyme FAC: 5nM is prepared in 1X enzyme dilution buffer. 16 ⁇ L/well of the reaction buffer containing ATP and substrate was carefully added with the ThermoFisher E1-ClipTipTM (16 channel, 2 to 125 ⁇ l), followed by addition of 4 ⁇ L/well of enzyme-buffer mix.
  • k inact /K I values for ITK and JAK3 are represented by letters according to the value: A: > 2000 (M -1 s -1 ) B: 500 – 2000 (M -1 s -1 ) C: 100 - ⁇ 500 (M -1 s -1 )
  • selectivity ITK/JAK3 is represented by the following symbols: +++: >10 ++: 5-10 +: 2- ⁇ 5 -: ⁇ 2
  • Example ITK JAK3 Selectivity k inact /K I k inact /K I ITK/JAK3 (M -1 s -1 ) (M -1 s -1 ) ratio kinact/KI Ritlecitinib C A -
  • ITK cellular activity assay IL-2 inhibition in Jurkat cells
  • the ITK Inhibitors’ potency inhibiting IL-2 cytokine was tested in Jurkat cells (Jurkat clone E6-1, ATCC-TIB-152) stimulated with PHA (Phytohemagglutinin PHA-M, Sigma-L8902) to activate the production of IL-2 in T-lymphocyte.
  • Method 1.00E 6 Jurkat cells/well in 130 ⁇ l of assay media (RPMI-1% Glutamax-10% FBS) were seeded in 96 well plates and incubated for 2 h.
  • ITK cellular activity assay IL-2 inhibition in PBMC cells
  • the ITK Inhibitors’ potency inhibiting IL-2 cytokine was tested in PBMC cells (isolated from healthy donors) stimulated with aCD3-aCD28 Dynabeads (Dynabeads Human T-activator CD3/CD28, Gibco-11132D) to activate the production of IL-2 in these cells.
  • Method 0.15x106 PBMC cells/well in 80 ⁇ l of assay media (RPMI/Glutamax, 20 mM Hepes, 10.000 U/mL penicillin/streptamycin, 10% FBS) were seeded in 96 well plates and incubated for 2 h at 37 oC, 5% CO2.
  • JAK3 cellular activity assay IL4-induced pSTAT6 assay in human reporter Ramos cells
  • IL4-induced pSTAT6 assay in Ramos cells transfected with a ⁇ -lactamase reporter gen system under the control of STAT6 promoter, Ramos STAT6-bla RA-1, (Life Technologies K1243) were seeded at a concentration of 0.75x10 6 cells/well in 384-well plate (40 ⁇ L) and incubated overnight at 37 oC, 5% CO 2 in complete Optimem Media containing 556 ng/mL CD40, 0.5% FBS, 10 mM non-essential aminoacids, 100 mM sodium pyruvate and 10.000 U/mL penicillin/streptamicin.
  • inhibitors were initially dissolved in 100% DMSO and curves prepared using 1/5 serial dilutions (10 dilutions, final range from 5 ⁇ M to 64 pM).5 ⁇ l of the inhibitor dilution curves, pre-diluted 1/50 in complete Optimem Media, were added to the cells and pre-incubated 60 min at 37 oC, 5% CO 2 ..
  • a solution of IL-4 was prepared at 10-fold its EC 80 in Optimem media and 5 ⁇ L were added to cells for IL-4 stimulation and incubated during 4h at 37 oC, 5% CO 2 .
  • To stop the reaction 10 ⁇ L of the b-lactamase substrate mixture was added to the wells and the plate was left over/night in the dark.
  • IC 50 values for ITK and JAK3 are represented by letters according to the value: A: ⁇ 100 nM B: 100 – 1000 nM C: >1000 – 10000 nM D: > 10000 nM And selectivity JAK3 IC 50 /ITK IC 50 is represented by the following symbols: +++: >100 ++: 30-100 +: 10- ⁇ 30 -: ⁇ 10 Ratio JAK3 JAK3 cellular ITK cell ce (Ramos)IC 50 (Jurkat) ll Example / ITK IC (Ramos) 50 cellular IC50 (nM) IC50 (nM) (Jurkat) A>100 B>30 C>10 Ritlecitinib A A - 1 A n.t.
  • heterobicyclic derivatives of the present invention are selective versus JAK3 in cells.
  • the heterobicyclic derivatives of the present invention also exhibit high selectivity against other kinases. 7.
  • NanoBRET ITK-NanoLuciferase and JAK3-NanoLuciferase fusion vectors were purchased from Promega. Nanoluciferase target fusion constructs and transfection carrier DNA were combined at a mass ratio of 1:10 before addition of FuGENE HD to form complexes at a ratio of 1:3 DNA:FuGENE according to the manufacturers protocol.20 parts of HEK cells resuspended at a density of 2 x 10 5 cells/ml in OptiMEM + 1% FBS were combined with 1 part of the transfection complexes (v/v).
  • Dual filtered luminescence was measured on BMG Labtech Pherastar FSX with a 450 nm BP filter (donor) and 610 LP filter (acceptor).
  • Some of the acronyms used above have the following meaning: n.t.: not tested 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.

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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. 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). 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. 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. 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. 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. 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. 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. Several companies are developing ITK inhibitors, but many of these also target additional tyrosine kinases. For instance, ritlecitinib is a marketed small molecule that covalently and irreversibly inhibits Janus kinase 3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC). ATI-2138 is a dual ITK/JAK3 inhibitor currently in phase II clinical trials for the treatment of autoimmune and inflammatory diseases. Similarly, VIT-801 is a dual ITK/BTK inhibitor that is expected to begin clinical development soon. A key aspect in the field of ITK inhibitors is finding compounds with the required selectivity to ensure proper safety profile in a clinical setting. There remains the need for new effective and selective compounds that avoid inhibition of kinases such as JAK kinases that are associated in some cases with adverse effects such as infections, thrombosis and hematological, liver enzymes or lipids alterations among others. SUMMARY OF THE INVENTION The present inventors have identified novel compounds which are inhibitors of ITK kinase. The present invention therefore provides a heterobicyclic derivative, which heterobicyclic derivative is a compound of formula (I) or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, wherein • X1 is N or CR1, wherein R1 is selected from H, halogen, nitrile, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and -C1-2 alkyl-O-C1-2 alkyl; • (a) X2 is C and X3 is NH or (b) X2 is N and X3 is CH, • G1 is a 5-7 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R3 groups and/or (b) two R3a groups, wherein each R3 group is independently selected from C1-4 alkyl, oxo, hydroxy, nitrile, C1-4 alkoxy, halogen, C1-4 haloalkyl and -C1-2 alkyl-O-C1-2 alkyl, provided that two hydroxy groups are not attached to the same atom, and wherein the two R3a groups are attached to the same carbon atom of the O- containing heterocyclic ring, and the two R3a groups together form a 3-to 6- membered spirocyclic group optionally comprising an O atom; • Y is selected from -N(R2)-, -O- and -C(HR2a)-, wherein R2 is selected from H, C1-4 alkyl and C1-4 haloalkyl; and R2a is selected from H, halogen, C1-4 alkyl and C1-4 haloalkyl; • n is 0 or 1; • G2 is a 4-10 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, hydroxy, C1-4 hydroxyalkyl and C1-4 alkoxy, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 6- membered spirocyclic group optionally comprising an O atom; and • G3 is selected from -C(=O)C2-4 alkenyl, -NR5C(=O)C2-4 alkenyl, -C(=O)C2-4 alkynyl, -NR5C(=O)C2-4 alkynyl and –(NR5)0-1CN, provided that G3 is neither - NR5C(=O)C2-4 alkenyl, -NR5C(=O)C2-4 alkynyl nor –(NR5)CN when G3 is attached to a N- atom in G2, wherein said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C1-2 haloalkyl, nitrile and N(R6)2, and said C2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C1-2 haloalkyl, nitrile and N(R6)2, wherein R5 is H or C1-4 alkyl, and each R6 is the same or different and is a C1-3 alkyl. DETAILED DESCRIPTION OF THE INVENTION When describing the compounds, compositions, combinations and methods of the present invention, the following terms have the following meanings, unless otherwise indicated. Definitions 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. 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. 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. The compounds 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 compounds 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 compounds 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. In the case of compounds of the invention 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. Compounds of the present invention containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. 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*)-1-(4-((5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one, wherein (R*) means that the configuration of the chiral center present in the compound is unknown, being R or S, in this case arbitrarily denoted as R, as opposed to (S*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one, which has the inverse configuration at same position. In case that more than one chiral center is present, the configurational descriptors R* or S* in each chiral center are assigned independently from one another. An example of such situation would be 1-((3S,5R)-3-methyl-5-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one, wherein (2R*,4R*) means that both chiral centers at the C2 and at the C4 position of the tetrahydropyrane ring are unknown, being each of them either R or S independently. In this same example, the chiral centers at the C3 and C5 positions of the piperidine ring are known to be S and R respectively. As used herein, "alkyl" is intended to include both branched and linear (straight- chain) saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" (or alkylene), is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. "C1-C3 alkyl" (or alkylene), is intended to include C1, C2 and C3 alkyl groups. Additionally, for example, "C1-C6 alkyl" denotes alkyl having 1 to 6 carbon atoms. "C1-C3 alkyl" denotes alkyl having 1 to 3 carbon atoms. Typically, C1-C6 alkyl is preferably C1-C4 alkyl, more preferably C1-C3 alkyl, and is more preferably methyl. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (for example n- propyl, i-propyl, preferably i-propyl) and butyl (for example n-butyl, i-butyl, sec-butyl and t-butyl, preferably t-butyl). For the avoidance of doubt, where two alkyl moieties are present in a group, the alkyl moieties may be the same or different. As used herein, “alkenyl” refers to a branched or linear (straight-chain) hydrocarbon group comprising one or more double bonds and having the specified number of carbon atoms. For instance, examples of C2-4 alkenyl include -CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C(CH3)=CH-CH3 and -CH=CH-CH=CH2. As used herein, “alkynyl” refers to a branched or linear (straight-chain) hydrocarbon group comprising one or more triple bonds and having the specified number of carbon atoms. For instance, examples of C2-4 alkynyl include -C≡CH, -CH2-C≡CH, - C≡C-CH3 and -C≡C-CH2-CH3. As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine, more preferably chlorine or fluorine, and most preferably fluorine. As used herein, the term “haloalkyl” is intended to include both branched and linear (straight-chain) saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, and which contains at least one halogen atom. The halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, fluorine or bromine, more preferably chlorine or fluorine, and most preferably fluorine. Typically, C1-C6 haloalkyl is preferably C1-C4 haloalkyl, and more preferably C1-C3 haloalkyl, for example C1-C3 fluoroalkyl. As used herein, the term “C1-C4 alkoxy” refers to a said C1-C4 alkyl group attached to an oxygen atom. As used herein, the term “spirocyclic group” refers to a cyclic or heterocyclic group formed on, and sharing one atom with, a second cyclic or heterocyclic group. A spirocyclic group formed from two alkyl groups bonded to the same carbon atom of a heterocyclic ring corresponds to a cycloalkyl group which together with the heterocyclic ring form a spiro bicyclic moiety. A spirocyclic group formed from two groups bonded to the same carbon atom of a heterocyclic ring corresponds to heterocyclyl group which together with the heterocyclic ring form a spiro bicyclic moiety. As used herein, "heterocyclyl”, “heterocycle” or "heterocyclic” (or “heterocyclylene”) refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic, spirocyclic), non-aromatic, saturated or partially unsaturated ring system whose ring atoms consist of carbon atoms and at least one heteroatom selected from O, S and N. The at least one heteroatom is commonly 1-3 heteroatoms, for instance 1-2 heteroatoms or 1 heteroatom. Preferably, the at least one heteroatom ring atom is selected from N and O, more preferably N. Preferably, the heterocyclyl is monocyclic or bicyclic. In one embodiment, the heterocyclyl is saturated. In one embodiment, the heterocyclyl is unsaturated. Two rings in a polycyclic heterocyclic may form a bridged bicyclic moiety (three or more atoms shared by the two rings), a fused bicyclic moiety (two adjacent atoms shared by the two rings), or a spiro bicyclic moiety (a single atom shared by the two rings). As used herein, the term “O-containing heterocyclic ring” refers to a heterocyclic ring comprising at least one oxygen atom as a ring atom and optionally one or more heteroatom ring atom selected from N and S. Typically, an O-containing heterocyclic ring comprises one or two heteroatom ring atoms which are O and zero or one heteroatom ring atom which is N. The ring atoms of an O-containing heterocyclic ring may consist of carbon and one or two O atoms. As used herein, the term “N-containing heterocyclic ring” refers to a heterocyclic ring comprising at least one nitrogen atom as a ring atom and optionally one or more heteroatom ring atom selected from O and S. Typically, an N-containing heterocyclic ring comprises one or two heteroatom ring atoms which are N and zero or one heteroatom ring atom which is O. The ring atoms of an N-containing heterocyclic ring may consist of carbon and one or two N atoms. Typical examples of heterocycles include 4- to 10-membered heterocycles, wherein “X-membered” means that the total number of ring atoms in the heterocycle is X. Preferred heterocycles are 5- to 10-membered heterocycles, 9- to 10-membered heterocycles, 4- to 7-membered heterocycles, 4- to 6-membered heterocycles, 4- to 5- membered heterocycles and 5- to 6-membered heterocycles. Examples of heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, piperazinyl, pyrazolidinyl, piperadinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, indolinyl and tetrahydropyrazolo[1,5-a]pyrazinyl. Preferred examples of heterocycles include oxetanyl, piperidinyl and pyrrolidinyl. As described herein, a heterocycle may be substituted by one or more oxo groups, typically one oxo group. Examples of heterocycles substituted by one oxo group include pyrrolidinonyl and oxoindolinyl. As described herein, the compounds of the present invention share a general formula (I), which contains the following core structure: The solid circle within the ring in the left-hand side ring represents the aromaticity of the ring. The solid circle within the ring in the right-hand side represents the different positions that can be adopted by the double rings of the right-hand side ring as shown below: Compounds The invention relates to compounds 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: Preferably, the heterobicyclic derivative of the invention is a compound as described herein or a pharmaceutically acceptable salt, or a solvate, or a tautomer, or a stereoisomer thereof. X1 is N or CR1 and either (a) X2 is C and X3 is NH or (b) X2 is N and X3 is CH. R1 is typically H, halogen, nitrile, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy. Preferably, R1 is H, halogen, nitrile, C1-2 alkyl, C1-2 haloalkyl, or C1-2 alkoxy. More preferably, R1 is H or F, for instance R1 is H. Typically, X1 is N or CR1, wherein R1 is selected from H and halogen, C1-2 alkyl, C1-2 haloalkyl and C1-2 alkoxy; and (a) X2 is C and X3 is NH or (b) X2 is N and X3 is CH. Preferably, R1 is H. Typically, X2 is C and X3 is NH. Preferably, X1 is N, X2 is C and X3 is NH. In another preferred embodiment, X1 is CR1, preferably CH, X2 is C and X3 is NH. G1 is a 5-7 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R3 groups and/or (b) two R3a groups. As such, the O-containing heterocyclic ring may be substituted with: one, two or three R3 groups and zero R3a groups; zero R3 groups and two R3a groups; or one, two or three R3 groups and two R3a groups. Each R3 group is typically independently selected from C1-4 alkyl, hydroxy, nitrile, C1-4 alkoxy, halogen, C1-4 haloalkyl. Each R3 group may be methyl or fluoro. Each R3a group is attached to the same carbon atom of the O-containing heterocyclic ring, and the two R3a groups together form a 3-to 6-membered spirocyclic group optionally comprising an O atom. As such, when the O-containing heterocyclic ring is substituted with two R3a groups, these are bonded to the same ring carbon atom in the heterocyclic ring and together form a 3-to 6-membered spirocylic ring on the heterocyclic ring. For instance, if G1 is tetrahydropyran substituted with two R3a groups might form spirocyclic groups as follows: Typically, G1 is a 5 or 6 membered O-containing heterocyclic ring, wherein said O- containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R3 groups and/or (b) two R3a groups. G1 may be a 5 or 6 membered O-containing heterocyclic ring, wherein said heterocyclic ring is unsubstituted or substituted with one, two or three R3 groups. More preferably, G1 is a 6 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R3 groups and/or (b) two R3a groups. G1 may be a 6 membered O-containing heterocyclic ring, wherein said heterocyclic ring is unsubstituted or substituted with one, two or three R3 groups. Preferably, G1 is saturated. If G1 is substituted with one, two or three R3 groups, R3 is preferably C1-4 alkyl, hydroxy, nitrile, C1-4 alkoxy, or C1-4 haloalkyl, provided that two hydroxy groups are not attached to the same atom. More preferably R3 is C1-3 alkyl, hydroxy, nitrile, C1-3 alkoxy, or C1-3 haloalkyl, provided that two hydroxy groups are not attached to the same atom. Yet more preferably, R3 is C1-2 alkyl, C1-2 alkoxy, halogen or C1-2 haloalkyl. Most preferably, R3 is methyl, methoxy or fluoro. If G1 is substituted, G1 is typically substituted by one or two R3 groups (and zero R3a groups). If G1 is substituted with at least one R3 group and two R3a groups, G1 is typically substituted with one or two R3 groups and two R3a groups. Preferably G1 is unsubstituted. G1 may be selected from oxetane, tetrahydrofuran, tetrahydropyran and oxepane. G1 is typically tetrahydropyran or tetrahydrofuran. G1 is preferably tetrahydropyran which is unsubstituted or substituted with one or two groups selected from methyl and fluoro. Preferably, G1 is other than 3,6-dihydro-2H-pyranyl, more preferably other than any dihydropyranyl group. Most preferably, G1 is saturated. G1 may be bonded to the rest of the compound via any of the carbon ring atoms in the O-containing heterocyclic ring. G1 may for instance be selected from: Y is selected from -N(R2)-, -O- and -C(HR2a)-. Y is typically -N(R2)- or-O-. Preferably, Y is -N(R2)-. R2 is preferably H or C1-4 alkyl. More preferably, R2 is H, or C1-3 alkyl. Most preferably R2 is H. If Y is -C(HR2a)-, R2a is typically H, halogen or C1-3 alkyl, preferably H. In another preferred embodiment, Y is -O-. In some embodiments, n is 1. In some embodiments, n is 0. When n is 0, Y is not present and G2 is directly bonded to the central bicyclic moiety. G2 is typically a 4-10 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-3 alkyl, halogen, C1-2 haloalkyl and C1-2 alkoxy, and wherein the two R4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R4a groups together form a 3- to 6-membered spirocyclic group optionally comprising an O atom. G2 may be an unsubstituted 4-10 membered N- containing monocyclic or bicyclic heterocyclic ring. G2 is preferably a 5-9 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups. More preferably, G2 is preferably a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N- containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups, , wherein each R4 is independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, hydroxy, C1-4 hydroxyalkyl and C1-4 alkoxy, and wherein the two R4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R4a groups together form a 3-to 6-membered spirocyclic group optionally comprising an O atom. G2 may be substituted with one or two R4 groups, where R4 is C1-3 alkyl, halogen, C1-3 haloalkyl or C1-3 alkoxy. Preferably R4 is C1-2 alkyl, halogen, C1-2 alkoxy, or C1-2 haloalkyl. More preferably, R4 is methyl or fluoro. G2 may be unsubstituted or substituted with one or two R4, wherein each R4 is independently selected from C1-2 alkyl, C1-2 alkoxy, halogen or C1-2 haloalkyl. If G2 is substituted with two R4a groups, the two R4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R4a groups together form a 3- to 6-membered spirocyclic group optionally comprising an O atom. Typically, the two R4a groups together form a 3-, 4-, 5- or 6-membered spirocyclic group. Preferably, the two R4a groups together form a 3-membered spirocyclic group (i.e. together form a cyclopropyl group with the G2 ring carbon atom to which they are bonded). In some instances, G2 is substituted with two R4a groups, wherein the two R4a groups are attached to the same carbon atom of the N-containing heterocyclic ring, and the two R4a groups together form a 3- to 6-membered spirocyclic group comprising an O atom (i.e. together form an oxetanyl group). G2 may be (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups. G2 may be substituted with (a) one, two or three R4 groups and/or (b) two R4a groups. If G2 is substituted, G2 is preferably substituted by one, or two R4 groups. Exemplary G2 groups include:
wherein, * and ** represent the points of attachment to the rest of the compound. For instance, * may be the point of attachment to (Y)n, and ** may be the point of attachment to G3. Alternatively, ** may be the point of attachment to (Y)n, and * may be the point of attachment to G3. In some embodiments, n is 1. When n is 1, Y is preferably -N(H)-. When n is 1, G2 is preferably selected from: wherein each of p, q, r, r’, s, t and t’ is independently 0, 1, 2 or 3; u is 1, 2 or 3; the point of attachment to Y is obtained by removing a hydrogen atom from one of the carbon atoms in G2; and the N atom in G2 is bonded to G3 and wherein G2 is unsubstituted or substituted as described herein. Preferably, G2 is unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are bonded to the same carbon atom in G2 and the two groups together form a spirocyclic cyclopropyl group. G2 is preferably unsubstituted or substituted with one methyl group. The sum of r, q and s and the sum of t and u are each such that G2 is at most a 10 membered N-containing bicyclic heterocyclic ring as defined herein (which may be unsubstituted or substituted as defined herein). Typically, p is 1 or 2. Typically, q is 0 or 1, r, r’, s and s’ are each independently 0, 1 or 2. Typically, t and t’ are each independently 0, 1 or 2 and u is 1 or 2. Preferably, when n is 1, G2 is selected from: wherein * represents the point of attachment to Y, and the N atom in G2 is bonded to G3, wherein G2 is unsubstituted or substituted with one or two substituents selected from methyl and fluoro. More preferably, when n is 1, G2 is selected from: wherein G2 is unsubstituted or substituted with one or two substituents selected from methyl and fluoro. For instance, when n is 1, G2 may be selected from: (i.e. in each case without further substituents) wherein * represents the point of attachment to Y, and the N atom in G2 is bonded to G3. In some embodiments, n is 0. When n is 0, G2 is typically selected from: wherein: each of p, q, r, r’, s, s’, t, t’, v and v’ is independently 0, 1, 2 or 3; m is 2 or 3; and wherein each of p, q, r, r’, s, s’, t, t’, v’and v’ is independently 0, 1, 2 or 3; m is 2 or 3; and one N is attached to the atom adjacent to X1 and the other N is attached to G3, and wherein G2 is unsubstituted or substituted as described herein. G2 is preferably unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are two groups bonded to the same carbon atom in G2 and the two groups together form a spirocyclic cyclopropyl group. The sum of m and p, the sum of q, r, r’, s and s’ and the sum of t, t’, v and v’ are each such that G2 is at most a 10 membered N-containing bicyclic heterocyclic ring as defined herein (which may be unsubstituted or substituted as defined herein). When n is 0, G2 may be: wherein: w is 1, 2 or 3, the dotted double bond is present or absent, the point of attachment to the atom adjacent to X1 is obtained by removing a hydrogen atom from a ring carbon atom, and the N is attached to G3, and wherein G2 is unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are two groups bonded to the same carbon atom in G2 and the two groups together form a spirocyclic cyclopropyl group. w is typically 1 or 2. When n is 0, G2 is typically selected from: wherein, * represents the point of attachment to the atom adjacent to X1, and ** represents the point of attachment to G3. For instance, when n is 0, G2 may be selected from wherein, * represents the point of attachment to the atom adjacent to X1, and ** represents the point of attachment to G3. In a preferred embodiment, when n is 0, G2 may be selected from wherein, * represents the point of attachment to the atom adjacent to X1, and ** represents the point of attachment to G3. G3 is typically selected from -C(=O)C2-4 alkenyl, -NR5C(=O)C2-4 alkenyl, - C(=O)C2-4 alkynyl, -NR5C(=O)C2-4 alkynyl and –(NR5)0-1CN, provided that G3 is neither - NR5C(=O)C2-4 alkenyl, -NR5C(=O)C2-4 alkynyl nor –(NR5)CN when G3 is attached to a N- atom in G2, wherein said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C1-2 haloalkyl and N(R6)2, and said C2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C1-2 haloalkyl and N(R6)2, wherein R5 is H, and each R6 is the same or different and is a C1-2 alkyl. If G3 is attached to a N-atom in G2, G3 is selected from -C(=O)C2-4 alkenyl, - C(=O)C2-4 alkynyl and -CN, wherein said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C1-2 haloalkyl, nitrile and N(R6)2, and said C2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C1-2 haloalkyl, nitrile and N(R6)2. Typically, said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from methyl, fluoro and N(CH3)2. Preferably, said C2-4 alkenyl is unsubstituted. Preferably, said C2-4 alkynyl is unsubstituted. If G3 is attached to a C-atom in G2, G2 is typically selected from -NR5C(=O)C2-4 alkenyl, a-NR5C(=O)C2-4 alkynyl and –(NR5)0-1CN . Preferably, said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, or N(CH3)2. Preferably, said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, or N(R6)2. Preferably said C2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C1-2 haloalkyl, or N(R6)2. Preferably R6 is a C1-2 alkyl. More preferably, R6 is methyl. More Preferably, said C2-4 alkenyl is unsubstituted. More preferably said C2-4 alkynyl is unsubstituted. More Preferably, said C2-4 alkenyl is unsubstituted. More preferably said C2-4 alkynyl is unsubstituted. Preferably R5 is H or C1-2 alkyl. More preferably, R5 is H or methyl. Most preferably, R5 is H. Typically, G3 is attached to a N-atom on G2, and G3 is selected from: . a on . Preferably, when G2-G3 is: wherein * represents the point of attachment to Y, G1 is other than 3,6-dihydro-2H-pyranyl, more preferably other than any dihydropyranyl group. In this embodiment, most preferably, G1 is saturated. The invention also provides a compound which compound is (a) a heterobicyclic derivative of formula (I), wherein Y, X1, X2, X3, G1, G2, G3 and n are as defined herein; or (b) a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative of said heterobicyclic derivative, provided that said compound is not 1-(5-((5-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one or any acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer thereof. Preferably, the heterobicyclic derivative is a compound of formula (Ii) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein X1, R1, X2, X3, Y, R2, R2a, n, G2, R4, R4a, G3, R5 and R6 are as defined above for formula (I). Typically, in formula (Ii), X1 is N or CR1, X2 is C, X3 is NH, Y is -O- or - N(R2)-, R2 is H or methyl, G3 is attached to a N-atom on G2, and G3 is selected from: . In some instances, the heterobicyclic derivative is a compound of formula (Iii) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein Y, R2, R2a, n, G2, R4, R4a, G3, R5 and R6 are as defined above for formula (I). In some instances, the heterobicyclic derivative is a compound of formula (Iiii) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein R1, Y, R2, R2a, n, G2, R4, R4a, G3, R5 and R6 are as defined above for formula (I). Preferably, the heterobicyclic derivative is a compound of formula (Iiv) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein Y, R2, R2a, n, G2, R4, R4a, G3, R5 and R6 are as defined above for formula (I). In some instances, the heterobicyclic derivative is a compound of formula (II) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:
wherein: Y is -NH- or -O-; G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2. In some instances, the heterobicyclic derivative is a compound of formula (IIa) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein: Y is -NH- or -O-; G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2. In some embodiments, in formula (II) and (IIa), Y is preferably -NH-. In other embodiment, in formula (II) and (IIa), Y is preferably -O-. In formula (II) and (IIa), if G2 is substituted with one or two R4 groups, R4 is preferably methyl or fluorine. If G2 is substituted, G2 is preferably substituted by one R4 group. Preferably, R7a is H. Preferably R7b is H. In formulae (Ii), (Iii), (Iiii), (Iiv), (II) and (IIa), G2 is typically selected from: wherein * represents the point of attachment to Y, and the N atom in G2 is bonded to G3, where G2 is unsubstituted or substituted with one or two substituents selected from methyl and fluoro. In some instances, the heterobicyclic derivative is a compound of formula (III) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- memebered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2. Preferably, R7a is H. Preferably R7b is H. In formula (III), G2 may be selected from In some instances, the heterobicyclic derivative is a compound of formula (IV) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative therof: wherein: G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring contains at least two nitrogen atoms, and is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2. In some instances, the heterobicyclic derivative is a compound of formula (IIIa) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- memebered spirocyclic group; and , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2. Preferably, R7a is H. Preferably R7b is H. In formula (IIIa), G2 may be selected from In some instances, the heterobicyclic derivative is a compound of formula (IVa) or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative therof: wherein: G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring contains at least two nitrogen atoms, and is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2. In formulae (IIIa) and (IVa), R1 is preferably H, F or CN. Preferably, R1 is H. Preferred compounds of formula (I) are: • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one • N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3- yl)acrylamide • 1-((1R,5R)-6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one • (R)-1-(2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(4-(3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1- yl)prop-2-en-1-one • (R)-1-(3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1- yl)prop-2-en-1-one • (S)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R,E)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one • (R,Z)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-yn-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-yn-1-one • (R)-2-methyl-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • (R)-2-fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • (R,E)-4-(dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (R,E)-4-(dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one • (R)-1-(3,3-difluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-fluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2R,5R)-2-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2S,5R)-2-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2S,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-3-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-3-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,4S)-3-fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)prop-2-en-1-one • 1-(7-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1R,2R,5R)-2-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1- yl)prop-2-en-1-one • rac-1-((4aR,7aR)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one • 1-((4aS,7aS)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one • 1-((4aR,7aR)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one • 1-((1R,4R)-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1S,4S)-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(2-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one • rac-1-((3aR,7aS)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one • 1-((3aS,7aR)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one • 1-((3aR,7aS)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one • rac-1-((3aR,7aR)-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one • 1-((3aS,7aS)-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one • 1-((3aR,7aR)-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl)prop-2-en-1-one • 1-(8-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one • 1-(5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)prop-2-en-1-one • 1-((1S,5S)-6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((1S,5R)-3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one • 1-((1R,5S)-3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one • 1-(7-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7- diazaspiro[3.5]nonan-1-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.5]nonan-1-yl)prop-2-en-1-one • 1-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one • 1-(2-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.5]nonan-6-yl)prop-2-en-1-one • 1-(2-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazaspiro[3.4]octan-5-yl)prop-2-en-1-one • 1-((2S,6R)-2,6-dimethyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one • 1-(7-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one • (S)-1-(2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one • 1-(2,2-dimethyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- dihydropyridin-1(2H)-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-1- yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dihydro- 1H-pyrrol-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-1- yl)prop-2-en-1-one • (R)-1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-1-yl)prop-2-en-1-one • (S)-1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-1-yl)prop-2-en-1-one • N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4- yl)acrylamide • (R)-N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)acrylamide • (R)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acrylamide • (S)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acrylamide • (S)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)acrylamide • 1-((1S*,4S*)-4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1R*,4R*)-4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-(4-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazin-1-yl)prop-2-en-1-one • rac-1-((1R,4R,5R)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-((1R*,4R*)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • rac-1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4- yl)cyanamide • 1-((1S*,4S*)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • (R)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)prop-2-en-1-one • 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-oxa-2,8- diazaspiro[3.5]nonan-8-yl)prop-2-en-1-one • (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 4-((1S,4S)-5-Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1R*,4R*,5R*)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-((1S*,4S*,5S*)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2S,3S)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-oxa-2,5- diazaspiro[3.5]nonan-5-yl)prop-2-en-1-one • 4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidine-1-carbonitrile • 1-((1S,4S)-5-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propan-1-one • (R)-4-((1-Acryloylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile • (R)-4-((1-Acryloylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-yn-1-one • 1-((3R,5R)-3-Methoxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.5]octan-5-yl)prop-2-en-1-one • 1-((1S*,5R*)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,6-diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one • 1-((1R*,5S*)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,6-diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one • 1-((3aR,6aR)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)prop-2-en-1-one • (R)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R*)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-azaspiro[2.5]octan-5-yl)prop-2-en-1-one • (S*)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-azaspiro[2.5]octan-5-yl)prop-2-en-1-one • 1-((1R*,4R*,7R*)-7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1S*,4S*,7S*)-7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(7-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one • 1-((3aS,6aS)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)prop-2-en-1-one • (R)-1-(3,3-Dimethyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-(Methyl(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-(Methyl(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azetidin-1-yl)prop-2-en-1-one • (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • (R*)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • (S*)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • 1-((2S,4R)-2-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3R,4S)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 4-(((2R,3R)-1-Acryloyl-2-methylpyrrolidin-3-yl)oxy)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-4-((1-Acryloyl-4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((2R,3R)-3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,4R)-2-Methyl-4-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,4R)-2-Methyl-4-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • (S*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2R*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2S*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3aS*,6aR*)-3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR*,6aS*)-3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR,6aS)-3a,6a-dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-(1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one • 1-((1S*,5R*)-1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one • 1-((1R*,5S*)-1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one • 1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • (S*)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (R*)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-Fluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (S*)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R*)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-(trifluoromethyl)piperidin-1-yl)prop-2-en-1-one • (S)-1-(4,4-Difluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,5R)-2-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 4-(((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 4-((3aR,6aS)-5-Acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 4-(((3R,6S)-1-Acryloyl-6-methylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 4-(((3R,5S)-1-Acryloyl-5-methylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((3S,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-(5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-((1R,4R)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((3S,4S)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one • rac-1-((1R,4R,6R)-6-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • rac-1-((1R,4R,6S)-6-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • (R)-1-(3-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,4S)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 4-(4-Acryloylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine-5-carbonitrile • 1-((3R,5R)-3-Hydroxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((R)-3-((5-((2R*,4R*)-2-Methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((R)-3-((5-((2S*,4S*)-2-Methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4S)-3-Hydroxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,5R)-2-Isopropyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((1S,5R,6R)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1-one • 1-((3S,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-((5-((S*)-3,3-Difluorotetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-((5-((R*)-3,3-Difluorotetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • rac-1-((3R,4R)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S*,4S*)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R*,4R*)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-(9-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,9- diazabicyclo[3.3.1]nonan-3-yl)prop-2-en-1-one • (S)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-yn-1-one • 1-((3R,4S)-3-Hydroxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-(8-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6,8- diazabicyclo[3.2.2]nonan-6-yl)prop-2-en-1-one • 1-((3S,4S)-4-Methoxy-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((S*)-oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((R*)-oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methoxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3- azabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one • 1-((2R,3R)-2-Isopropyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,5R)-5-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Isopropyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-5- azaspiro[2.4]heptan-5-yl)prop-2-en-1-one • (R)-1-(3,3-Dimethyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,5S)-3-((5-((3R*,4R*)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • 1-((3R,5S)-3-((5-((3S*,4S*)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one • 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-yn-1-one • 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one • 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-yn-1-one • (E)-1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-en-1-one • (Z)-1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-en-1-one • (Z)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • 1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)but-2-yn-1-one • 2-Fluoro-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (E)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • 1-((3aR,6aS)-5-(3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4R)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (S*,E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (R*,E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (S,E)-1-(4,4-Difluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)but-2-en-1- one • (E)-4-(Dimethylamino)-1-((3R,4S)-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)piperidin-1-yl)but-2-en-1- one • 4-(((3S,4S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-4-fluoropiperidin-3-yl)amino)- 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • (S,E)-4-((1-(4-(Dimethylamino)but-2-enoyl)-4,4-difluoropiperidin-3-yl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • (E)-4-(Diethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-1-((3S)-4,4-Difluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1- one • (E)-1-((S)-4,4-Difluoro-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1- one • (E)-1-((S)-4,4-Difluoro-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1- one • (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one • rac-(E)-1-((2R,3R,5S)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1- one • (E)-1-((2S*,3S*,5R*)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1- one • (E)-1-((2R*,3R*,5S*)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1- one • 4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (R,E)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)but-2-en-1-one • (R,E)-4-((1-(4-(Dimethylamino)but-2-enoyl)-4,4-dimethylpyrrolidin-3-yl)amino)- 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((2R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpyrrolidin-1-yl)but-2-en-1-one • 4-(((3R,5S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-5-methylpiperidin-3-yl)amino)- 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • (E)-4-(Dimethylamino)-1-((2S,5R)-5-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)but-2-en-1-one • (R,E)-4-(Dimethylamino)-1-(7-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)but-2-en-1-one • (E)-4-(Diisopropylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)-5-methylpiperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((1R*,5S*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((1S*,5R*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)but-2-en-1-one • 4-(((3R,6S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-6-methylpiperidin-3-yl)amino)- 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • (E)-4-(Dimethylamino)-1-((1S*,4R*,6R*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((1R*,4S*,6S*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((1R*,4S*,6R*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((1S*,4R*,6S*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one • 4-(Dimethylamino)-1-(5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one • (E)-1-((3aR,6aS)-3a,6a-difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(dimethylamino)but- 2-en-1-one • (E)-4-(Dimethylamino)-1-((2S,5R)-2-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-((2R*,4R*)-2-methyltetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-((2S*,4S*)-2-methyltetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-fluoro-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (R,E)-4-(Dimethylamino)-1-(4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)but-2-en-1-one • (S,E)-1-(4,4-Difluoro-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)piperidin-1-yl)-4-(dimethylamino)-3-methylbut-2-en-1-one, or • (E)-1-((3aR,6aS)-3a,6a-Difluoro-5-(3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4- (dimethylamino)but-2-en-1-one In one embodiment, the heterobicyclic derivative is other than: . In one embodiment, the compound of formula (I) is other than: . Uses and Methods Heterobicyclic derivatives of the invention as described herein are inhibitors of ITK kinase. Preferably, the heterobicyclic derivative has an IC50 against ITK of no more than 10,000 nM, more preferably no more than 1,000 nM, or no more than 100 nM, or no more than 10 nM. The IC50 may be as measured by a method as defined herein, for instance by the in vitro ITK kinase Assay as defined herein. 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, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis. 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, alopecia areata, hidradenitis suppurativa and vitiligo. Typically, the patient or subject treated in the present invention is an animal, preferably a human. The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibition 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 selected from atopic dermatitis, psoriasis, chronic hand eczema, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis, comprising administering a therapeutically effective amount of the heterobicyclic derivatives of the invention. The invention also provides the use of a heterobicyclic derivative of the invention, or a pharmaceutical composition of the invention, for the manufacture of a medicament. The invention also provides the use of a heterobicyclic derivative of the invention, or a pharmaceutical composition of the invention, for the manufacture of a medicament for treating a condition or disease selected from cancer, T-cell lymphoma, asthma, inflammatory bowel disease, atopic dermatitis, psoriasis, chronic hand eczema, alopecia areata, hidradenitis suppurativa, vitiligo, and multiple sclerosis. 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 inhibition 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 combinations of the invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of ITK, such as the ones previously described. 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, alopecia areata, hidradenitis suppurativa and vitiligo. The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibition of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described, comprising administering a therapeutically effective amount of a combination of the heterobicyclic derivatives of the invention together with one or more other therapeutic agents. 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 inhibition of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described. 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 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, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis, 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, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis, 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), 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 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 inhibition of Interleukin-2-inducible T-cell kinase (ITK), such as the ones previously described, 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. General synthetic schemes 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 particular reactants or solvents 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 –10 are described in detail in the experimental section. Scheme 1 As illustrated in Scheme 1, compounds of Formula (I) may be prepared directly from haloderivatives of Formula (IB) by reaction with nucleophiles of Formula (IC) such as an amine or an alcohol, in the presence of a suitable base and in a suitable solvent. Scheme 2 Compounds of Formula (IB) may be prepared as illustrated in Scheme 2 from dihalogenated compounds of Formula (X) by reaction with boronic acids or boronic esters of Formula (XIa) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457). 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 or potassium phosphate, at temperatures ranging from 60-140 ºC with or without the use of microwave irradiation to give compounds of Formula (XII). Compounds of Formula (XII) can then be reduced with hydrogen at a pressure between atmospheric pressure and 60 psi in the presence of a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney in a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 ºC to give compounds of Formula (IB).
Scheme 3 Alternatively, compounds of Formula (I) may be prepared in a two-step synthesis, as illustrated in Scheme 3, from compounds of Formula (IB). In a first step, compounds of Formula (IB) may be reacted with amines or alcohols of Formula (IV) in the presence of a suitable base and in a suitable solvent to give compounds of Formula (V). In a second step, amines of Formula (V) may be reacted with acyl chlorides of Formula (VIa) or with carboxylic acids of Formula (VIb) to give compounds of Formula (I).
Scheme 4 As illustrated in Scheme 4, in the particular case where Y is a NR2 group, compounds of Formula (IB) may be treated with amines of Formula (IVa) in the presence of a suitable base such as cesium carbonate or triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile or dimethylsulfoxide or ethanol or butanol or N-N- dimethylacetamide at a temperature ranging from 60-180 ºC with or without the use of microwave irradiation to give compounds of Formula (Va). Alternatively, compounds of Formula (IB) may be treated with amines of Formula (IVa) 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 to give compounds of Formula (Va). Compounds of Formula (Va) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 ºC to give compounds of Formula (Ia). Alternatively, compounds of Formula (Va) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Ia).
Scheme 5 As illustrated in Scheme 5, in the particular case where Y is an oxygen atom, compounds of Formula (IB) may be treated with alcohols of Formula (IVb) in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in an appropriate solvent such as 1,4-dioxane or tetrahydrofurane or dimethylsulfoxide to give compounds of Formula (Vb). Compounds of Formula (Vb) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 ºC to give compounds of Formula (Ib). Alternatively, compounds of Formula (Vb) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Ib)
Scheme 6 As illustrated in Scheme 6, in the particular case where in the formula (Y)n the value of n equals 0, compounds of Formula (IB) may be treated with amines of Formula (IVc) in the presence of a suitable base such as cesium carbonate or triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile or dimethylsulfoxide or ethanol or butanol or N-N-dimethylacetamide at a temperature ranging from 60-180 ºC with or without the use of microwave irradiation to give compounds of Formula (Vc). Alternatively, compounds of Formula (IB) may be treated with amines of Formula (IVc) 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 to give compounds of Formula (Vc). Compounds of Formula (Vc) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 ºC to give compounds of Formula (Ic). Alternatively, compounds of Formula (Vc) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Ic)
Scheme 7 Alternatively, as illustrated in Scheme 7, in the particular case where in the formula (Y)n the value of n equals 0, compounds of Formula (IB) may be treated with boronic acids or boronic esters of Formula (IVd) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457). 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 or potassium phosphate, at temperatures ranging from 60-140 ºC with or without the use of microwave irradiation to give compounds of Formula (Vd1). Compounds of Formula (Vd1) can then be reduced with hydrogen at a pressure between atmospheric pressure and 60 psi in the presence of a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney in a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 ºC to give compounds of Formula (Vd2). Compounds of Formula (Vd2) can then be treated with acyl chlorides of Formula (VIa) in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature ranging from -20 to 60 ºC to give compounds of Formula (Id). Alternatively, compounds of Formula (Vd2) can be treated with carboxylic acids of Formula (VIb) in the presence of a suitable coupling agent such as HATU or HBTU or T3P or HOBT to give compounds of Formula (Id). Scheme 8 Alternatively, compounds of Formula (V) may be prepared as illustrated in Scheme 8 from dihalogenated compounds of Formula (X) by reaction with amines or alcohols of Formula (IV) in the presence of a suitable base and in a suitable solvent to give compounds of Formula (XI). Compounds of Formula (XI) may be reacted with boronic acids or boronic esters of Formula (XIa) under Suzuki–Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457). 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 or potassium phosphate, at temperatures ranging from 60-140 ºC with or without the use of microwave irradiation to give compounds of Formula (XII). Compounds of Formula (XII) can then be reduced with hydrogen at a pressure between atmospheric pressure and 60 psi in the presence of a suitable catalyst such as palladium on carbon or platinum (IV) oxide or Nickel-Raney in a suitable solvent such as methanol or tetrahydrofurane or ethyl acetate or a mixture of them at a temperature between room temperature and 50 ºC to give compounds of Formula (V).
Scheme 9 Alternatively, compounds of Formula (XI) can be transformed directly into compounds of Formula (V) as illustrated in Scheme 9 using photochemistry by treatment with carboxylic acids of Formula (XIIIa) or carboxylic acid derivatives of Formula (XIIIb) in the presence of a suitable Nickel catalyst such as [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride and a suitable base such as sodium hydrogen carbonate in a suitable solvent such as N,N-dimethylacetamide and under irradiation of visible light at wavelenght typically between 380 nm and 430 nm. Alternatively compounds of Formula (XI) can also be transformed directly into compounds of Formula (V) via a photochemical reaction by treatment with bromides of Formula (XIIIc) in the presence of a suitable catalyst such as [4,4′-Bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride in the presence of a suitable reagent such as bis(trimethylsilyl)silyl- trimethylsilane and a base such as 2,6-dimethylpyridine in a solvent such as 1,2- dimethoxyethane under irradiation of visible light at wavelenght typically between 380 nm and 430 nm.
Scheme 10 Compounds of Formula (II) can also be prepared directly from compounds of Formula (X) as illustratedin Scheme 10 via a photochemical reaction, by treatment of compounds of Formula (X) with carboxylic acids of Formula (XIIIa) or carboxylic acid derivatives of Formula (XIIIb) in the presence of a suitable Nickel catalyst such as [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride and a suitable base such as sodium hydrogen carbonate in a suitable solvent such as N,N-dimethylacetamide and under irradiation of visible light at wavelenght typically between 380 nm and 430 nm. Alternatively, compounds of Formula (X) can also be transformed directly into compounds of Formula (II) via a photochemical reaction by treatment with bromides of Formula (XIIIc) in the presence of a suitable catalyst such as [4,4′-Bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride in the presence of a suitable reagent such as Bis(trimethylsilyl)silyl- trimethylsilane and a base such as 2,6-dimethylpyridine in a solvent such as 1,2- dimethoxyethane under irradiation of visible light at wavelenght between 380 nm and 430 nm. 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, these 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 these 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 296) including Intermediates (1 to 27) and are given 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 app Apparent BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl br Broad nBuOH n-Butanol 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 Eq Equivalents 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, iPrOH 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 r.t. room temperature RT retention time s Singlet SFC Superfluid chromatography t Triplet td Triple doublet TFA Trifluoroacetic acid THF Tetrahydrofuran T3P ® Propylphosphonic Anhydride 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: 6 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. LC-MS method 2, LCMS 2 Apparatus: Agilent 1290 Infinity II; Bin. Pump: 1290 High speed Pump, 1290 Multisampler; 1290 DAD WR; LC/MSD IQ; ESI, pos/neg 100-1000; column: Infinitylab Poroshell 120 EC-C182,1X50mm, 50x2.1mm, 1.9µm, Temp column: 50ºC, Flow rate: 0.65 mL/min, Gradient: from 4% B to 98% 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). Chromatograms were processed at 210 nm. LC-MS method 3, LCMS 3 Apparatus: Agilent 1290 Infinity II; Bin. Pump: 1290 High speed Pump, 1290 Multisampler; 1290 DAD WR; LC/MSD IQ; ESI, pos/neg 100-1000; column: Infinitylab Poroshell 120 EC-C182,1X50mm, 50x2.1mm, 1.9µm, Temp column: 50ºC, Flow rate: 0.65 mL/min, Gradient: from 4% B to 98% 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). Chromatograms were processed at 210 nm. LC-MS method 4, LCMS 4 Analytical UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.6 mL/min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. LC-MS method 5, LCMS 5 Analytical UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex® Evo C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL/min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = water + 0.2% ammonium hydroxide and B = acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. LC-MS method 6, LCMS 6 Analytical UHPLC-MS were performed in reverse phase using a Waters UPLC BEH C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 55 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL/min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE, QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. LC-MS method 7, LCMS 7 Analytical UHPLC-MS were performed in reverse phase system using a Waters UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.9 mL/min and a gradient of 5 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.05 min and held for 0.10 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. LC-MS method 8, LCMS 8 Analytical UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex® Evo C18 column (2.1 mm × 50 mm, 1.7 μm; temperature 40°C), with an injection volume of 1 μL at a flow rate of 1.0 mL/min and a gradient of 1 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = water + 0.2% ammonium hydroxide and B = acetonitrile. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. LC-MS method 9, LCMS 9 Analytical UHPLC-MS were performed in reverse phase using a Waters UPLC BEH C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 55 °C), with an injection volume of 1 μL at a flow rate of 1.0 mL/min and a gradient of 1 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE, a QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. 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 Bruker Avance III HD 500 MHz NMR (B114) Bruker Avance III HD 400 MHz NMR (B114) Bruker NEO 400 MHz NMR (B111) 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: 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 or in a Phenomenex Gemini® purification system equiped with a C18 column. Typical conditions: Gradient of water-acetonitrile/MeOH (1:1) from 0% to 100% acetonitrile/MeOH (1:1) in 40 column volumes. If required, 0.1% v/v formic acid or ammonium formate was added in both phases to achieve a better separation. The appropriate fractions were collected, and the solvents were typically evaporated under reduced pressure and/or liofilized. Preparative LC-MS Preparative HPLC Method 1A (P1A): Apparatus: Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. 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). Preparative HPLC Method 1B (P1B): Apparatus: Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. 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). Preparative HPLC Method 1E (P1E): Purification LC were performed in reverse phase using a Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL/min at 10% B for 1.90 min then a gradient of 10 – 95% B over 14.10 min and held for 2.0 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95 – 10% B was then applied over 0.20 min and held for a further 1.25 min. UV spectra were recorded at 215 nm. Preparative HPLC Method 3E (P3E): Purification LC were performed in reverse phase using a Waters XBridge C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL/min at 10% B for 2.00 min then a gradient of 10 – 95% B over 14.00 min and held for 2.00 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. A second gradient of 95 – 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm. 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 4-Chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine A solution of 1,2-dimethoxyethane (96 mL) and water (24 mL) was added to a mixture of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (40 g, 97.63 mmol, 1 eq.), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.65 g, 117 mmol, 1.2 eq.) and potassium carbonate (27 g, 195 mmol, 2 eq.) under nitrogen. The reaction was purged with a stream of nitrogen then [1,1′- bis(diphenylphosphino) ferrocene]dichloropalladium (II) (3.6 g, 4.9 mmol, 0.05 eq.) was added. The reaction was stirred at 60 °C for 20 h. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was partitioned between water (250 ml) and EtOAc (200 ml). The organic was separated and the aqueous extracted with EtOAc (3 x 200 ml). The organics were combined, washed with brine (100 ml) and concentrated under reduced pressure to give the crude product. The crude product was dry loaded onto silica and purified by column chromatography using Biotage Isolera apparatus through a column: Biotage Sfär Duo 350 g (Flow rate: 200 mL/min) eluting with 0-100% EtOAc in heptane. The relevant fractions were combined and concentrated in vacuo to afford the desired product, 4-chloro-5-(3,6-dihydro-2H-pyran-4- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (27 g, 70.10 mmol, 95 mass%, 72% yield). LCMS 7: RT 1.06 min, m/z 366 [M+H]+, 95%. INTERMEDIATE 2 4-Chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine A suspension of 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (27 g, 70 mmol, 95 mass%, 1 eq.) and platinum dioxide (3.2 g, 14 mmol, 0.24 eq.) in ethanol (100 mL) and ethyl acetate (100 mL) was put under a hydrogen atmosphere and was stirred for 3 days. The reaction was filtered over a bed of celite and washed with ethyl acetate (700 mL). The filtrate was collected and the solvent was removed in vacuo. The residue was dry loaded onto silica gel and split into two parts. Each part was purified by normal-phase Biotage, 350 g Sfar Duo, 0-100% EtOAc/heptane, to give 8.54 g (22.1 mmol, 95 mass%, 31.5% yield) and 8.09 g (20.9 mmol, 95 mass%, 29.8% yield) respectively of the final compound as a tan powder. LCMS 7: RT 1.07 min, m/z 369 [M+H]+, 95%. INTERMEDIATE 3 4-Chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 4-Chloro-5-fluoro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (3g, 7.07 mmol, 1 eq.) (prepared as described at WO2014139328 A1) and 2-(3,6-dihydro- 2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.55 g, 7.38 mmol, 1.05 eq.) were dissolved in 1,4-dioxane (44 mL) in a Schlenk and potassium triphosphate (4.47g, 21.1 mmol, 3 eq.) and water (14 mL) were added. Three cycles vacuum/argon were done and then [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (574 mg, 0.70 mmol, 0.1 eq.) were added, and additional three cycles vacuum/argon were done. The mixture was heated at 80 ºC for 2 h. Once at room temperature, the mixture was dissolved in EtOAc and water. The organic layer was separated and the aqueous one was further extracted with ethyl acetate (2x60 mL). The combined organic phases were dried over sodium sulfate, filtered and the solvents were evaporated under reduced pressure. Purification by normal-phase chromatography, 20 g Biotage, 0-25% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to give 4-chloro-3-(3,6- dihydro-2H-pyran-4-yl)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridine (2.99 g, 3.83 mmol, 90 mass%, 55% yield) as an oil. LCMS 2: RT 2.32 min, m/z 383 [M+H]+, 90%. INTERMEDIATE 4 4-Chloro-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridine 4-Chloro-3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridine (1.63 g, 3.83 mmol, 1 eq.) was dissolved in a mixture of ethanol (26 mL) and ethyl acetate (26 mL). This mixture was cooled under an ice bath and platinum(IV)oxide (435 mg, 1.92 mmol, 0.5 eq.) was added under a stream of argon. The reaction flask was connected to a balloon filled with hydrogen and three cycles of vacuum/hydrogen were done. The reaction mixture was stirred at room temperature for 2 h. Then, the catalyst was filtered and the solvents were evaporated. The product was purified by normal-phase chromatography, 80 g Biotage, 0-20% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to obtain 4-chloro-5-fluoro-3- (tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridine (1.08 g, 2.34 mmol, 61% yield) as an oil. LCMS 2: RT 2.42 min, m/z 385 [M-H]+, 98%. INTERMEDIATE 5 tert-Butyl 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)piperazine-1-carboxylate 3,4-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.23 mmol, 100 mass%, 1 eq.) (prepared as described in WO2012170752 A1), tert-butyl piperazine-1-carboxylate (275 mg, 1.48 mmol, 1.2 eq.) and caesium carbonate (602 mg, 1.85 mmol, 1.5 eq.) were suspended in 1,4-dioxane (5 mL) in a Schlenk flask. Three cycles vacuum/argon were done and then palladium diacetate (30 mg, 0.13 mmol, 0.11 eq.) and Xantphos® (142 mg, 0.25 mmol. 0.2 eq.) were added, and three additional cycles of vacuum/argon were done. The mixture was stirred at 80 ºC overnight. Once at room temperature, the mixture was filtered through Celite®, washed with EtOAc and the solvents were evaporated under reduced pressure. Purification by normal-phase chromatography, 20 g Biotage, 0-25% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to obtain tert-butyl 4- (3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine- 1-carboxylate (310 mg, 0.61 mmol, 100 mass%, 49% yield) as an oil. LCMS 2: RT 2.49 min, m/z 511/513 [M+H]+, 100%. INTERMDIATE 6 tert-Butyl 4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (430 mg, 0.84 mmol, 1eq.) and 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.19 mmol, 1.42 eq.) were dissolved in 1,4-dioxane (8 mL) in a Schlenk flask, and potassium triphosphate (635 mg, 2.99 mmol, 3.6 eq.) and water (2 mL) were added. Three cycles vacuum/argon were done and then [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium (82 mg, 0.10 mmol, 0.12 eq.) were added, and three additional cycles of vacuum/argon were done. The mixture was stirred at 100 ºC for 4h. Once at room temperature, the mixture was partitioned between EtOAc and water. The organic phase was separated and the aqueous layer was further extracted with ethyl acetate (2x60 mL). The organic phases were gathered, dried over sodium sulfate, filtered and the solvents were evaporated under reduced pressure. Purification by normal-phase chromatography, 20 g Biotage, 0-100% hexane/diethyl ether. The product tubes were collected, and the solvent was removed in vacuo to obtain tert-butyl 4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate (366 mg, 0.71 mmol, 85 mass%, 84.6% yield) as an oil. LCMS 2: RT 2.40 min, m/z 515 [M+H]+, 85%. INTERMEDIATE 7 tert-Butyl 4-(3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (366 mg, 0.71 mmol, 1 eq.) was dissolved in methanol (30 mL). This solution was cooled under an ice bath and palladium on carbon (30 wt%) (75 mg, 0.21 mmol, 0.3 eq.) was added under a stream of argon. The reaction flask is placed in a Parr hydrogenator where the reaction mixture was rocked at room temperature under 40 psi of hydrogen for 18h. The catalyst was then filtered through a Whatman Glass Microfiber Filters GF/B (25 mm diameter, CAT No. 1821-025) and the solvents were evaporated, the crude tert-butyl 4-(3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (340 mg, 0.57 mmol, 86 mass%, 80% yield) was used in the next step without further purification LCMS 2: RT 2.40 min, m/z 517 [M+H]+, 86%. INTERMEDIATE 8 Tert-butyl (R)-3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidine-1-carboxylate 3,4-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (579 mg, 1.43 mmol, 1 eq.), tert-butyl (R)-3-aminopiperidine-1-carboxylate (343 mg, 1.71 mmol, 1.2 eq.) and caesium carbonate (697 mg, 2.14 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a Schlenk tube. Three cycles vacuum/argon were done and then palladium diacetate (32 mg, 0.14 mmol, 0.1 eq.) and Xantphos® (165 mg, 0.29 mmol.0.2 eq.) were added, and three additional cycles of vacuum/argon were done. The mixture was stirred overnight at 80 ºC. Once at room temperature, the mixture was filtered through Celite®, washed with EtOAc and the solvents evaporated under reduced pressure. Purification by normal-phase chromatography, 20 g Biotage, 0-50% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to get the title compound (663 mg, 1.26 mmol, 89% yield) as an oil. LCMS 2: RT 2.44 min, m/z 526 [M+H]+, 100%. INTERMEDIATE 9 Tert-butyl (R)-3-((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate In a sealed tube, a mixture of tert-butyl (R)-3-((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (663 mg, 1.26 mmol, 1 eq.), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (292 mg, 1,39 mmol, 1.1 eq.) and potassium phosphate (536 mg, 2.53 mmol, 2 eq.) in Dioxane/H2O (4:1) (5.0 mL) was purged with N2 for 5 min. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (51 mg, 78.3 μmol, 0.06 eq.) was added and the mixture was purged with N2 for 2 min. The reaction mixture was heated at 80 ºC for 30 h. The reaction mixture was filtered through a pad of Celite® and rinsed with EtOAc. The filtrate was dried over MgSO4, filtered and removed under reduced pressure to give a crude that was purified by flash column chromatography on silica gel eluting with a gradient of hexanes-EtOAc (100:0 to 35:5) to yield tert-butyl (R)-3-((3-(3,6- dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidine-1-carboxylate (472 mg, 0.89 mmol, 71% yield) as yellow solid. LCMS 2: RT: 2.14 min, m/z 529 [M+H]+, 100% INTERMEDIATE 10 Tert-butyl (R)-3-((3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate tert-Butyl (R)-3-((3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate (472 mg, 0.89 mmol, 1 eq.) was dissolved in methanol (35 mL). This solution was cooled under an ice bath and palladium on carbon (10 wt%) (95 mg, 0.89 mmol, 1.0 eq.) was added under a stream of argon. The reaction flask is placed in a Parr hydrogenator where the reaction mixture was rocked at room temperature under 40 psi of hydrogen for 48h. The catalyst was then filtered through a Whatman Glass Microfiber Filters GF/B (25 mm diameter, CAT No. 1821-025) and the solvents were evaporated, the crude tert-butyl (R)-3-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (469 mg, 0.88 mmol, 79 mass%, 99% yield) was used in the next step without further purification LCMS 2: RT 2.07 min, m/z 531 [M+H]+, 79%. INTERMEDIATE 11 Tert-butyl 4-(5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate A mixture of 5-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (321 mg, 1.38 mmol, 1 eq.), tert-butyl piperazine-1-carboxylate (385 mg, 2.07 mmol, 1.5 eq.) and N-ethyl-N-isopropyl- propan-2-amine (357 mg, 2.76 mmol, 2 eq.) in iPrOH (5.0 mL) was heated at 120 ºC for 16 h. The reaction mixture was diluted in EtOAc, washed with water, brine, dried over anh. MgSO4, filtered and removed under reduced pressure. The crude was purified by flash column chromatography on silica gel eluting with a gradient of heptanes-EtOAc (100:00 to 85:15) to yield tert-butyl 4-(5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazine-1- carboxylate (0.454 g, 1.18 mmol, 85% yield, 99% purity) as a colourless oil that solidified on standing as a white solid. LCMS 10: RT 1.36 min, m/z 382/384 [M+H]+, 99% INTERMEDIATE 12 Tert-butyl 4-[5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl]piperazine-1-carboxylate In a sealed tube, a mixture of tert-butyl 4-(5-bromopyrrolo[2,1-f][1,2,4]triazin-4- yl)piperazine-1-carboxylate (434 mg, 1.12 mmol, 1 eq.) , 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (472 mg, 2.25 mmol, 2 eq.) and Cs2CO3 (1.10 g, 3.37 mmol, 3 eq.) in Dioxane/H2O (4:1) (5.0 mL) was purged with N2 for 5 min. Then, Pd(PPh3)4 (83 mg, 72 μmol, 0.06 eq.) was added and the mixture was purged with N2 for 2 min. The reaction mixture was heated at 95 ºC for 19 h. The reaction mixture was filtered through a pad of Celite® and rinsed with EtOAc. The filtrate was dried over MgSO4, filtered and removed under reduced pressure to give a crude that was purified by flash column chromatography on silica gel eluting with a gradient of heptanes-EtOAc (100:00 to 70:30) to yield tert-butyl 4-[5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl]piperazine-1-carboxylate (418 mg, 1.03 mmol, 92% yield, 95% purity) as yellow solid. LCMS 10: RT 1.25 min, m/z 386 [M+H]+, 95% INTERMEDIATE 13 tert-Butyl 4-(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazine-1- carboxylate In a round bottom flask, a suspension of tert-butyl 4-[5-(3,6-dihydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazine-1-carboxylate (378 mg, 0.93 mmol, 1 eq.) in THF (5 mL) was purged with nitrogen. Then, palladium on carbon wet (10 %) (496 mg, 466 μmol, 10% purity, 0.5 eq.) was added and the system was pumped using vacuum and hydrogen (balloon, ca.1 atm). The mixture was stirred at 25 °C for 16 h. The mixture was filtered through celite and rising with MeOH. Solvent was removed under reduced pressure to yield tert-butyl 4-(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazine-1- carboxylate (339 mg, crude) as a white solid. LCMS 10: RT 1.21 min, m/z 388 [M+H]+; 96% INTERMEDIATE 14 Tert-butyl 4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate In a sealed tube, 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (403 mg, 1.30 mmol, 1.2 eq), potassium carbonate (602 mg, 4.36 mmol, 4 eq) and PdCl2(dppf)·DCM (40 mg, 0.054 mmol, 0.05 eq) were evacuated and flushed with nitrogen three times.1,4-dioxane (16 mL) and water (4 mL) was added and the reaction mixture was degassed by bubbling through with nitrogen for 5 min. The tube was sealed and heated at 80 °C for 19 h. The reaction mixture was cooled to r.t. and diluted with ethyl acetate (40 mL), washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo. Purification by column chromatography, 100 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected and the solvent was removed in vacuo to give the title compound (563 mg, 0.985 mmol, 91% yield) as a beige solid. LCMS 7: RT 1.11 min, m/z 515 [M+H]+, 90% INTERMEDIATE 15 5-(Tetrahydro-2H-pyran-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride Hydrochloric acid (3 mL, 12 mmol, 4N in 1,4-dioxane, 62 eq) was added to a solution of tert-butyl 4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.194 mmol) in dichloromethane (2 mL) and was stirred at r.t. for 1.5 h. The solvent was removed in vacuo to give the title compound (114 mg, 0.177 mmol, 91% yield) as an orange solid. LCMS 7: RT 0.75 min, m/z 415 [M+H]+, 70% INTERMEDIATE 16 Tert-butyl 4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-1-carboxylate A suspension of Tert-butyl 4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (200 mg, 0.35 mmol, 90 mass%, 1 eq) and palladium (on carbon) (75 mg, 0.035 mmol, 5 mass%, 0.1 eq) in ethanol (2.5 mL) and ethyl acetate (2.5 mL) was put under a hydrogen atmosphere and was stirred at r.t for 22 h. Additional palladium (on carbon) (75 mg, 0.035 mmol, 5 mass%, 0.1 eq) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 5 h. The reaction was filtered over a bed of celite and washed with ethyl acetate (40 mL). The filtrate was collected and the solvent was removed in vacuo to give the title compound (194 mg, 0.338 mmol, 97% yield) as a yellow oil. LCMS 7: RT 1.14 min, m/z 517 [M+H]+, 100% INTERMEDIATE 17 4-(Piperidin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine hydrochloride Hydrochloric acid (3 mL, 4N in 1,4-dioxane, 12.0 mmol, 11 eq) was added to a solution of tert-butyl 4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-1-carboxylate (194 mg, 0.338 mmol, 1 eq) in dichloromethane (2 mL) at r.t. and stirred at r.t. for 1 h. The solvent was removed in vacuo to give the title compound (184 mg, 0.325 mmol, 96% yield) as a white solid. LCMS 7: RT 0.76 min, m/z 417 [M+H]+, 91% INTERMEDIATE 18 Tert-butyl 3-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate Tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (433 mg, 1.48 mmol, 1.35 eq), 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.09 mmol, 100 mass%, 1 eq) and Na2CO3 (345 mg, 3.26 mmol, 3 eq) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL) in a sealed vial. The reaction mixture was sparged with nitrogen for 10 min. before the addition of PdCl2(dppf)·DCM (89 mg, 0.11 mmol, 0.1 eq) and was sparged with nitrogen for a further 10 min. The reaction mixture was heated at 80 °C in a sealed tube for 16 h. The reaction mixture was diluted with water (20 mL) and ethyl acetate (20 mL), the aqueous layer was extracted with EtOAc (2 x 20 mL), the organics combined, washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification by flash column chromatography (0-100% EtOAc in Heptanes). The product tubes were collected, and the solvent was removed in vacuo to afford the title compound (543 mg, 0.98 mmol, 90% yield) as a pale-yellow oil. LCMS 7: RT 1.20 min, m/z 501 [M+H]+, 92%. INTERMEDIATE 19 4-(2,5-Dihydro-1H-pyrrol-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine Hydrochloric acid (4M in dioxane, 5 mL, 20 mmol) was added to a solution of tert-butyl 3- (5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (200 mg, 0.40 mmol, 90 mass%) in dichloromethane (3 mL) at r.t. and stirred at r.t. for 1 h. The solvent was removed in vacuo and passed through a 1 g SCX cartridge, washed with MeOH (1 x 10mL), followed by 2N ammonia in MeOH (2 x 10 mL). The product tubes were collected and the solvent removed in vacuo to the title compound (243 mg, 0.39 mmol, 99% yield) as an orange solid. LCMS 7: RT 0.78 min, m/z 401 [M+H]+, 71% INTERMEDIATE 20 Tert-butyl 3-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-1-carboxylate Tert-butyl 3-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (343 mg, 0.69 mmol, 1 eq) was dissolved in ethyl acetate (2 mL). The reaction flask was evacuated and purged with nitrogen 3 times, to which palladium on carbon (72 mg, 0.07 mmol, 10 mass%, 0.1 eq) was added, which was then evacuated and purged with nitrogen 3 times. The suspension was then stirred under an atmosphere of hydrogen at r.t. for 8 days. The reaction mixture was filtered through celite, washed with ethyl acetate (3 x 10 mL) and the solvent was removed in vacuo to give the title compound (300 mg, 0.60 mmol, 87% yield) as a colourless oil. LCMS 7: RT 1.10 min, m/z 503 [M+H]+, 88% INTERMEDIATE 21 4-(Pyrrolidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine Hydrochloric acid (4M in dioxane) (5 mL, 20 mmol) was added to a solution of tert-butyl 3- (5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrrolidine-1-carboxylate (300 mg, 0.60 mmol, 90 mass%) in dichloromethane (3 mL) at r.t. and stirred at r.t. for 1 h. The solvent was removed in vacuo and passed through a 5 g SCX cartridge, washed with MeOH (3 x 10mL), followed by 2N NH3 in MeOH (3 x 10 mL). The product tubes were collected and the solvent removed in vacuo to give the title compound (217 mg, 0.54 mmol, 92% yield) as an orange solid. LCMS 7: RT 0.77 min, m/z 403 [M+H]+, 92% INTERMEDIATE 22 4-Chloro-3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine To a solution of 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridine (15.0 g, 41.4 mmol, 1.00 eq) (prepared as described in WO2023110843) in 1,4- dioxane (90 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (9.00 g, 42.8 mmol, 1.03 eq) at 20 °C. Aqueous solution of potassium carbonate (2 M, 62.2 mL, 3.00 eq) and Pd(dppf)Cl2.CH2Cl2 (3.39 g, 4.15 mmol, 0.10 eq) were added at 20 °C under nitrogen and the mixture was stirred at 40 °C for 12 h. The mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 0-100% petroleum diethylether/EtOAc to give the title compound (75.5 g, 178 mmol, 62% yield) as a yellow oil. LCMS 2: RT 2.39 min, m/z 366 [M+H]+, 90%. INTERMEDIATE 23 4-Chloro-3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine The title compound was obtained in a hydrogenation process in a continuous flow system. A solution of 4-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridine (60.0 g, 164 mmol, 1.0 eq.) in isopropanol (600 mL) and THF (300 mL) was stirred at 20 °C until it became a clear solution. The fixed bed (named FLR1) was completely packed with granular catalyst^10% Ru/SiO2 and was heated to 60 °C. The hydrogen back pressure regulator was adjusted to 1.5 MPa. The solution was pumped into the fixed bed at a flow rate of 0.3 mL/min, and the flow rate of hydrogen was 30 mL/min. HPLC (ET83879-83-P1C) showed trace of compound 3 remained and 96.0% of desired compound was detected. The reaction mixture was concentrated. The crude product was purified by re-crystallization from Petroleum ether (120 mL) at -30°C. The title compound (30 g, 79.1 mmol, 48% yield, 96.7% purity) was obtained as a white solid. LCMS 2: RT 2.41 min, m/z 368 [M+H]+, 99%. INTERMEDIATE 24 4-Chloro-3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile A solution of 4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridine-5-carbonitrile (1.00 g, 2.30 mmol, 1 eq.) (prepared as described in WO2015092592), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.10 g, 4.32 mmol, 1.9 eq.) and 1,3-dioxoisoindolin-2-yl tetrahydro-2H-pyran-4-carboxylate (1.32 g, 4.32 mmol, 1.3 eq.) (prepared as described in Journal of the American Chemical Society, 2016, 138 (7), 2174-2177) and sodium hydrogen carbonate (388 mg, 4.61 mmol, 2 eq.) was degassed with nitrogen under sonication in N,N-dimethylacetamide (20 mL). NiBr2.dtbbpy (112 mg, 0.23 mmol, 0.1 eq.) was added, the solution was degassed and the mixture irradiated at 390 nm in a Penn PhD PR m2 photoreactor overnight. The reaction was quenched with water (30 ml) and the product extracted with 1:1 Heptane and TBME (3 x 25 ml). The combined organics were washed with 2 M HCl (3 x 20 ml) and concentrated under reduced pressure. The residue was taken up in tert-butyl methyl ether and acetonitrile (1:1), filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography eluting with 0-100% Heptane/EtOAc. The relevant fractions were combined and concentrated in vacuo to afford the title product (645 mg, 1.10 mmol, 48% yield) as a colourless oil which crystallized on standing. LCMS 2: RT 1.12 min, m/z 265 [M+H]+, 67%. INTERMEDIATE 25 4-Chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine A suspension of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (2.00 g, 4.88 mmol, 1 eq.), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5- dicarboxylate (2.31 g, 9.12 mmol, 1.9 eq.), 1,3-dioxoisoindolin-2-yl 2-methyltetrahydro-2H- pyran-4-carboxylate (1.83 g, 6.33 mmol, 1.3 eq.) (prepared as described in Journal of the American Chemical Society, 2016, 138 (7), 2174-2177) and sodium hydrogen carbonate (820 mg, 9.76 mmol, 2 eq.) were dissolved in N,N-dimethylacetamide (20 mL) and degassed via sonication for 5 mins. To the reaction mixture was added NiBr2. dtbbpy (238 mg, 0.49 mmol, 0.1 eq.) and degassed for a further 5 mins under sonication. The reaction mixture was sealed and irradiated under 395 nm light in a Penn PhD PR m2 photoreactor for 20 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (2 x 50 mL) and concentrated in vacuo The crude was purified by flash chromatography 0-40% heptane/EtOAc followed by a second purification by reverse phase column chromatography eluting with a gradient of 10-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid). The fractions containing the desired product were combined and concentrated in vacuo to afford the title compound (800 mg, 2.03 mmol, 42% yield) as a colourless oil. LCMS 7: RT 1.21 min, m/z 382 [M+H]+, 97%. INTERMEDIATE 26 4-Fluoro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine Sodium hydride (260 mg, 6.50 mmol, 60 mass%) was added to a solution of 4-fluoro-3-iodo- 1H-pyrrolo[2,3-b]pyridine (1.40 g, 5.30 mmol, 1 eq.) in 2-methyltetrahydrofurane (10 mL) under nitrogen at 0 °C. After stirring at 0 °C for 30 min., (2- (chloromethoxy)ethyl)trimethylsilane (1.40 mL, 7.90 mmol, 1.5 eq.) was added drop-wise. The reaction was allowed to warm to room temperature and stirred for 1 h. Water (15 ml) was added to the reaction mixture and the product was extracted with EtOAc (3 x 10 ml). The organics were combined, washed with brine (5 ml) and concentrated under reduced pressure. The crude product was purified by flash column chromatography, 0-100% heptane/EtOAc. The relevant fractions were combined and concentrated in vacuo to afford the title compound (1.88 g, 4.07 mmol, 76% yield) as a yellow oil. LCMS 7: RT 1.24 min, m/z 393 [M+H]+, 99%. INTERMEDIATE 27 4-Chloro-3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridine 4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (4.00 g, 9.79 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.60 g, 18.00 mmol, 1.8 eq.), (1,3-dioxoisoindolin-2-yl) 2-methyltetrahydropyran-4-carboxylate (3.67 g, 12.70 mmol, 1.3 eq.) and sodium hydrogen carbonate (1.64 g, 19.5 mmol, 2 eq.) were dissolved in N,N-dimethylacetamide (40 mL) and degassed via sonication for 5 mins. To the reaction mixture was added NiBr2.dtbbpy (475 mg, 0.97 mmol, 0.1 eq.) and degassed for a further 5 mins under sonication. The reaction mixture was sealed and irradiated under 395 nm light in a Penn PhD PR m2 photoreactor for 20 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated, and the organic layer was washed with water (100 mL) and brine (2 x 100 mL) and concentrated in vacuo. The crude was purified by flash chromatography, 0-30% ethyl acetate in heptane followed by acidic reverse phase column chromatography using eluting with a gradient of 10-100% ACN (0.1% formic acid) in water (0.1% formic acid) to give the title compound (1.60 g, 4.20 mmol, 43% yield). LCMS 7: RT 1.29 min, m/z 381 [M+H]+, 100%. EXAMPLES Synthesis method 1: EXAMPLE 1 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (R)-3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carboxylat A solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (250 mg, 0.68 mmol, 1 eq), tert-butyl (R)-3-aminopiperidine- 1-carboxylate (272 mg, 1.36 mmol, 2 eq) and DIEA (0.4 mL, 2.0 mmol, 3 eq) in acetonitrile (4 mL) was heated at 110 °C in a sealed tube for 22 h. Additional tert-butyl (R)-3- aminopiperidine-1-carboxylate (272 mg, 1.36 mmol, 2 eq) and DIEA (0.4 mL, 2.0 mmol, 3 eq) was added and the reaction mixture was heated at 110 °C for a further 24 h. The reaction mixture was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate and the solvent was removed in vauco. Purification by normal phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl (R)- 3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (147 mg, 0.26 mmol, 93 mass%, 38% yield) as a yellow oil. LCMS 7: RT 1.10 min, m/z 532 [M+H]+, 93%. Step 2 (R)-N-(Piperidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine A solution of tert-butyl (R)-3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carboxylate (147 mg, 0.26 mmol, 1 eq) and trifluoroacetic acid (0.4 mL, 5 mmol, 20 eq) in dichloromethane (5 mL) was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (in methanol) (5 mL, 35 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo. The reaction mixture was dissolved in methanol (2 mL) and loaded onto an SCX column (2 g), then washed with methanol. The product was eluted with ammonia in methanol (7N) and the solvent was removed in vacuo. The residue was dissolved in ammonia (in methanol) (5 mL, 35 mmol, 7 mol/L) and stirred at r.t. for 18 h. The solvent was removed in vacuo to give N-[(3R)-3-piperidyl]-5- tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (68 mg, 0.18 mmol, 69% yield) as a yellow solid. LCMS 9: RT 0.50 min, m/z 302 [M+H]+, 78%. Step 3 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Acryloyl chloride (18 μL, 0.22 mmol, 1.2 eq) was added to a solution of N-[(3R)-3- piperidyl]-5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (68 mg, 0.18 mmol, 78 mass%, 1 eq) and triethylamine (0.7 mL, 5 mmol, 3 eq) in dichloromethane (2 mL) at 0 °C under nitrogen and stirred for 20 h. Additional acryloyl chloride (18 μL, 0.22 mmol, 1.2 eq) was added and the reaction mixture was stirred at r.t. for a further 3 days. The reaction mixture was diluted with DCM (5 mL) and water (5 mL) and filtered through a phase separator. The organic layer was collected, and the solvent was removed in vacuo. Purification by normal-phase chromatography, 10 g Sfar Duo, 0-10% MeOH/DCM. The product tubes were collected, and the solvent was removed in vacuo. Purification by basic reverse-phase HPLC (Gilson 6). The product tubes were collected, and the solvent was removed in vacuo. The residue was dissolved in acetonitrile:water (1:1) and lyophilised to give (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one (4.7 mg, 0.01 mmol, 95 mass%, 7.1% yield) as a white powder. LCMS 4: RT 1.38 min, m/z 356 [M+H]+, 95%. 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.38 (s, 1H), 8.11 (d, J = 11.6 Hz, 1H), 6.88 (s, 1H), 6.87 – 6.56 (m, 1H), 6.19 – 5.96 (m, 1H), 5.77 – 5.48 (m, 2H), 4.36 – 4.13 (m, 1H), 3.98 – 3.82 (m, 3H), 3.79 – 3.60 (m, 1H), 3.60– 3.41 (m, 4H), 3.21 – 3.04 (m, 1H), 2.05 – 1.76 (m, 4H), 1.76 – 1.62 (m, 1H), 1.62 – 1.41 (m, 3H). Synthesis method 2: EXAMPLE 2 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one Step 1 Tert-butyl 3-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.54 mmol, 1 eq), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.66 mmol, 1.2 eq) and DIEA (0.5 mL, 3.0 mmol, 5 eq) in 1-butanol (3 mL) and was heated at 120 °C in a sealed tube for 23 h. The reaction was retreated with DIEA (0.5 mL, 3.0 mmol, 5 eq) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.66 mmol, 1.2 eq) and stirred for a further 3 days at 120 °C. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate and the solvent was removed in vauco. Purification by normal-phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl 3-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.52 mmol, 96% yield) as a yellow oil. LCMS 7: RT 1.25 min, m/z 544 [M+H]+, 99%. Step 2 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidine hydrochloride Hydrochloric acid (in dioxane) (5 mL, 20 mmol, 4 mol/L) was added to a solution of tert- butyl 3-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.52 mmol) in dichloromethane (3 mL) at r.t. and stirred at r.t. for 1 h. The solvent was removed in vacuo to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine hydrochloride (343 mg, 0.44 mmol, 83% yield) as an orange solid. LCMS 7: RT 0.79 min, m/z 444 [M+H]+, 61%. Step 3 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one Acryloyl chloride (50 μL, 0.62 mmol, 1.2 eq) was added to a solution of 4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (343 mg, 0.50 mmol, 61 mass%, 1 eq) and triethylamine (0.21 mL, 1.5 mmol, 3 eq) in dichloromethane (5 mL) at 0 °C under nitrogen, warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (0.8 mL, 10 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2.5 h. Additional trifluoroacetic acid (0.8 mL, 10 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (in methanol) (10 mL, 70 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo. Purification by basic reverse-phase HPLC (Gilson 5). The product tubes were collected, and the solvent was removed in vacuo. The residue was dissolved in acetonitrile:water (1:1) and lyophylised to give 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (48.3 mg, 0.13 mmol, 26% yield) as a beige powder. LCMS 8: RT 2.03 min, m/z 368 [M+H]+, 99%. 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.68 (s, 1H), 8.20 (s, 1H), 7.08 (s, 1H), 6.78 (dd, J = 16.7, 10.4 Hz, 1H), 6.22 (dd, J = 16.7, 2.4 Hz, 1H), 5.74 (dd, J = 10.3, 2.4 Hz, 1H), 4.71 – 4.58 (m, 2H), 4.05 (dd, J = 22.4, 12.3 Hz, 2H), 3.98 – 3.82 (m, 2H), 3.47 (t, J = 11.6 Hz, 2H), 3.31 – 3.16 (m, 2H), 3.05 (t, J = 11.6 Hz, 1H), 1.97 – 1.61 (m, 6H), 1.51 (qd, J = 12.2, 4.2 Hz, 2H). Synthesis method 3: EXAMPLE 3 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one Step 1 Tert-butyl 6-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate A solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.54 mmol, 1 eq), tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate;oxalic acid (190 mg, 0.66 mmol, 1.2 eq) and DIEA (0.5 mL, 3.0 mmol, 5 eq) in 1-butanol (3 mL) and was heated at 120 °C in a sealed tube for 23 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate and the solvent was removed in vauco. Purification by normal-phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl 6-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (228 mg, 0.39 mmol, 71% yield) as a tan solid. LCMS 7: RT 1.00 min, m/z 530 [M+H]+, 90%. Step 2 4-(2,6-Diazaspiro[3.3]heptan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidine Trifluoroacetic acid (0.65 mL, 8.5 mmol, 20 eq) was added to a solution of tert-butyl 6-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (230 mg, 0.40 mmol) in dichloromethane (5 mL) at r.t. and stirred at r.t. for 17 h. The solvent was removed in vacuo. Ammonia (in methanol) (5 mL, 35 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 5 h. The solvent was removed in vacuo. The residue was dissolved in methanol and loaded onto an SCX column (5 g) and flushed with methanol (~4 CV). The product was eluted with ammonia in methanol (7N, ~4 CV). The filtrate was collected, and the solvent was removed in vacuo to give 4-(2,6- diazaspiro[3.3]heptan-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (115 mg, 0.36 mmol, 91% yield) as a yellow oil. LCMS 8: RT 0.50 min, m/z 300 [M+H]+, 81%. Step 3 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one HATU (153 mg, 0.40 mmol, 1.1 eq) was added to a solution of 4-(2,6-diazaspiro[3.3]heptan- 2-yl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (115 mg, 0.36 mmol, 1.0 eq) and DIPEA (0.19 mL, 1.1 mmol, 3 eq) in N,N-dimethylformamide (2 mL) at r.t. Acrylic acid (28 μL, 0.41 mmol, 1.1 eq) was added and the reaction mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo. Purification by basic reverse-phase prep HPLC. The product tubes were collected, and the solvent was removed in vacuo. The residue was dissolved in water:acetonitrile (1:1) and lyophilised to give 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (23.3 mg, 0.06 mmol, 16% yield) as a white powder. LCMS 8: RT 1.73 min, m/z 354 [M+H]+, 100%. 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.54 (s, 1H), 8.16 (s, 1H), 6.96 (s, 1H), 6.30 (dd, J = 17.0, 10.3 Hz, 1H), 6.11 (dd, J = 17.0, 2.3 Hz, 1H), 5.68 (dd, J = 10.3, 2.3 Hz, 1H), 4.44 (s, 2H), 4.39 (s, 4H), 4.14 (s, 2H), 3.98 – 3.85 (m, 2H), 3.56 (td, J = 11.8, 1.8 Hz, 2H), 3.01 – 2.87 (m, 1H), 1.97 – 1.85 (m, 2H), 1.53 (qd, J = 12.1, 4.2 Hz, 2H). Synthesis method 4: EXAMPLE 4 N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3- yl)acrylamide Step 1 Tert-butyl (1-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-yl)carbamate A solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.54 mmol), tert-butyl azetidin-3-ylcarbamate (112 mg, 0.65 mmol, 1.2 eq) and DIEA (0.5 mL, 3 mmol, 5 eq) in 1-butanol (3 mL) was heated at 120 °C in a sealed tube for 21 h. The solvent was removed in vacuo. Purification by normal-phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl (1-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)azetidin-3-yl)carbamate (221 mg, 0.42 mmol, 77% yield) as a yellow oil. LCMS 7: RT 0.95 min, m/z 504 [M+H]+, 100%. Step 2 1-(5-(Tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-amine Trifluoroacetic acid (0.65 mL, 8.5 mmol, 20 eq) was added to a solution of tert-butyl (1-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)azetidin-3-yl)carbamate (221 mg, 0.42 mmol, 1.0 eq) in dichloromethane (5 mL) at r.t. and stirred at r.t. for 2 h. The solvent was removed in vacuo. The residue was dissolved in methanol and loaded onto an SCX column (5 g). The column was flushed with methanol (~4 CV), then the product was eluted with ammonia in methanol (7N, ~4 CV). The solvent was removed in vacuo to give 1-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-amine (150 mg, 0.32 mmol, 78% yield) as a yellow oil. LCMS 7: RT 0.71 min, m/z 404.3 [M+H]+, 87%. Step 3 N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3- yl)acrylamide HATU (156 mg, 0.41 mmol, 1.1 eq) was added to a solution 1-(5-(tetrahydro-2H-pyran-4- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-amine (150 mg, 0.37 mmol, 87 mass%, 1.0 eq) and DIPEA (0.2 mL, 1 mmol, 3 eq) in N,N- dimethylformamide (2 mL) at r.t. Acrylic acid (28 μL, 0.41 mmol, 1.1 eq) was added and the reaction mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo. Dichloromethane (5 mL) was added to the residue, followed by trifluoroacetic acid (0.9 mL, 20 eq) and stirred at r.t. for 3 h. Additional trifluoroacetic acid (0.9 mL, 20 eq) was added and the reaction mixture was stirred at r.t. for a further 18 h. Additional trifluoroacetic acid (0.9 mL, 20 eq) was added and the reaction mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo. Ammonia (in methanol) (10 mL, 70 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 3.5 h. The solvent was removed in vacuo. Purification by basic prep HPLC. The product tubes were collected, and the solvent was removed in vacuo. The residue was dissolved in water:acetonitrile (1:1) and lyophilised to give N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3- yl)acrylamide (39.2 mg, 0.11 mmol, 29% yield) as a white powder. LCMS 8: RT 1.57 min, m/z 328.4 [M+H]+, 91%. 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.56 (s, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.17 (s, 1H), 7.03 – 6.87 (m, 1H), 6.30 – 6.06 (m, 2H), 5.65 (dd, J = 9.7, 2.5 Hz, 1H), 4.81 – 4.65 (m, 1H), 4.51 (t, J = 8.4 Hz, 2H), 4.08 (dd, J = 8.9, 5.5 Hz, 2H), 4.00 – 3.84 (m, 2H), 3.50 (td, J = 11.8, 1.8 Hz, 2H), 2.92 (t, J = 11.6 Hz, 1H), 1.99 – 1.83 (m, 2H), 1.53 (qd, J = 12.2, 4.3 Hz, 2H). Synthesis method 5: EXAMPLE 5 1-((1R,5R)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one Step 1 Tert-butyl (1R,5R)-6-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptane-3-carboxylate A solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.82 mmol, 1 eq), tert-butyl (1R,5R)-3,6- diazabicyclo[3.2.0]heptane-3-carboxylate hydrochloride (230 mg, 0.98 mmol, 1.2 eq) and DIEA (0.7 mL, 4 mmol, 5 eq) in 1-butanol (3 mL) and was heated at 120 °C in a sealed tube for 2 days. The solvent was removed in vacuo. Purification by normal-phase chromatography, 25 g Sfar Duo, 0-50% EtOAc/heptane. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl (1R,5R)-6-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (280 mg, 0.53 mmol, 65% yield) as a yellow oil. LCMS 7: RT 0.92 min, m/z 530 [M+H]+, 100%. Step 2 4-((1S,5R)-3,6-Diazabicyclo[3.2.0]heptan-6-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine Trifluoroacetic acid (1.3 mL, 17 mmol, 20 eq) was added to a solution of tert-butyl (1R,5R)- 6-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (432 mg, 0.82 mmol, 1 eq) in dichloromethane (5 mL) at 0 °C and stirred at 0 °C for 3 h. The solvent was removed in vacuo. The residue was dissolved in methanol and loaded onto an SCX column (5 g). The column was flushed with methanol (~ 4CV), then the product was eluted with ammonia in methanol (7N, ~ 4CV). The solvent was removed in vacuo to give 4-((1S,5R)-3,6- diazabicyclo[3.2.0]heptan-6-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (171 mg, 0.24 mmol, 60 mass%, 29% yield) as a colourless oil. LCMS 7: RT 0.72 min, m/z 430 [M+H]+, 60%. Step 3 1-((1R,5R)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one Acryloyl chloride (40 μL, 0.49 mmol, 1.2 eq) was added to a solution of 4-((1S,5R)-3,6- diazabicyclo[3.2.0]heptan-6-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (171 mg, 0.40 mmol, 1 eq) and triethylamine (0.17 mL, 1.2 mmol, 3 eq) in dichloromethane (5 mL) at 0 °C under nitrogen, warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (0.61 mL, 8.0 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2.5 h. Additional trifluoroacetic acid (0.61 mL, 8.0 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (in methanol) (5 mL, 35 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo. Purification by basic reverse-phase HPLC. The product was collected, and the solvent was removed in vacuo. The residue was dissolved in water:acetonitrile (1:1) and lyophilised to give 1-((1R,5R)-6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one (71 mg, 0.20 mmol, 50% yield) as a white powder. LCMS 4: RT 1.14 min, m/z 354 [M+H]+, 99%. 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.60 – 11.38 (m, 1H), 8.19 – 8.07 (m, 1H), 6.97 – 6.87 (m, 1H), 6.81 – 6.44 (m, 1H), 6.20 – 5.98 (m, 1H), 5.77 – 5.50 (m, 1H), 5.31 – 5.11 (m, 1H), 4.35 – 4.18 (m, 1H), 4.19 – 4.05 (m, 1H), 4.05 – 3.87 (m, 3H), 3.84 – 3.71 (m, 1H), 3.55 – 3.41 (m, 3H), 3.29 – 3.04 (m, 2H), 2.91 – 2.75 (m, 1H), 1.97 – 1.79 (m, 2H), 1.79 – 1.59 (m, 1H), 1.35 – 1.13 (m, 1H). Synthesis method 6: EXAMPLE 6 (R)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (R)-2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate A solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.82 mmol, 1 eq), tert-butyl (R)-2-methylpiperazine- 1-carboxylate (245 mg, 1.22 mmol, 1.5 eq) and DIEA (284 µL, 1.60 mmol, 2 eq) in N,N- dimethylformamide (3 mL) was heated at 85 °C in a sealed tube for 18 h. Additional tert- butyl (R)-2-methylpiperazine-1-carboxylate (245 mg, 1.22 mmol, 1.5 eq) and DIEA (284 mL, 1.60 mmol, 2 eq) was added and the reaction mixture was heated at 85°C for a further 48 h. The solvent was evaporated under reduced pressure to yield a crude material. Purification by normal phase chromatography, 0-100% EtOAc/hexane. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl (R)-2-methyl-4-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (296 mg, 0.56 mmol, 68% yield) as a yellow oil. LCMS 2: RT 2.24 min, m/z 532 [M+H]+, 100%. Step 2 (R)-4-(3-Methylpiperazin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine A solution of tert-butyl (R)-2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (296 mg, 0.56 mmol, 1 eq) and hydrochloric acid (4M in dioxane) (6.7 mL, 26.8 mmol, 48 eq) in dichloromethane (4.6 mL) was stirred at r.t. for 40 min. The solvent was removed in vacuo. The reaction mixture was dissolved in ethyl acetate and then washed with 4% sodium bicarbonate. The phases were separated and the organic phase was successively washed with brine and water, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. Product was eluted with ammonia in methanol (7N) and the solvent was removed in vacuo to give (R)-4-(3-methylpiperazin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (222 mg, 0.51 mmol, 92% yield) as a yellow solid. LCMS 2: RT 1.61 min, m/z 432 [M+H]+, 93%. Step 3 (R)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one Acrylic acid (47.4 mg, 0.66 mmol, 1.0 eq) was dissolved in dimethylformamide (3.5 mL). Diisopropylethylamine (0.26 mL, 1.72 mmol, 3.5 eq) was added at room temperature followed by T3P (50% in DMF, 0.26 mL, 0.55 mmol.1 eq) and the mixture stirred at room temperature for 30 min. This solution was cooled with an ice bath and a mixture of (R)-4- (3-methylpiperazin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (218 mg, 0.51 mmol, 93 mass%) and diisopropylethylamine (0.26 mL, 1.72 mmol, 3.5 eq) in N,N- dimethylformamide (3.5 mL) was dropwise added Once the addition was over, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. A new batch of the mixture of acrylic acid (47.4 mg, 0.66 mmol, 1.0 eq), diisopropylethylamine (0.26 mL, 1.72 mmol, 3.5 eq) and T3P (50% in DMF, 0.26 mL, 0.55 mmol. 1 eq) in N,N- dimethylformamide (3.5 mL). was prepared as previously described and, after 30 min of stirring, was dropwise added at 0ºC to the reaction mixture and then stirred at room temperature for 3 h. Ethyl acetate was added and the reaction mixture was poured onto water. After phase separation, the organic one was successively washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. Purification by normal-phase chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(2-methyl-4-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (60 mg, 0.12 mmol, 24% yield) as an oil. LCMS 2: RT 2.12 min, m/z 486 [M+H]+, 100%. Step 4 (R)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one A solution of (R)-1-(2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en- 1-one (60 mg, 0.12 mmol) and trifluoroacetic acid (0.42 mL, 5.5 mmol, 46 eq) in dichloromethane (0.64 mL) was stirred at r.t. for 1 h. The solvent was removed in vacuo. Ammonia (in methanol) (1 mL, 7 mmol, 7 mol/L) was added and the reaction mixture was stirred overnight at r.t. The solvent was removed in vacuo. Purification by basic reverse-phase chromatography. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (31 mg, 0.09 mmol, 70.6% yield) as a white powder. LCMS 1: RT 1.56 min, m/z 356 [M+H]+, 86%. 1H NMR (400 MHz, MeOD) ^^^^ 7.90 (s, 1H), 7.68 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 16.8, 10.6 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.79 (dd, J = 10.6, 1.9 Hz, 1H), 4.07 – 4.02 (m, 2H), 3.90 – 3.82 (m, 4H), 3.60 (t, J = 9.3 Hz, 6H), 3.24 – 3.15 (m, 1H), 1.88 – 1.80 (m, 4H). Synthesis method 7: EXAMPLE 7 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (R)-3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate Tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (112 mg, 0.60 mmol, 1.1 eq) and potassium tert-butoxide (61.1 mg, 0.54 mmol, 1 eq) in 1,4-dioxane (5.7 mL) were stirred at room temperature for 30 min under argon. Then 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.54 mmol, 1 eq) was added and the reaction mixture was stirred overnight at room temperature. An additional 0.5 eq of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate and potassium tert-butoxide were added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (60 mL) and water (30 mL), the interphase solid was removed by filtration. The organic phase was separated and the aqueous layer was further extracted with ethyl acetate (2x60 mL). The organic phases were gathered, dried over sodium sulfate, filtered and the solvents evaporated under reduced pressure. Purification by normal-phase chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to give tert-butyl (R)-3-((5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidine-1-carboxylate (249.5 mg, 0.48 mmol, 88% yield) as an oil. LCMS 2: RT 2.39 min, m/z 519 [M+H]+, 99%. Step 2 (R)-4-(Pyrrolidin-3-yloxy)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (R)-3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate (249 mg, 0.48 mmol, 1 eq.) in dichloromethane (4 mL), hydrochloric acid (4M in 1,4-dioxane) (5.9 mL, 23.6 mmol, 49 eq.) was added and the mixture was stirred at room temperature for 1 h. Solvents were evaporated under reduced pressure (heating below 35 ºC) and the resulting crude 257 mg (purity: 53%) was used in the next synthetic step without further purification. LCMS 2: RT 1.7 min, m/z 419 [M+H]+, 53%. Step 3 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Acrylic acid (0.043 mL, 0.63 mmol, 1.3 eq) was dissolved in N,N-dimethylformamide (3.5 mL). Diisopropylethylamine (0.38 mL, 2.19 mmol, 4.5 eq) was added at room temperature followed by T3P (50% in DMF, 0.31 mL, 0.54 mmol.1.1 eq) and the mixture stirred at room temperature for 30 min. This solution was cooled with an ice bath and a mixture of (R)-4- (pyrrolidin-3-yloxy)-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (257 mg, 0.26 mmol, 53% mass) and diisopropylethylamine (0.38 mL, 2.19 mmol, 4.5 eq) in N,N-dimethylformamide (3.5 mL) was dropwise added. Once the addition was over, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and trifluoroacetic acid (3 mL, 38.9 mmol, 80 eq) was added dropwise and stirred overnight at room temperature. The solvent was removed in vacuo. Ammonia (in methanol) (1 mL, 7 mmol, 7 mol/L) was added and the reaction mixture was stirred overnight at r.t. The solvent was removed in vacuo, dichloromethane was added and the solvent was removed in vacuo, repeating this operation twice. Then ammonia (in methanol) (4 mL, 28 mmol, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 1h. The solvent was removed in vacuo. Purification by normal-phase chromatography, 0-100% DCM/DCM:MeOH 95:5. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(3-((5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2- en-1-one (83.3 mg, 0.24 mmol, 50% yield) as white solid. LCMS 1: RT 1.25 min, m/z 343 [M+H]+, 100%. 1H NMR (400 MHz, MeOD) ^^^^ 8.31 (s, 1H), 7.02 (s, 1H), 6.64 (ddd, J = 38.1, 16.8, 10.4 Hz, 1H), 6.30 (ddd, J = 16.8, 12.8, 2.0 Hz, 1H), 5.97 (d, J = 11.0 Hz, 1H), 5.77 (ddd, J = 21.4, 10.4, 2.0 Hz, 1H), 4.06 – 3.64 (m, 6H), 3.57 – 3.41 (m, 2H), 3.05 (tt, J = 11.7, 3.8 Hz, 1H), 2.49 – 2.22 (m, 2H), 1.94 – 1.68 (m, 4H), 1.38 – 1.24 (m, 1H). Synthesis method 8: EXAMPLE 8 (R)-1-(3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 tert-Butyl (R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate 4-Chloro-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine (292 mg, 0.76 mmol, 1 eq.), tert-butyl (R)-3-aminopiperidine-1- carboxylate (188 mg, 0.94 mmol, 1.2 eq.) and caesium carbonate (381 mg, 1.17 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (5 mL) in a Schlenk. Three cycles vacuum/argon were done and then palladium diacetate (18 mg, 0.08 mmol, 0.11 eq.) and Xantphos (91 mg, 0.16 mmol. 0.2 eq.) were added, and three additional cycles of vacuum/argon were done. The mixture was stirred overnight at 80 ºC. Once at room temperature, the mixture was filtered through Celite®, washed with EtOAc and the solvents evaporated under reduced pressure. Purification by normal-phase chromatography, 0-50% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to get tert-butyl (R)-3-((5-fluoro-3- (tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidine-1-carboxylate (354 mg, 0.65 mmol, 85% yield) as an oil. LCMS 2: RT 2.45 min, m/z 549 [M+H]+, 100%. Step 2 (R)-5-Fluoro-N-(piperidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine To a solution of tert-butyl (R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (354 mg, 0.65 mmol, 1 eq.) in 1,4-dioxane (1 mL), hydrochloric acid (4M in 1,4-dioxane) (2.0 mL, 8 mmol, 12 eq.) was added and the mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, taken up in MeOH and passed through a SCX cartridge. After rinsing with MeOH, the product was eluted with 7M NH3/MeOH. The organics were concentrated in vacuo to afford the desired product (201 mg, 0.45 mmol, 70 % yield). This crude was used in the next synthetic step without further purification. LCMS 2: RT 1.62 min, m/z 449 [M+H]+, 100%. Step 3 (R)-1-(3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one Acryloyl chloride (62 μL, 0.76 mmol, 1.3 eq) was added to a solution of (R)-5-fluoro-N- (piperidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-amine (270 mg, 0.60 mmol, 1 eq) and triethylamine (0.3 mL, 2.15 mmol, 3 eq) in dichloromethane (15 mL) at 0 °C under nitrogen and the mixture stirred for 2 h. The reaction was quenched with saturated aqueous NaHCO3 (7 mL). The layers were separated and the product extracted with DCM (3 x 3 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by normal-phase chromatography, 0-20% hexane/AcOEt. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(3-((5-fluoro-3- (tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one (102 mg, 0.20 mmol, 34% yield) as an oil. LCMS 2: RT 2.17 min, m/z 502 [M+H]+, 95%. Step 4 (R)-1-(3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one A solution of (R)-1-(3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop- 2-en-1-one (102 mg, 0.20 mmol, 1 eq) and trifluoroacetic acid (1.50 mL, 19.5 mmol, 96 eq) in dichloromethane (5 mL) was stirred overnight at r.t. The solvent was removed in vacuo. Ammonia (7N in methanol) (5 mL, 3.5 mmol, 7 mol/L) was added and the reaction mixture was stirred overnight at r.t. The solvent was removed in vacuo. Water was added and then pH adjusted to 12 with aqueous ammonia. The product was extracted with ethyl acetate (x3). The organic phase was dried over magnesium sulfate, filtered and the solvents were removed in vacuo. Purification by basic reverse-phase chromatography. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (4.3 mg, 0.01 mmol, 6% yield) as a white powder. LCMS 1: RT 1.18 min, m/z 373 [M+H]+, 80%. 1H NMR (400 MHz, MeOD) ^^^^ 7.87 (d, J = 6.0 Hz, 1H), 7.01 (s, 1H), 6.84 (dd, J = 16.6, 10.6 Hz, 1H), 6.53 (dd, J = 16.7, 10.6 Hz, 1H), 6.22 (d, J = 15.2 Hz, 1H), 6.02 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 8.6 Hz, 1H), 5.59 – 5.44 (m, 1H), 4.15 – 3.96 (m, 3H), 3.89 (d, J = 13.4 Hz, 1H), 3.79 – 3.55 (m, 4H), 3.06 (s, 1H), 2.11 (s, 1H), 2.06 – 1.88 (m, 2H), 1.88 – 1.54 (m, 4H), 1.29 (m, 1H). Synthesis method 9 EXAMPLE 9 1-(4-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1- yl)prop-2-en-1-one Step 1 4-(Piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine A solution of tert-butyl 4-(3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (103 mg, 0.20 mmol, 1 eq) and trifluoroacetic acid (0.15 mL, 1.95 mmol, 9.8 eq) in dichloromethane (1 mL) was stirred overnight at r.t. The solvent was removed in vacuo. The solvent was removed in vacuo. Ammonia (7N in methanol) (2 mL, 1.4 mmol, 7 mol/L) was added and the reaction mixture was stirred overnight at r.t. The solvent was removed in vacuo. Purification by reverse-phase chromatography. The product tubes were collected, and the solvent was removed in vacuo to give 4-(piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine (76 mg, 0.19 mmol, 95% yield) as a white powder. LCMS 2: RT 0.33 min, m/z 287 [M+H]+, 87 mass% Step 2 1-(4-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1- yl)prop-2-en-1-one Acrylic acid (16 mL, 0.23 mmol, 1.2 eq) was dissolved in N,N-dimethylformamide (0.5 mL). Diisopropylethylamine (0.1 mL, 0.57 mmol, 6 eq) was added at room temperature followed by T3P ® (50% in DMF, 56 mL, 0.19 mmol. 1.0 eq) and the mixture stirred at room temperature for 30 min under argon atmosphere. This solution was cooled with an ice bath and a mixture of 4-(piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine and diisopropylethylamine (0.2 mL, 0.15 mmol, 6 eq) in N,N-dimethylformamide (0.5 mL) was dropwise added. Once the addition was over, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. Purification by reverse-phase chromatography. The product tubes were collected, and the solvent was removed in vacuo to give 1-(4-(3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazin-1-yl)prop-2-en-1-one (8.8 mg, 25.9 mmol, 14% yield) as a white solid. LCMS 1: RT 0.94 min, m/z 341 [M+H]+, 100%. 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.38 (s, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.65 (d, J = 5.3 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.5, 2.4 Hz, 1H), 3.95 (dd, J = 11.1, 3.2 Hz, 2H), 3.79 (s, 4H), 3.50 (t, J = 11.1 Hz, 2H), 3.14 – 2.95 (m, 5H), 2.02 (s, 2H), 1.67 – 1.52 (m, 2H). Synthesis method 10: EXAMPLE 10 (R)-1-(3-((3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 (R)-N-(Piperidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine To a solution of tert-butyl (R)-3-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (100 mg, 0.19 mmol, 1 eq.) in dichloromethane (1.5 mL), hydrochloric acid (4M in 1,4-dioxane, 2.3 mL, 9.2 mmol, 48 eq.) was added and the mixture was stirred at room temperature for 1h. The reaction was concentrated under reduced pressure, taken up in ethyl acetate and successively washed with 4% sodium bicarbonate aqueous solution and brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a yellow oil (55 mg, 0.13 mmol, 68 % yield). The crude product was used in the next synthetic step without further purification. LCMS 2: RT 1.31 min, m/z 431 [M+H]+, 100%. Step 2 (R)-1-(3-((3-(Tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one Acryloyl chloride (65 μL, 0.80 μmol, 1.2 eq) was added to a solution of (R)-N-(piperidin-3- yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-amine (292 mg, 0.68 mmol, 1 eq) and triethylamine (0.16 mL, 1.81 mmol, 2.7 eq) in dichloromethane (5 mL) was added at 0 °C under nitrogen. The resulting mixture was stirred for 18 h and then it was directly injected into a chromatographic column in order to isolate the final compound. Purification by normal-phase chromatography, 0-100% DCM/DCM:MeOH 9:1. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(3-((3- (tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one (19 mg, 39.2 μmol, 6% yield) as an oil. LCMS 2: RT 1.74 min, m/z 485 [M+H]+, 95%. Step 3 (R)-1-(3-((3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one A solution of (R)-1-(3-((3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (19 mg, 39 μmol, 1 eq., 95 mass%) and trifluoroacetic acid (45 mg, 0.39 mmol, 10 eq) in dichloromethane (1 mL) was stirred at r.t. for 2h and then the solvent was removed in vacuo. Ammonia (7N in methanol) (3 mL, 2.1 mmol, 7 mol/L) was added and the reaction mixture was stirred overnight at r.t. The solvent was removed in vacuo. Purification by basic reverse-phase chromatography. The product tubes were collected, and the solvent was removed in vacuo to give (R)-1-(3-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (5.5 mg, 15.5 μmol, 40% yield) as a white powder. LCMS 1: RT 0.99 min, m/z 355 [M+H]+, 100%. 1H NMR (400 MHz, MeOD) ^^^^ 7.85 (t, J = 5.7 Hz, 1H), 6.89 (s, 1H), 6.88 – 6.77 (m, 1H), 6.49 (dd, J = 16.7, 10.6 Hz, 1H), 6.39 (d, J = 5.8 Hz, 1H), 6.32 (d, J = 5.7 Hz, 1H), 6.26 (d, J = 16.7 Hz, 1H), 6.04 (d, J = 16.9 Hz, 1H), 5.81 (d, J = 10.6 Hz, 1H), 5.49 (d, J = 10.6 Hz, 1H), 4.01 (s, 2H), 3.86 (d, J = 13.5 Hz, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.68 – 3.54 (m, 4H), 3.41 (s, 1H), 3.07 (d, J = 16.4 Hz, 1H), 2.10 (s, 2H), 1.99 (d, J = 14.0 Hz, 2H), 1.82 – 1.63 (m, 4H). Synthesis method 11: EXAMPLE 11 1-(4-(5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1- yl)prop-2-en-1-one Step 1 4-(Piperazin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine A solution of tert-butyl 4-(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4- yl)piperazine-1-carboxylate (319 mg, 790.35 μmol, 1 eq.) in TFA (10 mL, 129.80 mmol, 164 eq.) was stirred at 25 °C for 1 h. The volatiles were removed under reduced pressure to yield 4-piperazin-1-yl-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazine (490 mg, crude trifluoroacetic salt) as a yellow oil, which was used directly in the next step. LCMS 10: RT 0.33 min, m/z: 288 [M+H]+, 79% Step 2 1-(4-(5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1- yl)prop-2-en-1-one In a round bottom flask, acryloyl chloride (64.07 μL, 788 μmol,) was added dropwise to a solution of 4-piperazin-1-yl-5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazine (490 mg, 751 μmol) and DIEA (418 μL, 3.0 mmol) in DCM dry (2 mL) at 0 °C. The mixture was allowed to room temperature and stirred for 3 h.1M aqueous HCl was added to the mixture. The organic layer was separated and washed with brine, dried over MgSO4 , filtered and concentrated under reduced pressure to yield 48 mg of a white solid. The product was purified by reverse phase chromatography to yield 1-[4-(5-tetrahydropyran- 4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl]prop-2-en-1-one (27 mg, 77 μmol, 10% yield) as a white solid. LCMS 1: RT 2.77 min, m/z 342 [M+H]+; 99% 1H NMR (400 MHz, MeOD) ^^^^ 7.90 (s, 1H), 7.68 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 16.8, 10.6 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.79 (dd, J = 10.6, 1.9 Hz, 1H), 4.07 – 4.02 (m, 2H), 3.90 – 3.82 (m, 4H), 3.60 (t, J = 9.3 Hz, 6H), 3.24 – 3.15 (m, 1H), 1.88 – 1.80 (m, 4H). EXAMPLE 12 (S)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (S)-3-aminopiperidine-1-carboxylate following the experimental procedure described in Synthesis method 1.15 mg of the title compound were obtained. LCMS 1: RT 1.32 min, m/z 356 [M+H]+, 89% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.48 (s, 1H), 8.26 – 8.13 (m, 1H), 7.02 – 6.69 (m, 2H), 6.27 – 6.10 (m, 1H), 5.85 – 5.60 (m, 2H), 4.43 – 4.22 (m, 1H), 4.07 – 3.91 (m, 3H), 3.85 – 3.67 (m, 1H), 3.67 – 3.49 (m, 4H), 3.29 – 3.12 (m, 1H), 2.11 – 1.86 (m, 4H), 1.86 – 1.52 (m, 4H). EXAMPLE 13 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 4-aminopiperidine-1-carboxylate following the experimental procedure described in Synthesis method 6.44 mg of the title compound were obtained. LCMS 1: RT 1.21 min, m/z 356 [M+H]+, 92% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 – 11.26 (m, 1H), 8.09 (s, 1H), 6.93 – 6.79 (m, 2H), 6.12 (dd, J = 16.6, 2.5 Hz, 1H), 5.74 (d, J = 8.1 Hz, 1H), 5.68 (dd, J = 10.4, 2.5 Hz, 1H), 4.48 – 4.34 (m, 2H), 4.15 – 4.01 (m, 1H), 3.96 – 3.83 (m, 2H), 3.61 – 3.46 (m, 2H), 3.31 – 3.12 (m, 2H), 2.81 (br t, J = 12.5 Hz, 1H), 1.95 (s, 2H), 1.88 – 1.77 (m, 2H), 1.68 – 1.40 (m, 4H). EXAMPLE 14 1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 3-aminopyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 6.23 mg of the title compound were obtained. LCMS 1: RT 1.15 min, m/z 342 [M+H]+, 94% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.14 (s, 1H), 6.88 (dd, J = 2.4, 2.4 Hz, 1H), 6.58 (ddd, J = 19.3, 16.8, 10.3 Hz, 1H), 6.13 (ddd, J = 16.8, 6.1, 2.5 Hz, 1H), 6.01 – 5.90 (m, 1H), 5.66 (ddd, J = 16.2, 10.3, 2.5 Hz, 1H), 4.93 – 4.62 (m, 1H), 3.99 – 3.83 (m, 2H), 3.79 – 3.37 (m, 6H), 3.30 – 3.20 (m, 1H), 2.32 – 1.99 (m, 2H), 1.91 – 1.74 (m, 2H), 1.63 – 1.41 (m, 2H). EXAMPLE 15 (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.33 mg of the title compound were obtained. LCMS 1: RT 1.18 min, m/z 342 [M+H]+, 95% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.45 – 11.35 (m, 1H), 8.14 (s, 1H), 6.91 – 6.86 (m, 1H), 6.65 – 6.52 (m, 1H), 6.19 – 6.09 (m, 1H), 6.00-5.93 (m, 1H), 5.70 – 5.61 (m, 1H), 4.88-4.65 (m, 1H), 3.96 – 3.82 (m, 3H), 3.76 – 3.37 (m, 6H), 2.32 – 2.01 (m, 2H), 1.89 – 1.75 (m, 2H), 1.62 – 1.42 (m, 2H). EXAMPLE 16 (R,E)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one Step 1 (R,E)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one A solution of (R)-N-(piperidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (50 mg, 0.107 mmol) (prepared following the experimental procedure described in Synthesis method 2, Step 1 and Step 2) and (E)-but-2-enoic acid (14 mg, 0.160 mmol, 1.5 eq) in DMF (1 mL) was treated with HATU (61 mg, 0.160 mmol, 1.5 eq) and N-ethyl-N-isopropyl-propan-2- amine (74 µL, 0.427 mmol, 4 eq) and stirred overnight at r.t. Then, EtOAc (2 mL) was added and the solution was washed with water (3 x 2 mL) The solvent was removed in vacuo to and the crude purified using flash column chromatography (Sfar Duo 12g silica, 0-100% EtOAc in heptane). Clean fractions were combined and the volatiles removed in vacuo to afford the title compound (23 mg, 0.044 mmol, 41% yield) as an off-white solid. LCMS 7: RT 0.96 min, m/z 500 [M+H]+, 96% Step 2 (R,E)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one A solution of (R,E)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but- 2-en-1-one (46 mg, 0.092 mmol) in DCM (3 mL) was treated with TFA (1.0 mL, 2.00 mmol, 22 eq) and the solution stirred overnight. The solvent was removed under a stream of nitrogen and ammonia (1 mL, 7.0 mmol, 7N in methanol, 76 eq). The solution was stirred for 3 h. The solvent was removed in vacuo and the crude was purified using preparative HPLC (Method P3E). Clean fractions were evaporated to afford (R,E)-1-(3-((5-(tetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one (22 mg, 0.0600 mmol, 100% mass , 65% yield) as an off-white solid. LCMS 1: RT 1.52 min, m/z 370 [M+H]+, 97% 1H NMR (500 MHz, d6-DMSO) ^^^^ 11.39 (s, 1H), 8.18 – 8.03 (m, 1H), 6.89 (s, 1H), 6.77 – 6.26 (m, 2H), 5.72 – 5.46 (m, 1H), 4.35 – 4.14 (m, 1H), 3.95 – 3.82 (m, 3H), 3.66 – 3.38 (m, 6H), 3.17 – 3.07 (m, 1H), 1.91 –1.79 (m, 5H), 1.66 – 1.50 (m, 5H). EXAMPLE 17 (R,Z)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one The title compound was prepared from (R)-N-(piperidin-3-yl)-5-(tetrahydro-2H-pyran-4- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride and (Z)-but-2-enoyl chloride following the experimental procedure described in Example 16.17 mg of the title compound were obtained. LCMS 1: RT 1.54 min, m/z 370 [M+H]+, 97% 1H NMR (400 MHz, DMSO, 353K) ^^^^ 11.16 (s, 1H), 8.12 (s, 1H), 6.90 – 6.82 (m, 1H), 6.17 – 5.78 (m, 2H), 5.49 – 5.34 (m,1H), 4.35 – 4.19 (m, 1H), 3.97 – 3.89 (m, 3H), 3.57 – 3.49 (m, 2H), 3.49 – 3.40 (m, 1H), 3.39 – 3.28 (m, 1H), 3.19 – 3.10 (m, 1H), 2.05 – 1.94 (m, 1H), 1.94 – 1.82 (m, 3H), 1.82 – 1.76 (m, 3H), 1.77 – 1.47 (m, 5H) EXAMPLE 18 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-yn-1-one The title compound was prepared from (R)-N-(piperidin-3-yl)-5-(tetrahydro-2H-pyran-4- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride and but-2-ynoic acid following the experimental procedure described in Example 16.22 mg of the title compound were obtained. LCMS 1: RT 1.47 min, m/z 368 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.18 – 8.08 (m, 1H), 6.94 – 6.87 (m, 1H), 5.64 – 5.56 (m, 1H), 4.33 – 4.21 (m, 1H), 4.02 – 3.74 (m, 5H), 3.65 – 3.44 (m, 5H), 3.24 – 3.11 (m, 1H), 2.00 – 1.80 (m, 5H), 1.67 – 1.45 (m, 4H). EXAMPLE 19 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-yn-1-one The title compound was prepared from (R)-N-(piperidin-3-yl)-5-(tetrahydro-2H-pyran-4- yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride and propiolic acid following the experimental procedure described in Example 16.4.5 mg of the title compound were obtained. LCMS 4: RT 1.42 min, m/z 354 [M+H]+, 100% 1H NMR (400 MHz, DMSO, 353K) ^^^^ 11.17 (s, 1H), 8.24 – 8.04 (m, 2H), 6.88 (s, 1H), 5.46 – 5.40 (m, 1H), 4.43 – 4.28 (m, 2H), 4.20 – 4.05 (m, 1H), 3.97 – 3.82 (m, 3H), 3.78 – 3.71 (m, 1H), 3.65 – 3.53 (m, 4H), 1.92 – 1.84 (m, 3H), 1.72 – 1.57 (m, 4H). EXAMPLE 20 (R)-2-Methyl-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2), tert-butyl (R)-3-aminopyrrolidine-1-carboxylate and methacryloyl chloride following the experimental procedure described in Synthesis method 6.42 mg of the title compound were obtained. LCMS 1: RT 1.59 min, m/z 370 [M+H]+, 97% 1H NMR (500 MHz, d6-DMSO) ^^^^ 11.46 – 11.25 (m, 1H), 8.09 (s, 1H), 6.93 – 6.84 (m, 1H), 5.66 (d, J = 7.3 Hz, 1H), 5.29 – 4.79 (m, 2H), 4.28 – 3.77 (m, 4H), 3.73 – 3.45 (m, 3H), 3.33-3.23 (m, 3H), 2.02 – 1.64 (m, 9H), 1.64 – 1.40 (m, 2H). EXAMPLE 21 (R)-2-Fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 (R)-2-Fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one T3P (50% w/w in EtOAc, 0.4 ml, 0.7 mmol, 1 eq) was added dropwise to a solution of (R)- N-(piperidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.46 mmol, 100 mass%, 1 eq) (prepared following the experimental procedure described in Synthesis method 2, Step 1 and Step 2) and sodium 2-fluoroacrylate (95 mg, 0.85 mmol, 1.8 eq) in acetonitrile (2 mL) at 0 °C under a nitrogen atmosphere. The reaction was allowed to warm to r.t. and stirred for 18 h. The reaction was filtered and diluted with water (5 mL). The product was extracted with EtOAc (3 x 3 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo to give (R)-2-fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one (198 mg, 0.275 mmol, 59% yield) as an off-white solid. LCMS 8: RT = 0.95 min, m/z = 504.5 [M+H]+, 70%. Step 2 (R)-2-Fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Trifluoroacetic acid (1 ml, 13.1 mmol, 48 eq) was added dropwise to a solution of (R)-2- fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (198 mg, 0.28 mmol, 70 mass%, 1 eq) in dichloromethane (1 mL). The reaction was stirred at r.t. for 18 h. The volatiles were removed under a stream of nitrogen and the residue taken up in ammonia (2 ml, 7 N in MeOH, 91.5 mmol). The reaction was stirred at r.t. for 6 h then concentrated under reduced pressure. Purification by preparative HPLC (Method P3E). The relevant fractions were combined, concentrated in vacuo and lyophilised to give (R)-2-fluoro-1-(3- ((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one (104 mg, 0.27 mmol, 37% yield) as a white solid. LCMS 1: RT 1.52 min, m/z 374 [M+H]+, 94% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.10 (s, 1H), 6.89 (d, J = 2.1 Hz, 1H), 5.66 (d, J = 7.1 Hz, 1H), 5.14 (d, J = 49.5 Hz, 2H), 4.25 (s, 1H), 3.97 (d, J = 13.0 Hz, 1H), 3.91 (d, J = 10.9 Hz, 2H), 3.84 – 3.60 (m, 2H), 3.52 (t, J = 11.4 Hz, 2H), 3.25 – 3.15 (m, 1H), 2.05 – 1.92 (m, 1H), 1.91 – 1.80 (m, 3H), 1.79 – 1.71 (m, 1H), 1.62 – 1.51 (m, 4H). EXAMPLE 22 (R,E)-4-(Dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2), tert-butyl (R)-3-aminopyrrolidine-1-carboxylate and (E)-4-(dimethylamino)but-2-enoic acid following the experimental procedure described in Synthesis method 3. 21 mg of the title compound were obtained. LCMS 5: RT 1.91 min, m/z 413 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 – 11.35 (m, 1H), 8.14 – 8.06 (m, 1H), 6.87 (s, 1H), 6.63 (s, 1H), 6.51 – 6.30 (m, 1H), 5.66 – 5.49 (m, 1H), 4.31 – 4.13 (m, 1H), 3.99 – 3.77 (m, 3H), 3.69 – 3.44 (m, 8H), 3.17 – 3.01 (m, 1H), 2.87 – 2.64 (m, 1H), 2.17 – 2.12 (m, 3H), 1.96 – 1.78 (m, 6H), 1.69 – 1.41 (m, 3H). EXAMPLE 23 (R,E)-4-(Dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one Step 1 (R,E)-4-(Dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)but-2-en-1-one DIPEA (0.16 mL, 0.92 mmol, 1.9 eq.) was added to a solution of (E)-4-(dimethylamino)but- 2-enoic acid hydrochloride (120 mg, 0.72 mmol, 1 eq.) in DMF (1.5 mL) at r.t. The reaction mixture was stirred at r.t. for 5 min, then HATU (237 mg, 0.62 mmol, 1.3 eq.) was added, followed by (R)-N-(pyrrolidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.48 mmol, 1.5 eq.) (prepared following the experimental procedure described in Synthesis method 2, Step 1 and Step 2). The reaction was stirred at r.t. overnight then further (E)-4- (dimethylamino)but-2-enoic acid hydrochloride (120 mg, 0.72 mmol, 1.5 eq.), DIPEA (0.16 mL, 0.92 mmol, 1.9 eq.) and HATU (237 mg, 0.62 mmol, 1.3 eq.) were added and stirred at r.t. for 4 h. The reaction was diluted with water (5 mL) and extracted using EtOAc (3 x 10 mL), washed with brine (2 x 10 mL), then concentrated to afford a brown oily solid. This crude was dissolved in 1:1:1 MeCN:MeCN:DMSO then purified by prep HPLC (Method P3E). The relevant fractions were combined and concentrated under reduced pressure to afford the title compound as an off-white solid (66 mg, 0.125 mmol, 26% yield). LCMS 8: RT 0.85 min, m/z 529 [M+H]+, 98%. Step 2 (R,E)-4-(Dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one To a mixture of (R,E)-4-(dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)but-2-en-1-one (60 mg, 0.11 mmol, 1 eq.) in DCM (5 mL) was added boron trifluoride diethyl etherate (0.14 mL, 1.1 mmol, 10 eq.) dropwise at 0 °C. The reaction mixture was stirred at r.t. for 1 h. The reaction mixture was washed with saturated NaHCO3 (10 mL), then extracted using first DCM (3 x 5 mL) then nBuOH (5 mL). The combined organic layers were concentrated to dryness. The crude intermediate was then dissolved in ethanol (5 mL) and water (0.5 mL), then potassium carbonate (56 mg, 0.567 mmol, 5 eq.) was added, stirred for one hour, then evaporated to dryness and purified by preparative HPLC (Method P3E). The product tubes were collected, and the solvent was removed in vacuo. The residue was dissolved in acetonitrile:water (1:1) and lyophilised to give (R,E)-4-(dimethylamino)-1-(3- ((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)but-2-en-1-one (25 mg, 0.063 mmol, 55%) as an off-white solid. LCMS 1: RT 0.73 min, m/z 399 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.14 (s, 1H), 6.88 (d, J = 3.5 Hz, 1H), 6.68 – 6.54 (m, 1H), 6.42 - 6.28 (m, 1H), 6.00 - 5.89 (m, 1H), 4.87-4.63 (m, 1H), 3.95 – 3.82 (m, 2H), 3.73 – 3.54 (m, 2H), 3.56 – 3.45 (m, 3H), 3.45 – 3.38 (m, 1H), 3.31 – 3.23 (m, 1H), 3.01 (dd, J = 12.3, 6.1 Hz, 2H), 2.34 – 2.01 (m, 8H), 1.88 - 1.77 (m, 2H), 1.62 – 1.44 (m, 2H). EXAMPLE 24 (R)-1-(3,3-Difluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (R)-5-amino-3,3-difluoropiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.16 mg of the title compound were obtained. LCMS 1: RT 1.55 min, m/z 392 [M+H]+, 92% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.55 (s, 1H), 8.35 – 8.17 (m, 1H), 7.13 – 6.93 (m, 1H), 6.76 – 6.54 (m, 1H), 6.20 (dd, J = 39.2, 16.3 Hz, 1H), 5.97 – 5.56 (m, 2H), 4.82 – 4.60 (m, 1H), 4.35 – 4.13 (m, 1H), 4.13 – 3.70 (m, 5H), 3.65 – 3.48 (m, 2H), 3.13 – 2.96 (m, 1H), 2.58 – 2.44 (m, 2H), 1.96 – 1.78 (m, 2H), 1.78 – 1.45 (m, 2H) EXAMPLE 25 1-((3S,5R)-3-Fluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3R,5S)-3-amino-5-fluoropiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.23 mg of the title compound were obtained. LCMS 4: RT 1.24 min, m/z 374 [M+H]+, 98% 1H NMR (400 MHz, DMSO, 353K) ^^^^ 11.17 (s, 1H), 8.14 (s, 1H), 6.86 (s, 1H), 6.77 - 6.25 (br. s, 1H), 5.99 (d, J = 15.6 Hz, 1H), 5.74 - 5.69 (m, 1H), 5.54 (br. s, 1H), 5.05 (d, J = 46.9 Hz, 1H), 4.63 (s, 1H), 4.43 (br. s, 2H), 3.95 – 3.79 (m, 2H), 3.54 - 3.21 (br.s, 2H), 3.44 - 3.32 (m, 2H), 2.88 – 2.77 (m, 1H), 2.36 – 2.18 (m, 2H), 1.84 - 1.71 (m, 2H), 1.64 (app. qd, J = 12.0, 4.3 Hz, 1H), 1.51 (app.qd, J = 12.0, 4.3 Hz, 1H). EXAMPLE 26 1-((3S,4R)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3S,4R)-3-amino-4-fluoropiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.27 mg of the title compound were obtained. LCMS 5: RT 1.97 min, m/z 374 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.49 (s, 1H), 8.27 – 8.05 (m, 1H), 6.98 – 6.93 (m, 1H), 6.93 – 6.70 (m, 1H), 6.19 – 6.08 (m, 1H), 5.81 – 5.64 (m, 1H), 5.64 – 5.46 (m, 1H), 5.24 – 4.98 (m, 1H), 4.64 – 4.33 (m, 2H), 4.09 – 3.83 (m, 4H), 3.53 – 3.44 (m, 2H), 3.27 – 3.00 (m, 2H), 2.12 – 1.83 (m, 4H), 1.72 – 1.47 (m, 2H). EXAMPLE 27 1-((2R,5R)-2-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2R,5R)-5-amino-2-methylpiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.36 mg of the title compound were obtained. LCMS 1: RT 1.47 min, m/z 370 [M+H]+, 95% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.41 (s, 1H), 8.14 (s, 1H), 7.02 – 6.27 (m, 2H), 6.25 – 5.86 (m, 1H), 5.54 – 5.32 (m, 1H), 4.41 (s, 3H), 3.99 – 3.78 (m, 2H), 3.52 – 3.37 (m, 2H), 3.37 – 3.04 (m, 2H), 3.01 – 2.86 (m, 1H), 2.14 – 1.95 (m, 1H), 1.90 – 1.73 (m, 4H), 1.73 – 1.58 (m, 1H), 1.53 – 1.36 (m, 2H), 1.22 (s, 3H). EXAMPLE 28 1-((2S,5R)-2-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2S,5R)-5-amino-2-methylpiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.26 mg of the title compound were obtained. LCMS 1: RT 1.55 min, m/z 370 [M+H]+, 98% 1H NMR (400 MHz, MeOD) ^^^^ 8.16 (s, 1H), 6.94 – 6.88 (m, 1H), 6.88 – 6.76 (m, 1H), 6.24 – 6.15 (m, 1H), 5.78 – 5.71 (m, 1H), 4.81 – 4.63 (m, 1H), 4.26 – 4.14 (m, 1H), 4.12 – 4.00 (m, 2H), 3.75 – 3.63 (m, 2H), 3.28– 3.16 (m, 1H), 3.08 – 2.94 (m, 1H), 2.09 – 1.91 (m, 5H), 1.89 – 1.63 (m, 4H), 1.33 (d, J = 7.0 Hz, 3H). EXAMPLE 29 1-((3R,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3R,5R)-3-amino-5-methylpiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.8.8 mg of the title compound were obtained. LCMS 4: RT 1.50 min, m/z 370 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.22 – 8.05 (m, 1H), 6.99 – 6.37 (m, 2H), 6.21 – 5.84 (m, 1H), 5.81 – 5.24 (m, 2H), 4.52 – 4.04 (m, 3H), 4.03 – 3.77 (m, 3H), 3.58 – 3.36 (m, 2H), 3.21 – 2.81 (m, 2H), 2.21 – 1.97 (m, 1H), 1.90 – 1.72 (m, 3H), 1.72 – 1.34 (m, 3H), 0.99 – 0.84 (m, 3H). EXAMPLE 30 1-((3S,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3S,5R)-3-amino-5-methylpiperidine-1-carboxylate following the experimental procedure described in Synthesis method 2.11 mg of the title compound were obtained. LCMS 1: RT 1.75 min, m/z 370 [M+H]+, 91% 1H NMR (400 MHz, MeOD) ^^^^ 8.16 (d, J = 14.2 Hz, 1H), 6.97 – 6.80 (m, 2H), 6.31 - 6.19 (m, 1H), 5.84 - 5.75 (m, 1H), 4.62 – 4.52 (m, 2H), 4.35 -4.19 (m, 1H), 4.08 - 4.04 (m, 2H), 3.73 – 3.66 (m, 2H), 3.29 – 3.18 (m, 1H), 2.97 – 2.65 (m, 1H), 2.41 - 2.18 (m, 1H), 2.00 (d, J = 12.8 Hz, 2H), 1.88 – 1.64 (m, 2H), 1.49 – 1.31 (m, 3H), 1.09 - 1.02 (m, 3H). EXAMPLE 31 1-((2S,4R)-2-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2S,4R)-4-amino-2-methylpyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.41 mg of the title compound were obtained. LCMS 1: RT 1.38 min, m/z 356 [M+H]+, 98% 1H NMR (500 MHz, d6-DMSO) ^^^^ 11.43 (s, 1H), 8.17 – 8.11 (m, 1H), 6.96 – 6.88 (m, 1H), 6.70 – 6.51 (m, 1H), 6.21 – 6.07 (m, 1H), 6.05 – 5.96 (m, 1H), 5.72 – 5.59 (m, 1H), 4.74 – 4.46 (m, 1H), 4.31 – 4.03 (m, 2H), 3.96 – 3.84 (m, 2H), 3.61 – 3.44 (m, 3H), 3.33 – 3.27 (m, 1H), 2.66 – 2.42 (m, 1H), 1.98 – 1.77 (m, 3H), 1.67 – 1.48 (m, 2H), 1.40 – 1.26 (m, 3H). EXAMPLE 32 1-((2R,4R)-2-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.16 mg of the title compound were obtained. LCMS 5: RT 1.69 min, m/z 356 [M+H]+, 86% 1H NMR (400 MHz, MeOD) ^^^^ 8.18 (s, 1H), 6.92 (s, 1H), 6.64 (ddd, J = 58.0, 16.8, 10.4 Hz, 1H), 6.30 (ddd, J = 37.9, 16.8, 2.0 Hz, 1H), 5.77 (ddd, J = 37.9, 10.4, 2.0 Hz, 1H), 5.05 – 4.92 (m, 1H), 4.47 – 4.33 (m, 1H), 4.15 – 3.92 (m, 3H), 3.77 – 3.55 (m, 3H), 3.24 – 3.12 (m, 1H), 2.46 – 2.30 (m, 1H), 2.28 – 2.06 (m, 1H), 2.02 – 1.85 (m, 2H), 1.79 – 1.62 (m, 2H), 1.42 - 1.33 (m, 3H). EXAMPLE 33 1-((3S,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3R,4S)-3-amino-4-methylpyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.91 mg of the title compound were obtained. LCMS 4: RT 1.50 min, m/z 356 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.17 – 8.05 (m, 1H), 6.97 – 6.82 (m, 1H), 6.68 – 6.48 (m, 1H), 6.22 – 6.06 (m, 1H), 6.04 – 5.89 (m, 1H), 5.73 – 5.58 (m, 1H), 4.62 – 4.34 (m, 1H), 4.15 – 3.73 (m, 4H), 3.63 – 3.48 (m, 2H), 3.48 – 2.94 (m, 3H), 2.60 – 2.37 (m, 1H), 1.97 – 1.75 (m, 2H), 1.75 – 1.56 (m, 1H), 1.56 – 1.37 (m, 1H), 1.06 (d, J = 6.6 Hz, 3H). EXAMPLE 34 1-((3R,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3R,4R)-3-amino-4-methylpyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.18 mg of the title compound were obtained. LCMS 1: RT 1.45 min, m/z 356 [M+H]+, 96% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.44 (s, 1H), 8.14 (s, 1H), 6.92 (m, 1H), 6.67 – 6.50 (m, 1H), 6.20 – 6.09 (m, 1H), 5.74 –5.58 (m, 2H), 4.92 – 4.71 (m, 1H), 3.98 – 3.87 (m, 3H), 3.86 – 3.79 (m, 1H), 3.76 – 3.54 (m, 2H), 3.54 – 3.44 (m, 2H), 3.25 – 3.15 (m, 1H), 2.75 – 2.56 (m, 1H), 1.94 – 1.77 (m, 2H), 1.72 – 1.59 (m, 1H), 1.57 – 1.42 (m, 1H), 1.02 – 0.95 (m, 3H). EXAMPLE 35 1-((2S,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2S,3R)-3-amino-4-methylpyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.86 mg of the title compound were obtained. LCMS 4: RT 1.38 min, m/z 356 [M+H]+, 96% 1H "1H NMR (400 MHz, d6-DMSO) ^^^^ 11.40 (s, 1H), 8.20 – 8.09 (m, 1H), 6.92 – 6.82 (m, 1H), 6.65 – 6.47 (m, 1H), 6.19 – 6.06 (m, 1H), 5.88 – 5.76 (m, 1H), 5.71 – 5.57 (m, 1H), 4.52 – 4.31 (m, 1H), 4.24 – 4.10 (m, 1H), 3.94 – 3.77 (m, 2H), 3.77 – 3.57 (m, 2H), 3.56 – 3.38 (m, 2H), 3.32 – 3.15 (m, 1H), 2.40 – 2.21 (m, 1H), 2.21 – 2.05 (m, 1H), 1.89 – 1.68 (m, 2H), 1.67 – 1.51 (m, 1H), 1.51 – 1.34 (m, 1H), 1.32 – 1.17 (m, 3H)." EXAMPLE 36 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2R,3R)-3-amino-4-methylpyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.20 mg of the title compound were obtained. LCMS 5: RT 1.90 min, m/z 356 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.78 (d, J = 18.5 Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H), 7.05 – 6.96 (m, 1H), 6.67 – 6.53 (m, 1H), 6.36 – 6.24 (m, 1H), 6.23-6.12 (m, 1H), 5.73 – 5.65 (m, 1H), 4.68 –4.47 (m, 2H), 3.97 – 3.86 (m, 2H), 3.80 – 3.70 (m, 1H), 3.58 – 3.50 (m, 4H), 2.34 – 2.14 (m, 2H), 1.90 – 1.81 (m, 2H), 1.71 – 1.45 (m, 2H), 1.00 (dd, J = 12.3, 6.4 Hz, 3H). EXAMPLE 37 1-((3R,4S)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate following the experimental procedure described in Synthesis method 2.36 mg of the title compound were obtained. LCMS 4: RT 1.50 min, m/z 360 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.56 – 11.40 (m, 1H), 8.21 – 8.12 (m, 1H), 6.99 – 6.88 (m, 1H), 6.70 – 6.53 (m, 1H), 6.25 – 6.11 (m, 1H), 5.92 (t, J = 7.0 Hz, 1H), 5.78 – 5.66 (m, 1H), 5.55 – 5.25 (m, 1H), 5.22 – 4.84 (m, 1H), 4.24 – 3.72 (m, 4H), 3.71 – 3.59 (m, 1H), 3.59 – 3.41 (m, 3H), 3.32 – 3.17 (m, 1H), 1.98 – 1.79 (m, 2H), 1.72 – 1.44 (m, 2H)." EXAMPLE 38 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (R)-3-aminoazepane-1-carboxylate following the experimental procedure described in Synthesis method 1 using 1-butanol as solvent in Step 1.20 mg of the title compound were obtained. LCMS4: RT 1.70 min, m/z 370 [M+H]+, 100% 1H 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.45 – 11.27 (m, 1H), 8.24 – 7.99 (m, 1H), 7.38 – 6.82 (m, 3H), 6.36 –6.13 (m, 1H), 5.86 – 5.63 (m, 1H), 4.68 – 4.22 (m, 1H), 4.16 – 4.05 (m, 1H), 3.98 – 3.91 (m, 1H), 3.90 –3.83 (m, 1H), 3.74 – 3.64 (m, 1H), 3.57 – 3.50 (m, 1H), 3.28 – 3.10 (m, 3H), 2.25 – 2.11 (m, 1H), 1.98 –1.89 (m, 1H),1.86 – 1.76 (m, 2H), 1.75 – 1.65 (m, 2H), 1.64 – 1.51 (m, 2H), 1.48 – 1.33 (m, 2H), 1.25 –1.13 (m, 1H). EXAMPLE 39 1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert- butyl 7-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate following the experimental procedure described in Synthesis method 2.164 mg of the title compound were obtained. LCMS4: RT 1.50 min, m/z 368 [M+H]+, 95% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.51 – 11.29 (m, 1H), 8.20 – 8.11 (m, 1H), 6.97 – 6.87 (m, 1H), 6.66 – 6.38 (m, 1H), 6.21 – 6.09 (m, 1H), 6.06 – 5.97 (m, 1H), 5.77 – 5.61 (m, 1H), 4.80 – 4.59 (m, 1H), 4.16 – 3.99 (m, 1H), 4.00 – 3.83 (m, 2H), 3.76 – 3.44 (m, 3H), 3.35 – 3.08 (m, 2H), 2.92 – 2.73 (m, 1H), 1.97 – 1.34 (m, 8H). EXAMPLE 40 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate following the experimental procedure described in Synthesis method 2.4.4 mg of the title compound were obtained. LCMS 4: RT 1.64 min, m/z 368 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.42 (s, 1H), 8.19 – 8.07 (m, 1H), 6.98 – 6.86 (m, 1H), 6.74 – 6.37 (m, 1H), 6.23 – 6.06 (m, 2H), 5.75 – 5.59 (m, 1H), 4.58 – 4.34 (m, 1H), 4.04 – 3.87 (m, 2H), 3.87 – 3.73 (m, 1H), 3.64 – 3.45 (m, 3H), 2.35 – 1.77 (m, 8H), 1.77 – 1.47 (m, 3H). EXAMPLE 41 1-((1R,2R,5R)-2-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate following the experimental procedure described in Synthesis method 2.22 mg of the title compound were obtained. LCMS 5: RT 2.17 min, m/z 382 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.50 – 11.30 (m, 1H), 8.23 – 8.06 (m, 1H), 7.06 – 6.64 (m, 2H), 6.28 – 6.15 (m, 1H), 5.83 – 5.65 (m, 1H), 5.64 – 5.39 (m, 1H), 4.75 – 4.60 (m, 1H), 4.55 – 4.46 (m, 1H), 4.44 – 4.08 (m, 1H), 3.97 – 3.87 (m, 2H), 3.63 – 3.50 (m, 2H), 3.33 – 3.23 (m, 1H), 2.17 – 1.45 (m, 12H). EXAMPLE 42 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)piperidin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (R)-3-hydroxypiperidine-1-carboxylate following the experimental procedure described in Synthesis method 7.79 mg of the title compound were obtained. LCMS 1: RT 1.92 min, m/z 357 [M+H]+, 97% 1H NMR (400 MHz, MeOD) ^^^^ 8.29 (d, J = 1.7 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.84 (dd, J = 16.7, 10.6 Hz, 1H), 6.37 (dd, J = 16.8, 10.6 Hz, 1H), 6.13 (dd, J = 16.7, 1.9 Hz, 1H), 5.92 (dd, J = 16.8, 1.9 Hz, 1H), 5.74 (dd, J = 10.6, 1.9 Hz, 1H), 5.60 (d, J = 16.3 Hz, 1H), 5.33 (dd, J = 10.6, 1.9 Hz, 1H), 4.64 (d, J = 10.1 Hz, 1H), 4.44 (d, J = 13.1 Hz, 1H), 4.34 (d, J = 14.6 Hz, 1H), 4.00 (dt, J = 11.2, 6.5 Hz, 2H), 3.70 – 3.46 (m, 2H), 3.46 – 3.35 (m, 1H), 3.17 – 2.99 (m, 1H), 2.06 (dt, J = 20.2, 10.2 Hz, 2H), 1.97 – 1.82 (m, 2H), 1.82 – 1.66 (m, 2H). EXAMPLE 43 1-(4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1- yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl piperazine-1-carboxylate following the experimental procedure described in Synthesis method 2.16 mg of the title compound were obtained. LCMS 1: RT 1.35 min, m/z 342 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.77 (s, 1H), 8.30 (s, 1H), 7.18 – 7.14 (m, 1H), 6.89 – 6.81 (m, 1H), 6.18 – 6.12 (m, 1H), 5.76 – 5.70 (m, 1H), 3.99 – 3.87 (m, 2H), 3.83 – 3.62 (m, 4H), 3.53 – 3.44 (m, 2H), 3.42 – 3.34 (m, 4H), 3.04 – 2.93 (m, 1H), 2.03 – 1.95 (m, 2H), 1.62 – 1.50 (m, 2H). EXAMPLE 44 rac-1-((4aR,7aR)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and rac-tert- butyl (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate following the experimental procedure described in Synthesis method 2.56 mg of the title compound were obtained. LCMS5: RT 2.12 min, m/z 382 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.87 – 11.64 (m, 1H), 8.49 – 8.33 (m, 1H), 7.21 – 7.07 (m, 1H), 6.59 – 6.25 (m, 1H), 6.09 – 5.94 (m, 1H), 5.72 – 5.42 (m, 1H), 4.38 – 4.09 (m, 1H), 4.09 – 3.92 (m, 1H), 3.92 – 3.64 (m, 2H), 3.63 – 3.40 (m, 4H), 3.04 – 2.86 (m, 2H), 2.84 – 2.60 (m, 1H), 2.06 – 1.51 (m, 8H), 1.32 – 1.04 (m, 2H). EXAMPLE 45 and EXAMPLE 46 1-((4aS,7aS)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one 1-((4aR,7aR)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of rac-1-((4aR,7aR)-1-(5- (Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl)prop-2-en-1-one (56 mg), prepared as described in Example 44. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Chiralpak AD-H (10 x 250mm, 5 µm, Eluent A: CO2, Eluent B: EtOH, Flux: 15 mL/min. First eluting peak (Example 45): Obtained as a white solid (8 mg). Purity by LCMS 97%. LCMS 1: RT 1.77 min, m/z 382 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.82 – 11.75 (m, 1H), 8.44 – 8.36 (m, 1H), 7.18 – 7.11 (m, 1H), 6.65 – 6.27 (m, 1H), 6.07 – 5.95 (m, 1H), 5.71 – 5.41 (m, 1H), 4.42 – 4.12 (m, 1H), 4.03 – 3.96 (m, 1H), 3.88 – 3.64 (m, 2H), 3.62 – 3.48 (m, 2H), 3.48 – 3.25 (m, 3H), 3.01 – 2.85 (m, 2H), 2.81 – 2.62 (m, 1H), 2.03 – 1.58 (m, 8H), 1.25 – 1.07 (m, 1H). Second eluting peak (Example 46): Obtained as a white solid (9.8 mg). Purity by LCMS 89%. LCMS 1: RT 1.77 min, m/z 382 [M+H]+, 89% 1H "1H NMR (400 MHz, d6-DMSO) ^^^^ 11.82 – 11.75 (m, 1H), 8.45 – 8.38 (m, 1H), 7.18 – 7.11 (m, 1H), 6.57 – 6.29 (m, 1H), 6.06 – 5.95 (m, 1H), 5.67 – 5.40 (m, 1H), 4.35 – 4.15 (m, 1H), 4.04 – 3.95 (m, 1H), 3.88 – 3.64 (m, 2H), 3.61 – 3.51 (m, 2H), 3.51 – 3.16 (m, 3H), 3.05 – 2.87 (m, 2H), 2.82 – 2.62 (m, 1H), 2.04 – 1.41 (m, 8H), 1.30 – 1.06 (m, 1H). EXAMPLE 47 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate following the experimental procedure described in Synthesis method 2.32 mg of the title compound were obtained. LCMS 1: RT 1.28 min, m/z 354 [M+H]+, 95% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.72 – 11.57 (m, 1H), 8.17 (s, 1H), 7.00 (dd, J = 2.6, 1.0 Hz, 1H), 6.58 (dd, J = 16.7, 10.4 Hz, 1H), 6.03 (dd, J = 16.7, 2.4 Hz, 1H), 5.61 (dd, J = 10.4, 2.5 Hz, 1H), 4.65 – 4.55 (m, 2H), 4.35 – 4.24 (m, 1H), 3.98 – 3.87 (m, 2H), 3.87 – 3.72 (m, 2H), 3.61 – 3.45 (m, 3H), 2.91 – 2.69 (m, 2H), 2.04 – 1.90 (m, 2H), 1.66 – 1.38 (m, 3H). EXAMPLE 48 1-((1R,4R)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate following the experimental procedure described in Synthesis method 2.13 mg of the title compound were obtained. LCMS 1: RT 1.17 min, m/z 354 [M+H]+, 96% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.59 (s, 1H), 8.22 – 8.08 (m, 1H), 7.00 – 6.91 (m, 1H), 6.82 – 6.69 (m, 1H), 6.46 – 6.32 (m, 1H), 6.14 – 6.03 (m, 1H), 5.67 – 5.59 (m, 1H), 4.98 – 4.81 (m, 2H), 3.99 – 3.88 (m, 1H), 3.88 – 3.81 (m, 0H), 3.81 – 3.76 (m, 1H), 3.73 – 3.64 (m, 1H), 3.57 – 3.37 (m, 3H), 3.07 – 2.96 (m, 1H), 2.54-2.53 (m, 1H), 2.05 – 1.88 (m, 3H), 1.88 – 1.79 (m, 1H), 1.77 – 1.62 (m, 1H), 1.36 – 1.23 (m, 1H). EXAMPLE 49 1-((1S,4S)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate following the experimental procedure described in Synthesis method 2.24 mg of the title compound were obtained. LCMS 1: RT 1.15 min, m/z 354 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.58 (s, 1H), 8.14 (d, J = 1.2 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.85 – 6.29 (m, 1H), 6.09 (dd, J = 16.9, 2.4 Hz, 1H), 5.63 (ddd, J = 10.2, 7.7, 2.3 Hz, 1H), 4.95 (d, J = 14.7 Hz, 1H), 4.87 (d, J = 13.7 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.89 – 3.79 (m, 1H), 3.74 – 3.63 (m, 1H), 3.57 – 3.43 (m, 2H), 3.40 – 3.20 (m, 2H), 3.04 – 2.95 (m, 1H), 2.04 – 1.79 (m, 4H), 1.74 – 1.60 (m, 1H), 1.36 – 1.23 (m, 1H). EXAMPLE 50 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate following the experimental procedure described in Synthesis method 4.41 mg of the title compound were obtained. LCMS 1: RT 1.14 min, m/z 368 [M+H]+, 90% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.54 (s, 1H), 8.20 – 8.09 (m, 1H), 7.01 – 6.88 (m, 1H), 6.58 (ddd, J = 16.8, 15.1, 10.3 Hz, 1H), 6.15 (ddd, J = 16.8, 5.3, 2.4 Hz, 1H), 5.68 (ddd, J = 10.0, 7.4, 2.4 Hz, 1H), 4.27 – 4.09 (m, 4H), 3.98 – 3.85 (m, 2H), 3.80 (s, 1H), 3.65 (t, J = 6.9 Hz, 1H), 3.61 (s, 1H), 3.57 – 3.42 (m, 3H), 2.94 (t, J = 11.6 Hz, 1H), 2.19 (t, J = 6.9 Hz, 1H), 2.09 (t, J = 7.0 Hz, 1H), 2.00 – 1.86 (m, 2H), 1.62 – 1.37 (m, 2H). EXAMPLE 51 rac-1-((3aR,7aS)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and rac-tert- butyl (3aR,7aS)-octahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate following the experimental procedure described in Synthesis method 2.72 mg of the title compound were obtained. LCMS 1: RT 1.32 min, m/z 382 [M+H]+, 96% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.55 (s, 1H), 8.16 (s, 1H), 6.96 (s, 1H), 6.93-6.72, m, 1H), 6.13 (dd, J = 16.6, 2.5 Hz, 1H), 5.72 – 5.66 (m, 1H), 4.62 – 4.53 (m, 1H), 4.20 – 3.62 (m, 6H), 3.57 –3.42 (m, 3H), 3.16 – 2.92 (m, 2H), 2.46 – 2.36 (m, 1H), 2.10 – 1.51 (m, 7H), 1.31 – 1.18 (m, 1H). EXAMPLE 52 and EXAMPLE 53 1-((3aS,7aR)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one 1-((3aR,7aS)-1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of rac-1-((3aR,7aS)-1-(5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-5H-pyrrolo[3,2- c]pyridin-5-yl)prop-2-en-1-one (65 mg), prepared as described in Example 51. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Chiralpak AS-H (10 x 250mm, 5 µm, Eluent A: CO2, Eluent B: MeOH, Flux: 15 mL/min. First eluting peak (Example 52): Obtained as a white solid (24 mg). Purity by LCMS 96%. LCMS 1: RT 1.24 min, m/z 382 [M+H]+, 96% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.55 (s, 1H), 8.16 (s, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.93-6.72 (m, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.73 – 5.64 (m, 1H), 4.63 – 4.54 (m, 1H), 4.16 – 3.42 (m, 8H), 3.33 – 2.95 (m, 3H), 2.42 (s, 1H), 2.07 – 1.63 (m, 7H), 1.32 – 1.17 (m, 1H) Second eluting peak (Example 53): Obtained as a white solid (26 mg). Purity by LCMS 96%. LCMS 1: RT 1.24 min, m/z 382 [M+H]+, 96% 1H 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.55 (s, 1H), 8.16 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.93-6.72 m, 1H), 6.13 (dd, J = 16.6, 2.5 Hz, 1H), 5.73 – 5.65 (m, 1H), 4.63 – 4.54 (m, 1H), 4.18 – 3.41 (m, 8H), 3.34 – 2.97 (m, 3H), 2.47-2.3 (m, 1H) 2.10 – 1.61 (m, 7H), 1.32 – 1.17 (m, 1H) EXAMPLE 54 rac-1-((3aR,7aR)-4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and rac-tert- butyl (3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate following the experimental procedure described in Synthesis method 2.34 mg of the title compound were obtained. LCMS 4: RT 1.70 min, m/z 382 [M+H]+, 93% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.81 (s, 1H), 8.45 – 8.30 (m, 1H), 7.29 – 7.14 (m, 1H), 6.89 – 6.56 (m, 1H), 6.35 – 6.19 (m, 1H), 5.86 – 5.70 (m, 1H), 4.81 – 4.52 (m, 1H), 4.35 – 4.16 (m, 1H), 4.14 – 3.96 (m, 2H), 3.87 – 3.49 (m, 6H), 3.16 – 2.97 (m, 1H), 2.50 – 2.33 (m, 1H), 2.26 – 1.90 (m, 4H), 1.86 – 1.46 (m, 5H). EXAMPLE 55 and EXAMPLE 56 1-((3aS,7aS)-4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one 1-((3aR,7aR)-4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of rac-((3aR,7aR)-4-(5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)prop-2-en-1-one (34 mg), prepared as described in Example 54. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Chiralpak AD- H (10 x 250mm, 5 µm, Eluent A: CO2, Eluent B: EtOH, Flux: 15 mL/min. First eluting peak (Example 55): Obtained as a white solid (8.2 mg). Purity by LCMS XX%. LCMS 4: RT 1.61 min, m/z 382 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.71 (s, 1H), 8.33 – 8.22 (m, 1H), 7.17 – 7.06 (m, 1H), 6.77 – 6.47 (m, 1H), 6.25 – 6.08 (m, 1H), 5.73 – 5.55 (m, 1H), 4.72 – 4.44 (m, 1H), 4.26 – 4.07 (m, 1H), 4.03 – 3.85 (m, 2H), 3.76 – 3.37 (m, 5H), 3.04 – 2.89 (m, 1H), 2.41 – 2.23 (m, 1H), 2.17 – 1.82 (m, 4H), 1.76 – 1.37 (m, 6H) Second eluting peak (Example 56): Obtained as a white solid (6.4 mg). Purity by LCMS XX%. LCMS 4: RT 1.62 min, m/z 382 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.71 (s, 1H), 8.27 (d, J = 5.7 Hz, 1H), 7.12 (s, 1H), 6.79 – 6.43 (m, 1H), 6.25 – 6.08 (m, 1H), 5.73 – 5.58 (m, 1H), 4.71 – 4.45 (m, 1H), 4.23 – 4.06 (m, 1H), 4.02 – 3.81 (m, 2H), 3.74 – 3.36 (m, 5H), 3.03 – 2.88 (m, 1H), 2.40 – 2.23 (m, 1H), 2.15 – 1.81 (m, 4H), 1.75 – 1.33 (m, 6H). EXAMPLE 57 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate following the experimental procedure described in Synthesis method 5.9 mg of the title compound were obtained. LCMS 5: RT 1.86 min, m/z 354 [M+H]+, 90% 1H NMR (400 MHz, MeOD) ^^^^ 8.17 (s, 1H), 7.04 – 6.98 (m, 1H), 6.53 – 6.44 (m, 1H), 6.31 – 6.25 (m, 1H), 5.79 – 5.75 (m, 1H), 4.80 – 4.76 (m, 1H), 4.62 – 4.53 (m, 1H), 4.48 – 4.40 (m, 1H), 4.29 – 4.17 (m, 2H), 4.05 – 3.98 (m, 3H), 3.70 – 3.56 (m, 2H), 3.21 – 3.13 (m, 1H), 2.79 – 2.69 (m, 1H), 2.09 – 2.01 (m, 2H), 1.73 – 1.69 (m, 1H), 1.68 – 1.53 (m, 2H) EXAMPLE 58 1-(8-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate following the experimental procedure described in Synthesis method 6.55 mg of the title compound were obtained. LCMS 1: RT 1.58 min, m/z 368 [M+H]+, 98% 1H NMR (400 MHz, MeOD) ^^^^ 8.24 (s, 1H), 7.17 – 7.02 (m, 1H), 6.80 (dd, J = 16.8, 10.6 Hz, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.79 (dd, J = 10.6, 1.9 Hz, 1H), 4.68 – 4.36 (m, 2H), 4.05 (t, J = 8.5 Hz, 2H), 3.81 – 3.50 (m, 2H), 3.30 – 3.00 (m, 5H), 2.14 (d, J = 13.3 Hz, 2H), 1.90 (d, J = 29.2 Hz, 2H), 1.70 (qt, J = 12.9, 6.2 Hz, 2H), 1.31 (d, J = 18.0 Hz, 2H). EXAMPLE 59 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate following the experimental procedure described in Synthesis method 6.48 mg of the title compound were obtained. LCMS 1: RT 1.31 min, m/z 368 [M+H]+, 98% 1H NMR (400 MHz, MeOD) ^^^^ 8.52 (s, 1H), 8.17 (d, J = 4.5 Hz, 1H), 6.99 (dd, J = 4.5, 0.9 Hz, 1H), 6.76 (dd, J = 16.7, 10.6 Hz, 1H), 6.62 (dd, J = 16.8, 10.5 Hz, 1H), 6.27 (ddd, J = 16.8, 12.7, 2.0 Hz, 1H), 5.77 (ddd, J = 12.4, 10.5, 2.0 Hz, 1H), 4.65 (d, J = 9.3 Hz, 1H), 4.48 (s, 1H), 4.07 – 3.97 (m, 2H), 3.97 – 3.78 (m, 2H), 3.71 – 3.51 (m, 2H), 3.12 (d, J = 3.3 Hz, 2H), 2.34 (s, 1H), 2.14 – 1.99 (m, 2H), 1.99 – 1.82 (m, 2H), 1.77 – 1.49 (m, 2H), 1.31 (m, 1H). EXAMPLE 60 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate following the experimental procedure described in Synthesis method 4.25 mg of the title compound were obtained. LCMS 4: RT 1.39 min, m/z 368 [M+H]+, 90% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.49 (s, 1H), 8.10 (s, 1H), 6.96 – 6.86 (m, 1H), 6.39 – 6.22 (m, 1H), 6.18 – 6.02 (m, 1H), 5.71 – 5.60 (m, 1H), 4.40 – 4.26 (m, 1H), 4.19 – 4.08 (m, 2H), 4.01 – 3.65 (m, 6H), 3.14 – 3.01 (m, 1H), 2.70 – 2.58 (m, 1H), 2.38 – 2.14 (m, 3H), 2.14 – 1.97 (m, 1H), 1.97 – 1.80 (m, 2H), 1.68 – 1.48 (m, 1H), 1.48 – 1.26 (m, 1H). EXAMPLE 61 1-(4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-diazepan-1- yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 1,4-diazepane-1-carboxylate following the experimental procedure described in Synthesis method 2.14 mg of the title compound were obtained. LCMS 1: RT 1.20 min, m/z 356 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.61 (d, J = 8.6 Hz, 1H), 8.21 – 8.11 (m, 1H), 7.08 – 6.98 (m, 1H), 6.84 – 6.69 (m, 1H), 6.10 – 6.00 (m, 1H), 5.71 – 5.56 (m, 1H), 3.94 – 3.86 (m, 2H), 3.85 – 3.80 (m, 1H), 3.78 – 3.71 (m, 3H), 3.66 – 3.56 (m, 4H), 3.51 – 3.44 (m, 2H), 3.08 – 2.95 (m, 1H), 2.04 – 1.98 (m, 1H), 1.96 – 1.90 (m, 3H), 1.50 (m, 2H). EXAMPLE 62 1-((1S,5S)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate following the experimental procedure described in Synthesis method 4.21 mg of the title compound were obtained. LCMS 1: RT 0.95 min, m/z 354 [M+H]+, 90% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.53 (s, 1H), 8.19 – 8.08 (m, 1H), 6.97 – 6.87 (m, 1H), 6.82 – 6.43 (m, 1H), 6.20 – 5.98 (m, 1H), 5.76 – 5.49 (m, 1H), 5.30 – 5.10 (m, 1H), 4.32 – 4.19 (m, 2H), 4.19 – 4.07 (m, 1H), 4.06 – 3.88 (m, 3H), 3.86 – 3.70 (m, 1H), 3.55 – 3.40 (m, 3H), 3.25 – 3.10 (m, 1H), 2.90 – 2.77 (m, 1H), 1.97 – 1.87 (m, 1H), 1.87 – 1.77 (m, 1H), 1.77 – 1.60 (m, 1H), 1.36 – 1.14 (m, 1H). EXAMPLE 63 1-((3aR,6aS)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate following the experimental procedure described in Synthesis method 2.79 mg of the title compound were obtained. LCMS 1: RT 1.06 min, m/z 368 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.59 – 11.47 (m, 1H), 8.09 (s, 1H), 6.98 – 6.92 (m, 1H), 6.62 – 6.52 (m, 1H), 6.20 – 6.08 (m, 1H), 5.69 – 5.62 (m, 1H), 3.94 – 3.75 (m, 5H), 3.65 – 3.54 (m, 3H), 3.54 – 3.48 (m, 1H), 3.42 (t, J = 11.6 Hz, 2H), 3.36 – 3.34 (m, 1H), 3.15 – 3.00 (m, 2H), 3.00 – 2.90 (m, 1H), 1.96 – 1.87 (m, 2H), 1.55 – 1.40 (m, 2H). EXAMPLE 64 1-((1S,5R)-3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (1S,5R)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate following the experimental procedure described in Synthesis method 3.28 mg of the title compound were obtained. LCMS 5: RT 1.35 min, m/z 354 [M+H]+, 94% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.76 – 11.58 (m, 1H), 8.21 – 8.17 (m, 1H), 7.11 – 7.05 (m, 1H), 6.55 – 6.15 (m, 1H), 6.15 – 6.00 (m, 1H), 5.76 – 5.57 (m, 1H), 5.11 – 4.75 (m, 1H), 4.34 – 4.10 (m, 2H), 4.04 – 3.96 (m, 1H), 3.91 – 3.77 (m, 3H), 3.55 – 3.37 (m, 2H), 3.30 – 2.96 (m, 4H), 2.04 – 1.86 (m, 2H), 1.66 – 1.32 (m, 2H) EXAMPLE 65 1-((1R,5S)-3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate following the experimental procedure described in Synthesis method 1 using 1-butanol instead of acetonitrile as solvent in Step 1.48 mg of the title compound were obtained. LCMS 5: RT 1.69 min, m/z 354 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.80 – 11.60 (m, 1H), 8.34 – 8.10 (m,1H), 7.16 – 7.00 (m, 1H), 6.59 – 6.16 (m, 1H), 6.15 – 6.01 (m, 1H), 5.73 –5.60 (m, 1H), 5.10 – 4.79 (m, 1H), 4.33 – 4.10 (m, 2H), 4.06 – 3.95 (m,1H), 3.94 – 3.76 (m, 3H), 3.55 – 3.47 (m, 1H), 3.29 – 3.10 (m, 3H), 3.05(m, 1H), 2.04 – 1.87 (m, 2H), 1.67 –1.32 (m, 2H). EXAMPLE 66 1-(7-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7- diazaspiro[3.5]nonan-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 1,7-diazaspiro[3.5]nonane-1-carboxylate following the experimental procedure described in Synthesis method 4.2.1 mg of the title compound were obtained. LCMS 4: RT 1.48 min, m/z 382 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.82 – 11.59 (m, 1H), 8.33 – 8.23 (m, 1H), 7.19 – 7.04 (m, 1H), 6.32 – 6.04 (m, 2H), 5.72 – 5.58 (m, 1H), 4.19 – 4.08 (m, 1H), 4.03 – 3.89 (m, 2H), 3.87 – 3.68 (m, 2H), 3.56 – 3.40 (m, 2H), 3.06 – 2.95 (m, 1H), 2.95 – 2.80 (m, 2H), 2.66 – 2.54 (m, 2H), 2.25 – 1.95 (m, 5H), 1.95 – 1.81 (m, 2H), 1.66 – 1.43 (m, 2H). EXAMPLE 67 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.5]nonan-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 1,6-diazaspiro[3.5]nonane-1-carboxylate following the experimental procedure described in Synthesis method 4.24 mg of the title compound were obtained. LCMS 4: RT 1.71 min, m/z 382 [M+H]+, 97% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.87 – 11.64 (m, 1H), 8.35 – 8.26 (m, 1H), 7.20 – 7.07 (m, 1H), 6.57 – 6.21 (m, 1H), 6.21 – 6.04 (m, 1H), 5.73 – 5.61 (m, 1H), 4.17 – 4.05 (m, 1H), 4.05 – 3.95 (m, 1H), 3.93 – 3.73 (m, 3H), 3.73 – 3.56 (m, 2H), 3.54 – 3.39 (m, 2H), 2.98 – 2.86 (m, 1H), 2.82 – 2.57 (m, 1H), 2.42 – 2.27 (m, 1H), 2.22 – 1.68 (m, 8H), 1.40 – 1.19 (m, 1H). EXAMPLE 68 1-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 1,6-diazaspiro[3.4]octane-6-carboxylate following the experimental procedure described in Synthesis method 5.6.9 mg of the title compound were obtained. LCMS 5: RT 2.09 min, m/z 368 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.57 (s, 1H), 8.14 – 8.04 (m, 1H), 7.09 – 7.03 (m, 1H), 6.80 – 6.59 (m, 1H), 6.31 – 6.21 (m, 1H), 5.83 – 5.72 (m, 1H), 4.65 – 4.37 (m, 4H), 4.09 – 3.99 (m, 2H), 3.91 – 3.81 (m, 1H), 3.74 – 3.63 (m, 1H), 3.63 – 3.54 (m, 2H), 3.28 – 3.08 (m, 2H), 2.56 – 2.41 (m, 2H), 2.18 – 2.04 (m, 1H), 2.02 – 1.93 (m, 2H), 1.76 – 1.58 (m, 2H). EXAMPLE 69 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.5]nonan-6-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate following the experimental procedure described in Synthesis method 4.15 mg of the title compound were obtained. LCMS 5: RT 1.98 min, m/z 382 [M+H]+, 96% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.52 (s, 1H), 8.13 (s, 1H), 6.99 – 6.78 (m, 2H), 6.20-6.07 (m, 1H), 5.69 (dd, J = 10.5, 2.5 Hz, 1H), 3.95 – 3.83 (m, 6H), 3.74 (s, 2H), 3.52 – 3.48 (m, 2H), 3.47 – 3.39 (m, 2H), 2.93 – 2.85 (m, 1H), 1.94 – 1.86 (m, 2H), 1.81 (s, 2H), 1.59 – 1.43 (m, 4H) EXAMPLE 70 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazaspiro[3.4]octan-5-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 2,5-diazaspiro[3.4]octane-5-carboxylate following the experimental procedure described in Synthesis method 3.4.5 mg of the title compound were obtained. LCMS 5: RT 1.84 min, m/z 368 [M+H]+, 97% 1H NMR (400 MHz, MeOD) ^^^^ 8.12 (s, 1H), 6.95 – 6.89 (m, 1H), 6.73 – 6.57 (m, 1H), 6.25 – 6.16 (m, 1H), 5.78 – 5.67 (m, 1H), 5.15 – 5.04 (m, 2H), 4.22 – 4.15 (m, 2H), 4.08 – 3.98 (m, 2H), 3.69 (m, 2H), 3.65 – 3.56 (m, 2H), 3.11 – 2.97 (m, 1H), 2.33 (m, 2H), 2.12 – 2.04 (m, 2H), 2.02-1.91 (m, 2H), 1.71 – 1.56 (m, 2H). EXAMPLE 71 1-((2S,6R)-2,6-Dimethyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate following the experimental procedure described in Synthesis method 2.190 mg of the title compound were obtained. LCMS 1: RT 1.70 min, m/z 370 [M+H]+, 93% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.76 (s, 1H), 8.29 (s, 1H), 7.16 (s, 1H), 6.80 (dd, J = 16.6, 10.5 Hz, 1H), 6.16 (dd, J = 16.6, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.53 (s, 2H), 3.92 (dd, J = 11.1, 3.3 Hz, 2H), 3.76 (d, J = 12.8 Hz, 2H), 3.48 (app. t, J = 11.2 Hz, 2H), 3.30 – 3.12 (m, 3H), 2.02 – 1.92 (m, 2H), 1.63 – 1.49 (m, 2H), 1.33 (d, J = 6.9 Hz, 6H) EXAMPLE 72 1-(7-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate following the experimental procedure described in Synthesis method 2.16 mg of the title compound were obtained. LCMS 1: RT 1.72 min, m/z 368 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.71 (s, 1H), 8.26 (s, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (s, 1H), 6.15 (dd, J = 16.8, 2.3 Hz, 1H), 5.73 (d, J = 10.4 Hz, 1H), 3.94 (d, J = 11.1 Hz, 2H), 3.52 (t, J = 11.7 Hz, 2H), 3.36 (s, 5H), 2.97 (t, J = 11.6 Hz, 1H), 2.04 (d, J = 13.0 Hz, 2H), 1.52 (s, 2H), 0.91 (s, 5H) EXAMPLE 73 (S)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (S)-2-methylpiperazine-1-carboxylate following the experimental procedure described in Synthesis method 6.29 mg of the title compound were obtained. LCMS 1: RT 1.57 min, m/z 356 [M+H]+, 90% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.76 (s, 1H), 8.29 (s, 1H), 7.52 (s, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.82 (dd, J = 16.6, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.3 Hz, 1H), 3.99 (d, J = 11.3 Hz, 1H), 3.89 (m, 2H), 3.67 (d, J = 12.9 Hz, 2H), 3.49 (q, J = 11.3 Hz, 2H), 3.23 (m, 2H), 3.03 (m, 1H), 2.85 (m, 2H), 1.99 (dd, J = 27.7, 12.7 Hz, 2H), 1.76 (d, J = 8.4 Hz, 1H), 1.51 – 1.26 (m, 1H), 1.16 (d, J = 11.3 Hz, 3H). EXAMPLE 74 1-(2,2-Dimethyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate following the experimental procedure described in Synthesis method 7.33 mg of the title compound were obtained. LCMS 1: RT 1.47 min, m/z 370 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.68 (s, 1H), 8.21 (s, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 16.8, 10.5 Hz, 1H), 6.04 (dd, J = 16.8, 2.3 Hz, 1H), 5.63 (dd, J = 10.5, 2.3 Hz, 1H), 3.98 – 3.87 (m, 2H), 3.87 – 3.78 (m, 2H), 3.71 – 3.63 (m, 2H), 3.58 (s, 2H), 3.50 (t, J = 11.0 Hz, 2H), 3.05 (t, J = 11.4 Hz, 1H), 1.96 (d, J = 12.5 Hz, 2H), 1.53 (qd, J = 12.4, 4.0 Hz, 2H), 1.42 (s, 6H). EXAMPLE 75 1-(4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- dihydropyridin-1(2H)-yl)prop-2-en-1-one Acryloyl chloride (18 μL, 0.22 mmol, 1.2 eq) was added to a solution of 5-(tetrahydro-2H- pyran-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine hydrochloride (114 mg, 0.177 mmol) and triethylamine (0.75 mL, 5.4 mmol, 3 eq) in dichloromethane (5 mL) at 0 °C under nitrogen, warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (0.3 mL, 4 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2.5 h. Additional trifluoroacetic acid (0.3 mL, 4 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (5 mL, 35 mmol, 7N in methanol, 200 eq) was added and the reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo. Purification by preparative HPLC (Method P3E). The product containing fractions were collected and the solvent was removed in vacuo to give the title compound (22.9 mg, 0.0610 mmol, 35% yield) as a beige powder. LCMS 1: RT 1.22 min, m/z 339 [M+H]+, 91% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.97 (s, 1H), 8.67 (s, 1H), 7.35 (s, 1H), 7.00 – 6.78 (m, 1H), 6.19 (t, J = 14.8 Hz, 1H), 6.04 – 5.89 (m, 1H), 5.84 – 5.65 (m, 1H), 4.42 – 4.20 (m, 2H), 3.94 – 3.72 (m, 4H), 3.43 – 3.34 (m, 2H), 3.03 – 2.84 (m, 1H), 2.73 – 2.57 (m, 2H), 1.86 – 1.66 (m, 2H), 1.65 – 1.43 (m, 2H). EXAMPLE 76 1-(4-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-1- yl)prop-2-en-1-one Acryloyl chloride (32 μL, 0.39 mmol, 1.2 eq) was added to a solution of 4-(piperidin-4-yl)- 5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine hydrochloride (184 mg, 0.325 mmol, 1 eq) and triethylamine (0.14 mL, 1.0 mmol, 3 eq) in dichloromethane (5 mL) at 0 °C under nitrogen, warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (0.5 mL, 7 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2 h. Additional trifluoroacetic acid (0.5 mL, 7 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo. Ammonia (5 mL, 35 mmol, 7N in methanol) was added and the reaction mixture was stirred at r.t. for 4 h. The solvent was removed in vacuo. Purification by preparative HPLC (method B). The product containing fractions were collected and the solvent was removed in vacuo to give the title compound (38.1 mg, 0.112 mmol, 35% yield) as a white powder. LCMS 1: RT 1.37 min, m/z 341 [M+H]+, 99% 1H NMR (400 MHz, d6-DMSO) ^^^^ 12.09 – 11.89 (m, 1H), 8.72 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 16.7, 10.5 Hz, 1H), 6.24 (dd, J = 16.7, 2.5 Hz, 1H), 5.80 (dd, J = 10.5, 2.5 Hz, 1H), 4.78 – 4.59 (m, 1H), 4.40 – 4.24 (m, 1H), 4.13 – 3.99 (m, 2H), 3.66 (td, J = 11.7, 2.0 Hz, 2H), 3.59 – 3.47 (m, 1H), 3.41 – 3.29 (m, 1H), 3.24 (tt, J = 11.8, 3.5 Hz, 1H), 2.99 – 2.81 (m, 1H), 2.07 – 1.88 (m, 6H), 1.88 – 1.72 (m, 2H). EXAMPLE 77 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dihydro- 1H-pyrrol-1-yl)prop-2-en-1-one Acrolyl chloride (60 μL, 0.74 mmol, 1.2 eq) was added to a solution of 4-(2,5-dihydro-1H- pyrrol-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (243 mg, 0.61 mmol, 1 eq) and triethylamine (253 μL, 1.82 mmol, 3 eq) in dichloromethane (3 mL) at 0 °C under nitrogen, warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (825 μL, 10.8 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen. Ammonia (in methanol) (5 mL, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen. Purification by preparative HPLC (Method P3E). The product tubes were collected, and the solvent was removed in vacuo. A subsequent additional purification was done by reverse phase chromatography (CSH C18100x19 mm 5 µm column, water/acetonitrile) to yield the pure title compound (2.4 mg, 0.12 mmol, 1.2% yield) as a beige solid. LCMS 5: RT 1.65 min, m/z 325 [M+H]+, 100% 1H NMR (400 MHz, MeOD) ^^^^ 8.72 – 8.62 (m, 1H), 7.41 – 7.37 (m, 1H), 6.75 – 6.64 (m, 1H), 6.42 – 6.30 (m, 2H), 5.87 – 5.81 (m, 1H), 5.06 – 4.98 (m, 1H), 4.84 – 4.73 (m, 2H), 4.66 – 4.58 (m, 1H), 4.06 – 3.95 (m, 2H), 3.60 – 3.47 (m, 2H), 3.21 – 3.09 (m, 1H), 1.96 – 1.83 (m, 2H), 1.79 – 1.61 (m, 2H). EXAMPLE 78 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-1- yl)prop-2-en-1-one Step 1 4-(Pyrrolidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine Hydrochloric acid (4M in dioxane) (5 mL, 20 mmol) was added to a solution of tert-butyl 3- (5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrrolidine-1-carboxylate (300 mg, 0.60 mmol, 90 mass%) in dichloromethane (3 mL) at r.t. and stirred at r.t. for 1 h. The solvent was removed in vacuo and passed through a 5 g SCX cartridge, washed with MeOH (3 x 10mL), followed by 2N NH3 in MeOH (3 x 10 mL). The product tubes were collected and the solvent removed in vacuo to give the title compound (217 mg, 0.54 mmol, 92% yield) as an orange solid. LCMS 7: RT 0.77 min, m/z 403 [M+H]+, 92% Step 2 1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-1- yl)prop-2-en-1-one Acrolyl chloride (53 μL, 0.65 mmol, 1.2 eq) was added to a solution of 4-(pyrrolidin-3-yl)- 5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (217 mg, 0.54 mmol, 1 eq) and triethylamine (225 μL, 1.61 mmol, 3 eq) in dichloromethane (3 mL) at 0 °C under nitrogen, warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (825 μL, 10.8 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 18 h. Additional trifluoroacetic acid (825 μL, 10.77 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 8 h. The solvent was removed under nitrogen. Ammonia (in methanol) (5 mL, 7 mol/L) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen. Purification by preparative HPLC (Method P3E). The product tubes were collected, and the solvent was removed in vacuo. The residue was dissolved in acetonitrile:water (1:1) and lyophylised to give the title compound (38.8 mg, 0.12 mmol, 22% yield) as a beige powder. LCMS 5: RT 1.82 min, m/z 327 [M+H]+, 98% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.95 (s, 1H), 8.66 – 8.62 (m, 1H), 7.42 – 7.33 (m, 1H), 6.69 – 6.56 (m, 1H), 6.20 – 6.11 (m, 1H), 5.73 – 5.61 (m, 1H), 4.15 – 3.62 (m, 7H), 3.57 – 3.48 (m, 2H), 3.22 – 3.10 (m, 1H), 2.42 – 2.10 (m, 2H), 1.91 – 1.80 (m, 2H), 1.76 – 1.61 (m, 2H). EXAMPLE 79 and EXAMPLE 80 (R)-1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 1-yl)prop-2-en-1-one (S)-1-(3-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 1-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of 1-(3-(5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-1-yl)prop-2-en-1-one (34 mg), prepared as described in Example 78. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Chiralcel OD-H (10 x 250mm, 5 µm, Eluent A: CO2, Eluent B: MeOH, Flux: 15 mL/min. First eluting peak (Example 80): Obtained as a white solid (39 mg). Purity by LCMS 100%. LCMS 5: RT 1.68 min, m/z 327 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.95 (s, 1H), 8.77 – 8.48 (m, 1H), 7.38 (s, 1H), 6.72 – 6.51 (m, 1H), 6.24 – 6.08 (m, 1H), 5.74 – 5.60 (m, 1H), 4.23 – 3.60 (m, 7H), 3.58 – 3.48 (m, 2H), 3.21 – 3.09 (m, 1H), 2.42 –2.10 (m, 2H), 1.93 – 1.81 (m, 2H), 1.80 – 1.60 (m, 2H). Second eluting peak (Example 79): Obtained as a white solid (39 mg). Purity by LCMS 100%. LCMS 5: RT 1.67 min, m/z 327 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.96 (s, 1H), 8.68 – 8.62 (m, 1H), 7.41 – 7.35 (m, 1H), 6.71 – 6.57 (m, 1H), 6.21 – 6.12 (m, 1H), 5.73 – 5.62 (m, 1H), 4.16 – 3.64 (m, 7H), 3.60 – 3.47 (m, 2H), 3.22 – 3.12 (m, 1H), 2.41 – 2.13 (m, 2H), 1.93 – 1.81 (m, 2H), 1.77 – 1.62 (m, 2H). EXAMPLE 81 N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4- yl)acrylamide The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl piperidin-4-ylcarbamate following the experimental procedure described in Synthesis method 2.14 mg of the title compound were obtained. LCMS 1: RT 1.22 min, m/z 356 [M+H]+, 97% 1H NMR (500 MHz, d6-DMSO) ^^^^ 11.74 – 11.62 (m, 1H), 8.27 (s, 1H), 8.14 (d, J = 7.7 Hz, 1H), 7.16 – 7.08 (m, 1H), 6.26 – 6.18 (m, 1H), 6.17 – 6.07 (m, 1H), 5.65 – 5.56 (m, 1H), 4.01 – 3.93 (m, 2H), 3.92 – 3.81 (m, 1H), 3.81 – 3.70 (m, 2H), 3.55 – 3.41 (m, 2H), 3.07 – 2.89 (m, 3H), 2.02 – 1.86 (m, 4H), 1.65 – 1.51 (m, 4H). EXAMPLE 82 (R)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 3-yl)acrylamide The title compound was prepared from 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) and tert-butyl (R)-pyrrolidin-3-ylcarbamate following the experimental procedure described in Synthesis method 2.79 mg of the title compound were obtained. LCMS 5: RT 1.64 min, m/z 342 [M+H]+, 100% 1H NMR (400 MHz, d6-DMSO) ^^^^ 11.50 (s, 1H), 8.34 (d, J = 6.3 Hz, 1H), 8.09 (s, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.27 – 6.17 (m, 1H), 6.14 – 6.04 (m, 1H), 5.62 – 5.54 (m, 1H), 4.34 (m, 1H), 3.95 – 3.83 (m, 3H), 3.83 – 3.66 (m, 2H), 3.58 – 3.40 (m, 3H), 3.15 – 3.03 (m, 1H), 2.21 – 2.06 (m, 1H), 1.96 – 1.81 (m, 3H), 1.62 – 1.43 (m, 2H) EXAMPLE 83 (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.4]heptan-5-yl)prop-2-en-1-one Step 1 Tert-butyl (R)-7-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptane-5-carboxylate A mixture of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (197 mg, 0.53 mmol, 1 eq.), tert-butyl (R)-7-amino-5- azaspiro[2.4]heptane-5-carboxylate (250 mg, 1.18 mmol, 2.2 eq.), caesium carbonate (436 mg, 1.34 mmol, 2.5 eq.), palladium diacetate (24 mg, 0.10 mmol, 0.2 eq.) and Xantphos (93 mg, 0.16 mmol, 0.3 eq.) in 1,4-dioxane (4 mL) was submitted to three cycles of vacuum/argon. The mixture was heated at 110 ºC for 1 h under microwave irradiation. Once at room temperature, the mixture was filtered through Celite®, washed with EtOAc and the solvents evaporated under reduced pressure. The resulting crude was purified by flash column chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to get tert-butyl (R)-7-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptane-5-carboxylate (67 mg, 0.12 mmol, 23% yield) as an oil. LCMS 2: RT 2.36 min, m/z 544 [M+H]+, 70%. Step 2 (R)-(4-((5-Azaspiro[2.4]heptan-7-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)methanol Trifluoroacetic acid (0.60 mL, 7.79 mmol, 90 eq.) was added to a solution of tert-butyl (R)- 7-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptane-5-carboxylate (47 mg, 0.03 mmol, 1.0 eq.) in dichloromethane (1.5 mL) and the solution was stirred at r.t. for 4 h. Solvents were evaporated under reduced pressure and the resulting crude 39 mg (purity: 73%) was used in the next synthetic step without further purification. LCMS 2: RT 0.87 min, m/z 344 [M+H]+, 76%. Step 3 (R)-1-(7-((7-(Hydroxymethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one Acrylic acid (8.0 mg, 0.11 mmol, 1.3 eq.) was dissolved in N,N-dimethylformamide (1.5 mL). Diisopropylethylamine (0.06 mL, 0.38 mmol, 4.5 eq.) was added at room temperature followed by T3P® (0.03 mL, 0.09 mmol.1.1 eq.) and the mixture stirred at room temperature for 30 min. This solution was cooled with an ice bath and a mixture of (R)-(4-((5- azaspiro[2.4]heptan-7-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)methanol (39 mg, 0.08 mmol, 73 mass%) and diisopropylethylamine (0.03 mL, 0.09 mmol. 1.1 eq.) in N,N-dimethylformamide (1.5 mL) was dropwise added Once the addition was over, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. Ethyl acetate was added, and the reaction mixture was poured onto water. After phase separation, the organic one was successively washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure and the resulting crude (purity: 73%) was used in the next synthetic step without further purification. LCMS 2: RT 1.23 min, m/z 398 [M+H]+, 73%. Step 4 (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.4]heptan-5-yl)prop-2-en-1-one 7 M ammonia in methanol (1 mL, 7 mmol, 7 mol/L) was added to (S)-1-(7-((7- (hydroxymethyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one (39 mg, 0.07 mmol, 1 eq.) and the solution was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure and the resulting crude was purified using preparative HPLC. Clean fractions were evaporated to afford (R)-1-(7-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one (6 mg, 0.01 mmol, 19% yield) as an off-white solid. LCMS 1: RT 1.18 min, m/z 368 [M+H]+, 100%. 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.11 (s, 1H), 6.90 (s, 1H), 6.56 (ddd, J = 23.2, 16.8, 10.3 Hz, 1H), 6.18 – 6.10 (m, 1H), 5.66 (ddd, J = 12.8, 10.0, 2.4 Hz, 2H), 4.53 (s, 1H), 4.41 (d, J = 5.9 Hz, 1H), 4.04 (dd, J = 10.6, 5.8 Hz, 2H), 3.97 – 3.88 (m, 2H), 3.88 – 3.81 (m, 1H), 3.78 (d, J = 4.7 Hz, 1H), 3.70 (d, J = 12.4 Hz, 1H), 3.57 – 3.45 (m, 2H), 3.22 (s, 2H), 1.84 (dd, J = 30.3, 13.4 Hz, 2H), 1.57 (dd, J = 67.6, 10.2 Hz, 1H), 0.92 – 0.59 (m, 2H). EXAMPLE 84 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate Potassium tert-butoxide (1N in THF) (2.85 mL, 2.85 mmol) was added to a solution of tert- butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (355 mg, 1.77 mmol) in dry THF (3 mL) and the mixture was stirred at 0 ºC for 30 min. A solution of 2-[(4-chloro-5- tetrahydropyran-4-yl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane (500 mg, 1.36 mmol) in dry THF (1.5 mL) was added dropwise and the mixture was stirred at room temperature for 18 h. The solution was partitioned between water and dichloromethane, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. The crude was purified by flash column chromatography, 0-20% heptane/EtOAc to give the title compound (691 mg, 1.28 mmol, 94% yield) as a colourless oil. Step 2 4-(((2R,3R)-2-Methylpyrrolidin-3-yl)oxy)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine Tert-butyl (3R)-3-[5-tetrahydropyran-4-yl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- d]pyrimidin-4-yl]oxypyrrolidine-1-carboxylate (691 mg, 1.28 mmol) was dissolved in TRIFLUOROACETIC ACID (6 mL) and the mixture was stirred at 25 ºC for 2 h. The volatiles were removed under reduced pressure and the residue was dissolved with 7 M ammonia in methanol (6 mL, 42 mmol, 7 mol/L) and the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the resulting crude 1.33 g was used in the next synthetic step without further purification. Step 3 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Diisopropylethylamine (0.93 mL, 5.34 mmol, 5 eq.) and T3P (50% in DMF, 0.77 mL, 1.30 mmol. 1.2 eq.) were added to a solution of acrylic acid (85 mg, 1.19 mmol, 1.1 eq.) in dry DMF (3 mL) under nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. The solution was cooled to 0 ºC and 4-(((2R,3R)-2-methylpyrrolidin-3-yl)oxy)-5- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (412 mg, 1.06 mmol, 1 eq.) in dry DMF (1.5 mL) was added. The mixture was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, 0-20% heptane/EtOAc followed by reverse phase chromatography from 81% [25 mM NH4HCO3] - 19% [ACN:MeOH (1:1)] to 45% [25 mM NH4HCO3] - 55% to give the title compound (73 mg, 0.20 mmol, 19% yield) as a white solid. LCMS 1: RT 2.30 min, m/z 357 [M+H]+, 99%. 1H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 7.06 (s, 1H), 6.81 – 6.53 (m, 1H), 6.46 – 6.18 (m, 1H), 5.95 – 5.61 (m, 2H), 4.81 – 4.51 (m, 1H), 4.12 – 3.97 (m, 2H), 3.93 – 3.64 (m, 2H), 3.64 – 3.50 (m, 2H), 3.25 – 3.09 (m, 1H), 2.59 – 2.41 (m, 1H), 2.42 – 2.19 (m, 1H), 2.04 – 1.91 (m, J = 11.7 Hz, 2H), 1.93 – 1.69 (m, 2H), 1.35 – 1.19 (m, 3H). EXAMPLE 85 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one Step 1 Tert-butyl 4-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[3.1.1]heptane-2-carboxylate Diisopropylethylamine (1.42 mL, 8.15 mmol, 5 eq.) was added to a solution of 4-chloro-5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (600 mg, 1.63 mmol, 1 eq.) and tert-butyl 4-amino-2- azabicyclo[3.1.1]heptane-2-carboxylate hydrochloride (520 mg, 1.96 mmol, 1.2 eq.) in 1- butanol (5 mL) in a pressure vial. The vial was sealed and the reaction stirred at 120 ºC for 72 h. The mixture was cooled to r.t. and concentrated under reduced pressure. The crude was purified by flash chromatography, 0-100% heptane/EtOAc to afford the title compound (574 mg, 1.03 mmol, 63% yield). LCMS 7: RT 1.01 min, m/z 544 [M+H]+, 98%. Step 2 N-(5-(Tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-azabicyclo[3.1.1]heptan-4-amine 4 M HCl in dioxane (4.0 mL, 16.0 mmol, 15 eq.) was added to a solution of tert-butyl 4-((5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[3.1.1]heptane-2-carboxylate (574 mg, 1.05 mmol, 1 eq.) in DCM (2 mL). The solution was stirred at room temperature for 1.5 h. The reaction was filtered and concentrated under reduced pressure. The crude product was taken up in MeOH and passed through a SCX column (Biotage SCX2, 5 g). After rinsing with MeOH (3 CV) the product was eluted with 7 M ammonia in MeOH (4 CV). The organics were concentrated in vacuo to afford N-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- azabicyclo[3.1.1]heptan-4-amine (288 mg, 0.65 mmol, 61% yield). LCMS 7: RT = 0.98 (88%), m/z = 444.5 [M+H]+ Step 3 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one Acryloyl chloride (0.064 mL, 0.79 mmol, 1.2 eq.) was added dropwise to a solution of N-(5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-azabicyclo[3.1.1]heptan-4-amine (288 mg, 0.65 mmol, 1 eq.) and triethylamine (0.27 mL, 1.90 mmol, 2.9 eq.) in DCM (5 mL) at 0 ºC under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 1.5 h. Trifluoroacetic acid (2.0 mL, 26.11 mmol, 40 eq.) was added and the solution stirred for 2.5 h. The volatiles were removed under a stream of nitrogen and the residue was treated with 7 M ammonia in MeOH (5.0 mL, 35.0 mmol, 54 eq.) and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and the crude was purified by preparative HPLC to afford the title compound (57.7 mg, 0.16 mmol, 24% yield) as a solid. LCMS 5: RT = 1.96 (99%), m/z = 368.4 [M+H]+ 1H NMR (400 MHz, CDCl3) δ 10.02 – 9.94 (m, 1H), 8.35 – 8.28 (m, 1H), 6.86 – 6.80 (m, 1H), 6.56 – 6.42 (m, 1H), 6.39 – 6.26 (m, 1H), 5.73 – 5.63 (m, 1H), 5.25 – 5.15 (m, 1H), 5.12 – 5.02 (m, 1H), 5.01 – 4.53 (m, 1H), 4.52 – 4.37 (m, 1H), 4.15 – 4.04 (m, 2H), 3.82 – 3.72 (m, 1H), 3.60 – 3.45 (m, 2H), 2.93 – 2.72 (m, 2H), 2.56 – 2.33 (m, 2H), 2.00 – 1.75 (m, 6H) EXAMPLE 86 and EXAMPLE 87 (R*)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one (S*)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one The title compounds were separated from a racemic mixture of 1-(4-((5-(tetrahydro-2H- pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)prop- 2-en-1-one, prepared as described in Example 85. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Waters X-Bridge 100x19mm, 5 µm, Eluent: MeCN / Water (+0.2% Ammonium Hydroxide), Flux: 20 mL/min. First eluting peak (Example 86): Obtained as a white solid (16 mg). Purity by LCMS 96%. LCMS 5: RT = 1.95 min, m/z = 368 [M+H]+, 96% 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.14 (s, 1H), 6.92 – 6.87 (m, 1H), 6.72 – 6.59 (m, 1H), 6.14 – 6.03 (m, 1H), 5.84 – 5.76 (m, 1H), 5.68 – 5.60 (m, 1H), 4.90 – 4.57 (m, 2H), 4.37 – 4.20 (m, 1H), 3.93 – 3.86 (m, 2H), 3.80 – 3.64 (m, 1H), 3.55 – 3.44 (m, 2H), 3.31 – 3.19 (m, 1H), 2.77 – 2.63 (m, 1H), 2.47 – 2.33 (m, 1H), 2.32 – 2.20 (m, 1H), 2.10 – 1.91 (m, 1H), 1.90 – 1.79 (m, 2H), 1.70 – 1.47 (m, 3H) Second eluting peak (Example 87): Obtained as a white solid (9 mg). Purity by LCMS 100%. LCMS 5: RT = 1.40 min, m/z = 368 [M+H]+, 100% 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.14 (s, 1H), 6.89 (s, 1H), 6.72 – 6.59 (m, 1H), 6.14 – 6.03 (m, 1H), 5.84 – 5.73 (m, 1H), 5.68 – 5.60 (m, 1H), 4.90 – 4.58 (m, 2H), 4.37 – 4.21 (m, 1H), 3.93 – 3.86 (m, 2H), 3.80 – 3.63 (m, 1H), 3.54 – 3.44 (m, 2H), 3.41 – 3.15 (m, 1H), 2.75 – 2.65 (m, 1H), 2.47 – 2.34 (m, 1H), 2.31 – 2.21 (m, 1H), 2.10 – 1.91 (m, 1H), 1.90 – 1.79 (m, 2H), 1.69 – 1.45 (m, 3H). EXAMPLE 88 1-((2S,4R)-2-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2S,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate Tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (328 mg, 1.63 mmol, 2 eq.) was dissolved in 1,4-dioxane (8 mL). Potassium tert-butoxide (91.0 mg, 0.85 mmol, 1 eq.) was added and the solution was stirred at room temperature, under argon atmosphere, for 30 min. 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.81 mmol, 1 eq.) was added and the mixture was stirred at room temperature overnight. The reaction was poured into water, extracted with ethyl acetate (x3), the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude was purified by flash chromatography, 0-100% hexane/EtOAc to give the title compound (164 mg, 0.31 mmol, 38% yield) as a colourless oil. LMCS 2: RT = 2.44 min, m/z = 533 [M+H]+, 95% Step 2 4-(((3R,5S)-5-Methylpyrrolidin-3-yl)oxy)-5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine Tert-butyl (2S,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate (164 mg, 0.31 mmol, 1 eq.) was dissolved in DCM (5 mL) and trifluoroacetic acid (2.10 mL, 27.20 mmol, 90 eq.) was added. The solution was stirred at room temperature for 5 h and concentrated under reduced pressure. 7 M ammonia in MeOH (3 mL, 21.00 mmol, 68 eq.) was added to the residue and the mixture was stirred at room temperature for 4 h. The solvent was concentrated in vacuo to give the title compound as a crude which was used in the next synthetic step without further purification. LMCS 2: RT = 0.86 min, m/z = 303 [M+H]+, 100% Step 3 Tert-butyl (2S,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate Diisopropylethylamine (0.24 mL, 1.38 mmol, 4.5 eq.) and T3P (50% in DMF, 0.20 mL, 0.46 mmol.1.2 eq.) were added to a solution of acrylic acid (85 mg, 1.19 mmol, 1.1 eq.) in dry DMF (1.5 mL) under nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. The solution was cooled to 0 ºC and 4-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)- 5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (93 mg, 0.30 mmol, 1 eq.) and diisopropylethylamine (0.24 mL, 1.38 mmol, 4.5 eq.) in dry DMF (1.5 mL) was added. The mixture was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC-MS (Method P1A) to give the title compound (18 mg, 0.05 mmol, 17% yield) as a white solid. LMCS 1: RT = 1.34 min, m/z = 357 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 6.96 (s, 1H), 6.46 – 6.66 (m, 1H), 6.21 (ddd, J = 20.7, 16.8, 2.0 Hz, 1H), 5.80 – 5.73 (m, 1H), 5.67 (ddd, J = 18.8, 10.4, 2.0 Hz, 1H), 4.35 (dt, J = 13.5, 7.1 Hz, 1H), 4.13 – 4.00 (m, 1H), 3.93 (d, J = 11.9 Hz, 3H), 3.75 (d, J = 14.8 Hz, 1H), 3.50 – 3.36 (m, 2H), 3.10 (t, J = 12.7 Hz, 1H), 2.64 – 2.43 (m, 1H), 2.09 (dd, J = 46.1, 14.4 Hz, 1H), 1.90 (dd, J = 12.9, 8.3 Hz, 2H), 1.75 – 1.61 (m, 2H), 1.40 (dd, J = 9.7, 6.6 Hz, 3H), 1.31 – 1.17 (m, 1H). EXAMPLE 89 1-((3aR,6aS)-3a,6a-difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one Step 1 Tert-butyl (3aR,6aS)- 3a,6a -difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate A solution of tert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (200 mg, 0.54 mmol, 1 eq.), tert-butyl (3aR,6aS)-3a,6a-difluorohexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxylate (161 mg, 0.65 mmol, 1.2 eq.) and diisopropylethylamine (0.47 mL, 2.7 mmol, in 1-butanol (2.5 mL) was heated at 120 °C in a sealed tube for 2 days. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL), the aqueous phase was extracted with EtOAc (2 x 10 mL), the combined organic layers were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The crude was purified by flash chromatography, 0-100%, heptane/EtOAc to afford the title compound (294 mg, 0.42 mmol, 77.42% yield) as a yellow oil. LCMS 7: R.T = 1.13, m/z = 580 [M+H]+, 83% Step 2 4-((3aR,6aS)-3a,6a-difluorohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(tetrahydro- 2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4 M hydrochloric acid in 1,4-dioxane (5 mL, 20 mmol, 47 eq.) was added to a solution of tert-butyl (3aR,6aS)- 3a,6a -difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (294 mg, 0.42 mmol, 1 eq.) in dichloromethane (3 mL) and the solution was stirred at room temperature for 2 h. The reaction was concentrated under vacuum to afford 2-[[4-[(3aS,6aR)-3a,6a-difluoro-2,3,4,6-tetrahydro-1H-pyrrolo[3,4- c]pyrrol-5-yl]-5-tetrahydropyran-4-yl-pyrrolo[2,3-d]pyrimidin-7-yl]methoxy]ethyl- trimethyl-silane (194 mg, 0.35 mmol, 84% yield) as an orange solid. LCMS 7: R.T = 0.66, m/z = 480 [M+H]+, 88% Step 3 1-((3aR,6aS)-3a,6a-difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one Acryloyl chloride (39 μL, 0.48 mmol, 1.2 eq.) was added to a solution of 4-((3aR,6aS)-3a,6a- difluorohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (194 mg, 0.40 mmol, 1 eq.) and triethylamine (169 mg, 1.67 mmol, 3 eq.) in dichloromethane (2 mL) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 1 h. Trifluoroacetic acid (0.62 mL, 8.08 mmol, 20 eq.) was added and the reaction mixture was stirred at room temperature for 18 h. 7 M ammonia in MeOH (10 mL, 70 mmol, 173 eq.) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under nitrogen and the crude was purified by reverse-phase HPLC. The fractions which contained the product were combined and concentrated under vacuum, to give the title compound (9.2 mg, 0.02 mmol, 5.2% yield) as a beige powder. LCMS 5: R.T = 2.09, m/z = 404 [M+H]+, 91% 1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 7.04 (m, 1H), 6.63 – 6.50 (m, 1H), 6.37 – 6.27 (m, 1H), 5.85 – 5.71 (m, 1H), 4.37 – 4.23 (m, 2H), 4.21 – 4.05 (m, 4H), 4.05 – 3.98 (m, 2H), 3.98 – 3.92 (m, 2H), 3.67 – 3.50 (m, 2H), 3.26 – 3.09 (m, 1H), 2.16 – 2.01 (m, 2H), 1.74 – 1.57 (m, 2H) EXAMPLE 90 1-((3aR,6aS)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one Step 1 Tert-butyl (3aR,6aS)-5-(5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate To a solution of 4-chloro-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 2.57 mmol, 1 eq.) and tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (655 mg, 3.09 mmol, 1.2 eq.) in dry tetrahydrofuran (25 mL) in a sealed tube, Pd2(dba)3 (3.30 mg, 3.60 μmol, 0.015 eq.) and dppf (242 mg, 2.85 mmol, 0.92 eq.) and sodium tert-butoxide (865 mg, 9.00 mmol, 3.5 eq.) were added. The resulting mixture was stirred at 70 °C for 16 h. The mixture was filtered over a pad of Celite and rinsed with EtOAc and the filtrate was concentrated under reduced pressure. The resulting crude was purified by flash column chromatography on silica gel eluting with a gradient of heptane/EtOAc (0 to 50%). The product fractions were combined and concentrated to yield the title compound (900 mg, 1.59 mmol, 62% yield) as a yellow oil. Step 2 5-Fluoro-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine A mixture of tert-butyl (3aR,6aS)-5-(5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate (880 mg, 1.55 mmol, 1 eq.) and TRIFLUOROACETIC ACID (8 mL) was stirred at room temperature for 3 h. TRIFLUOROACETIC ACID was removed under vacuum and 7 ammonia in MeOH (15 mL) was added. The mixture was stirred at room temperature for 72 h, the solvent was removed under reduced pressure and the crude (1 g) was used in the next synthetic step without further purification Step 3 1-((3aR,6aS)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one Acrylic acid (0.20 mL, 2.91 mmol) was dissolved in dry DMF (5 mL) under nitrogen atmosphere. Diisopropylethylamine (2.1 mL, 13.30 mmol, 4.5 eq.) and T3P 50 % in DMF (1.85 g, 2.91 mmol, 1.1 eq.) were added and the resulting mixture was stirred at room temperature for 30 min. The reaction was cooled to 0 ºC and a solution of 5-fluoro-4- ((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine (970 mg, 2.64 mmol), diisopropylethylamine (2.1 mL, 13.30 mmol, 4.5 eq.) in dry DMF (5 mL) was added dropwise. The mixture was stirred at room temperature, under nitrogen atmosphere, for 16 h. Saturated aqueous solution of sodium bicarbonate and DCM/MeOH 90:10 was added, the organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (heptane/EtOAc/DCM/DCM:MeOH 9:1100:0:0:0 to 0:0:76:24) to give the title compound (150 mg, 0.38 mmol, 15% yield) as a white solid. LCMS 1: R.T = 2.10 min, m/z = 385 [M+H]+, 97% 1H NMR (400 MHz, MeOD) δ 8.00 (d, J = 5.5 Hz, 1H), 7.21 (s, 1H), 6.69 (dd, J = 16.8, 10.4 Hz, 1H), 6.32 (dd, J = 16.8, 2.0 Hz, 1H), 5.78 (dd, J = 10.5, 2.0 Hz, 1H), 4.00 (dt, J = 10.5, 4.0 Hz, 3H), 3.93 (dd, J = 13.0, 8.5 Hz, 1H), 3.65 (dddd, J = 23.6, 18.0, 12.2, 4.6 Hz, 4H), 3.56 – 3.43 (m, 2H), 3.29 – 3.23 (m, 3H), 3.19 – 3.10 (m, 2H), 1.96 (dd, J = 13.0, 1.7 Hz, 2H), 1.77 – 1.64 (m, 2H) EXAMPLE 91 1-((3R,4S)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3R,4S)-4-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1- carboxylate Cesium carbonate (1.10 g, 3.40 mmol, 2.5 eq.) was added to a solution of 4-chloro-5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (500 mg, 1.36 mmol, 1 eq.) and tert-butyl (3R,4S)-3-amino-4- methylpiperidine-1-carboxylate (350 mg, 1.63 mmol, 1.2 eq.) in 1,4-dioxane (10 mL) in a pressure vial. The reaction was degassed with nitrogen for 5 mins and BrettPhos-Pd-G3 (125 mg, 0.13 mmol, 0.1 eq.) was added. The vial was sealed and the reaction stirred at 60 °C overnight. The reaction was cooled to RT and filtered. The filtrate was taken up in EtOAc (20 mL) and washed with water (2 x 10 ml) and brine (5 ml) then concentrated under reduced pressure. The crude product was purified by column chromatography (Biotage Sfär Duo 10g, 40 ml/min) eluting with 0-100% heptane/EtOAc. The relevant fractions were combined and concentrated in vacuo to afford the desired product (209 mg, 0.31 mmol, 22% yield) LCMS 7: RT = 1.08 min, m/z = 546.4 [M+H]+ (ESI+), 78% Step 2 N-((3R,4S)-4-Methylpiperidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 4 M HCl in dioxane (3 mL) was added to a solution of tert-butyl (3R,4S)-4-methyl-3-((5- (tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (200 mg, 0.36 mmol, 1 eq.) in dichloromethane (2 mL) and the reaction was stirred at room temperature for 2.5 h. The reaction was concentrated in vacuo to afford the desired product (235 mg, 0.38 mmol, 78 mass%) as a crude which was taken through to the next step without further purification. LCMS 7: RT = 0.98 min, m/z = 446 [M+H]+ (ESI+), 78% Step 3 1-((3R,4S)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Acryloyl chloride (35 μL, 0.43 mmol, 1.2 eq.) was added dropwise to a solution of N- ((3R,4S)-4-Methylpiperidin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (235 mg, 0.35 mmol, 1 eq.) and triethylamine (147 μL, 1.05 mmol, 3 eq.) in dichloromethane (3 mL) at 0 °C under nitrogen atmosphere. The reaction was allowed to warm to r.t. and stirred for 2 h. Trifluoroacetic acid (1 mL, 13.06 mmol, 20 eq.) was added and the reaction was stirred at r.t. for 2 h. The volatiles were removed under a stream of nitrogen, the residue treated with 7 M ammonia in methanol (3 mL, 100 mass%) and the mixture was stirred at r.t. overnight. The reaction was concentrated under reduced pressure and the crude was purified by preparative HPLC to give the title compound (34.4 mg, 0.09 mmol, 26% yield). LCMS 5: R.T = 2.13 min, m/z = 370 [M+H]+, 97% 1H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 8.13 – 8.04 (m, 1H), 6.95 – 6.71 (m, 2H), 6.16 – 5.74 (m, 2H), 5.73 – 5.67 (m, 1H), 4.58 – 3.77 (m, 5H), 3.61 – 3.51 (m, 2H), 3.31 – 3.23 (m, 1H), 3.14 – 2.95 (m, 1H), 2.80 – 2.69 (m, 1H), 2.02 – 1.69 (m, 5H), 1.53 – 1.14 (m, 2H), 0.99 – 0.90 (m, 3H). EXAMPLE 92 1-((3S,5R)-3-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3S,5R)-3-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate In a sealed tube, a mixture of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 2.70 mmol, 1 eq.), tert-butyl (3R,5S)-3-amino-5-methylpiperidine-1-carboxylate (578 mg, 2.70 mmol, 1 eq.) and cesium carbonate (1.11 g, 3.40 mmol, 1.2 eq.) in dry 1,4-dioxane (11 mL) was submitted to three cycles of vacuum/nitrogen. Pd2(dba)3 (148 mg, 0.16 mmol, 0.06 eq.) and XantPhos® (109.27 mg, 0.19 mmol, 0.07 eq.) were added and the mixture was submitted to three additional cycles of vacuum/nitrogen. The tube was sealed and the reaction mixture was stirred at 95 °C for 16 h. The mixture was filtered over a pad of Celite®, rinsed with EtOAc and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel eluting with a gradient of heptane/EtOAc (0 to 20%). to yield the title compound (1.10 g, 1.88 mmol, 70% yield) as a pale yellow solid. Step 2 N-((3R,5S)-5-Methylpiperidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine Tert-butyl (3S,5R)-3-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (1.10 g, 1.88 mmol, 1 eq.) was dissolved in TRIFLUOROACETIC ACID (5 mL) and the solution was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure, 7 M ammonia in MeOH (5 mL) was added and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the crude was purified by flash chromatography DCM/DCM:MeOH (9:1) 0 to 100% to afford the title compound (1.00 g, 1.78 mmol, 95% yield). Step 3 1-((3S,5R)-3-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one Acrylic acid (61 μL, 0.89 mmol, 1 eq.) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. T3P 50% in DMF (0.58 mL, 0.98 mmol, 1.1 eq.) and DIPEA (0.69 mL, 4.01 mmol, 4 eq.) were added to the solution and the mixture was stirred at r.t. for 30 min. The reaction mixture was cooled to 0 ºC and a solution of N-((3R,5S)-5-methylpiperidin-3-yl)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (500 mg, 0.89 mmol, 1 eq.) and diisopropylethylamine (0.70 mL, 4.01 mmol, 4 eq.) in dry DMF (2 mL) was added. The solution was stirred at room temperature for 16 h under nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by reverse phase from 72% [25mM NH4HCO3] - 28% [ACN:MeOH (1:1)] to 36% [25mM NH4HCO3] - 64% [ACN:MeOH (1:1)]) to obtain the title compound (30 mg, 0.08 mmol, 9% yield) as a white solid. LCMS 1: R.T = 1.90 min, m/z = 369 [M+H]+, 91% 1H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 6.86 (s, 1H), 6.76 (dd, J = 16.8, 10.7 Hz, 1H), 6.28 (d, J = 5.5 Hz, 1H), 6.10 (dd, J = 16.8, 2.1 Hz, 1H), 5.67 (dd, J = 10.7, 2.1 Hz, 1H), 4.86 – 4.10 (m, 2H), 4.00 – 3.87 (m, 2H), 3.63 – 3.41 (m, 3H), 3.27 – 3.10 (m, 1H), 2.22 – 2.12 (m, 1H), 2.08 – 1.86 (m, 3H), 1.80 – 1.47 (m, 4H), 1.37 – 1.24 (m, 3H), 0.97 (d, J = 6.5 Hz, 3H). Example 93 4-(((2R,3R)-1-Acryloyl-2-methylpyrrolidin-3-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Step 1 Tert-butyl (2R,3R)-3-((5-cyano-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2- methylpyrrolidine-1-carboxylate Potassium tert-butoxide (74 mg, 0.66 mmol, 1 eq.) was added to a solution of tert-butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (160 mg, 0.79 mmol, 1 eq.) in 1,4- dioxane (2 mL) . The reaction mixture was stirred at r.t. for 30 min and 4-chloro-3- (tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridine-5-carbonitrile (265 mg, 0.66 mmol, 1 eq.) was added. The reaction mixture was stirred at r.t. for 8 h. Additional potassium tert-butoxide (74 mg, 0.66 mmol, 1 eq.) was added and the reaction mixture was stirred at 60 ºC for 18 h. The solvent was concentrated in vacuo to afford a yellow oil. The oil was partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL). The combined organics were washed with brine (2 x 20 mL) and were concentrated in vacuo to afford the title compound (521 mg, 0.62 mmol, 93% yield). LCMS 7: R.T = 1.21 min, m/z = 557 [M+H]+, 91% Step 2 4-(((2R,3R)-2-Methylpyrrolidin-3-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 4 M HCl in dioxane (2 mL, 8 mmol, 13 eq.) was added to a solution of tert-butyl (2R,3R)-3- ((5-cyano-3-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate (521 mg, 0.62 mmol, 1 eq.) in dichloromethane (3 mL) and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was dissolved in MeOH and passed through a 5 g SCX cartridge, washed with MeOH (3 x10 mL) and 7 M ammonia in MeOH (3 x 10 mL). The basic fractions were combined and concentrated under vacuum to afford the title compound (252 mg, 0.42 mmol, 69% yield) as a yellow oil. LCMS 7: R.T = 0.70 min, m/z = 457 [M+H]+, 77% Step 3 4-(((2R,3R)-1-Acryloyl-2-methylpyrrolidin-3-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Acryloyl chloride (50 μL, 0.61 mmol, 1.2 eq.) was added to a solution of 4-[(2R,3R)-2- methylpyrrolidin-3-yl]oxy-3-tetrahydropyran-4-yl-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carbonitrile (252 mg, 0.51 mmol, 1 eq.) and triethylamine (0.29 mL, 2.12 mmol, 4 eq.) in dichloromethane (2 mL) under nitrogen atmosphere and at 0 °C. The reaction was warmed to r.t. and stirred for 1 h. Trifluoroacetic acid (786 μL, 10.26 mmol, 20 eq.) was added and the solution was stirred at r.t. for 3 h. Additional trifluoroacetic acid (786 μL, 10.26 mmol, 20 eq.) was added and the reaction mixture was stirred at r.t. for 3 h. The solvent was removed under vacuum, 7 M ammonia in methanol (3.67 mL, 25.7 mmol, 50 eq.) was added and the solution was stirred at room temperature overnight. The solvent was removed under vacuum and the crude was purified by reverse-phase HPLC. Product fractions were combined and concentrated under vacuum, the residue was dissolved in acetonitrile:water (1:1) and lyophilized to give the title compound (76 mg, 0.20 mmol, 39% yield) as an off-white powder. LCMS 5: R.T = 2.13, m/z = 381 [M+H]+, 97% 1H NMR (500 MHz, DMSO) δ 12.19 – 12.00 (m, 1H), 8.42 – 8.38 (m, 1H), 7.34 – 7.29 (m, 1H), 6.70 – 6.54 (m, 1H), 6.24 – 6.13 (m, 1H), 5.77 – 5.59 (m, 2H), 4.71 – 4.45 (m, 1H), 3.97 – 3.91 (m, 2H), 3.75 – 3.62 (m, 2H), 3.57 – 3.35 (m, 2H), 3.21 – 3.10 (m, 1H), 2.34 – 2.18 (m, 2H), 1.91 – 1.83 (m, 2H), 1.70 – 1.54 (m, 2H), 1.40 – 1.24 (m, 3H). EXAMPLE 94 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-2-methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate Potassium tert-butoxide (147 mg, 1.31 mmol, 1 eq.) was added to a solution of tert-butyl (2R,3R)-3-hydroxy-2-methyl-pyrrolidine-1-carboxylate (316 mg, 1.57 mmol, 1.2 eq.) in 1,4- dioxane (10 mL) and the reaction mixture was stirred at r.t. for 30 min. 4-chloro-5-(2- methyltetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (500 mg, 1.31 mmol, 1 eq.) was added and the mixture was stirred at 60 ºC for 8 h. The solvent was concentrated in vacuo to afford a yellow oil, which was partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL). The combined organics were washed with brine (2 x 20 mL) and concentrated in vacuo. The crude was purified via flash chromatography (gradient 0-100% EtOAc in heptane) to give the title compound (380 mg, 0.69 mmol, 53% yield). LCMS 7: R.T = 1.29 min, m/z = 547 [M+H]+, 92% Step 2 4-(((2R,3R)-2-Methylpyrrolidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4 M HCl in dioxane (5 mL, 20.00 mmol, 29 eq.) was added to a solution of 4-(((2R,3R)-2- methylpyrrolidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (380 mg, 0.69 mmol, 1 eq.) in dichloromethane (3 mL) and the solution was stirred at r.t. for 1 h. The reaction was concentrated under vacuum and filtered through 5 g SCX eluting with MeOH (2 x 5 mL), and 7 M ammonia in MeOH (3 x 5 mL). The basic fractions were concentrated under vacuum to afford the title compound (200 mg, 0.31 mmol, 45% Yield) as an orange oil. LCMS 7: R.T = 0.73 min, m/z = 477 [M+H]+, 70% Step 3 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Acryloyl chloride (44 μL, 0.54 mmol, 1.2 eq.) was added to a solution of trimethyl-[2-[[4- [(2R,3R)-2-methylpyrrolidin-3-yl]oxy-5-(2-methyltetrahydropyran-4-yl)pyrrolo[2,3- d]pyrimidin-7-yl]methoxy]ethyl]silane (200 mg, 0.45 mmol, 1 eq.) and triethylamine (187 μL, 1.34 mmol, 3 eq.) in dichloromethane (2 mL) at 0 °C under nitrogen. The solution was warmed to r.t. and stirred for 1 h . Trifluoroacetic acid (0.68 mL, 8.95 mmol, 20 eq.) and stirred for 7 h. Additional trifluoroacetic acid (0.68 mL, 8.95 mmol, 20 eq.) was added and the solution was stirred at r.t. for 24 h. The reaction mixture was concentrated under vacuum, 7 M ammonia in methanol (3.20 mL, 22.5 mmol, 50 eq.) was added and the mixture was stirred at room temperature for 24 h (IPC6). The reaction was concentrated under vacuum and the crude was purified by reverse-phase HPLC. Product fractions were combined and concentrated under vacuum, the residue was dissolved in acetonitrile:water (1:1) and lyophilized to the title compound (35 mg, 0.09 mmol, 21% yield) as a white powder. LCMS 5: R.T = 2.25, m/z = 371 [M+H]+, 96% 1H NMR (500 MHz, MeOD) δ 8.35 – 8.31 (m, 1H), 7.06 – 7.03 (m, 1H), 6.79 – 6.57 (m, 1H), 6.40 – 6.26 (m, 1H), 5.87 – 5.80 (m, 1H), 5.80 – 5.73 (m, 1H), 4.80 – 4.58 (m, 1H), 4.12 – 4.02 (m, 1H), 3.91 – 3.82 (m, 1H), 3.83 – 3.75 (m, 1H), 3.75 – 3.66 (m, 1H), 3.66 – 3.56 (m, 2H), 3.24 – 3.14 (m, 1H), 2.59 – 2.41 (m, 1H), 2.41 – 2.23 (m, 1H), 2.11 – 2.02 (m, 1H), 1.99 – 1.87 (m, 1H), 1.86 – 1.68 (m, 1H), 1.54 – 1.36 (m, 1H), 1.29 (d, 1H), 1.25 – 1.18 (m, 4H). EXAMPLE 95 and EXAMPLE 96 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one The title compounds were separated from the isomeric mixture of 1-((2R,3R)-2-methyl-3- ((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin- 1-yl)prop-2-en-1-one, prepared as described in Example 94. Chiral separation of the two isomers was done by preparative HPLC. Column: Chiralpak AD-H (10 x 250mm, 5 µm, Eluent A: CO2, Eluent B: EtOH, Flux: 15 mL/min. First eluting peak (Example 95): Obtained as a solid (12 mg). Purity by LCMS 97%. LCMS 5: RT = 2.27 min, m/z = 371 [M+H]+, 97% 1H NMR (400 MHz, MeOD) δ 8.34 – 8.29 (m, 1H), 7.08 – 7.02 (m, 1H), 6.74 – 6.59 (m, 1H), 6.38 – 6.25 (m, 1H), 5.88 – 5.72 (m, 2H), 4.79 – 4.53 (m, 1H), 4.11 – 4.03 (m, 1H), 3.97 – 3.52 (m, 4H), 3.24 – 3.13 (m, 1H), 2.58 – 2.41 (m, 1H), 2.40 – 2.21 (m, 1H), 2.04 (m, 1H), 1.97 – 1.87 (m, 1H), 1.87 – 1.67 (m, 1H), 1.52 – 1.37 (m, 1H), 1.33 – 1.11 (m, 6H). Second eluting peak (Example 96): Obtained as a solid (11 mg). Purity by LCMS 97%. LCMS 5: RT = 2.27 min, m/z = 371 [M+H]+, 97% 1H NMR (400 MHz, MeOD) δ 8.36 – 8.31 (m, 1H), 7.09 – 7.04 (m, 1H), 6.76 – 6.61 (m, 1H), 6.40 – 6.27 (m, 1H), 5.92 – 5.75 (m, 2H), 4.84 – 4.59 (m, 1H), 4.12 – 4.04 (m, 1H), 3.93 – 3.74 (m, 1H), 3.74 – 3.58 (m, 3H), 3.29 – 3.13 (m, 1H), 2.59 – 2.43 (m, 1H), 2.43 – 2.25 (m, 1H), 2.12 – 2.02 (m, 1H), 2.02 – 1.91 (m, 1H), 1.82 – 1.63 (m, 1H), 1.54 – 1.45 (m, 1H), 1.35 – 1.27 (m, 2H), 1.27 – 1.20 (m, 5H). EXAMPLE 97 (R)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (R)-3,3-dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1- carboxylate In a sealed tube, a mixture of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (225 mg, 0.60 mmol, 1 eq.), tert- butyl (R)-4-amino-3,3-dimethylpyrrolidine-1-carboxylate (193 mg, 0.90 mmol, 1.5 eq.) was dissolved in dry THF (3 mL) and submitted to three cycles of vacuum/nitrogen. RuPhosPdG3 (50 mg, 0.06 mmol) and cesium carbonate (489 mg, 1.50 mmol, 2.5 eq.) were added and the mixture was submitted to three additional cycles of vacuum/nitrogen. The tube was sealed and the reaction was stirred at 90 ºC for 16 h. The mixture was filtered over a pad of Celite®, rinsed with EtOAc and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography with 0-40% heptane/EtOAc, 0-40% to give the title compound (0.29 g, 0.52 mmol, 88%) as a gum. Step 2 (R)-N-(4,4-Dimethylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 4 M hydrochloric acid in 1,4-dioxane (0.24 mL, 0.94 mmol, 25 eq.) was added to a solution of tert-butyl (R)-3,3-dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1- carboxylate (20.0 mg, 36.34 μmol, 1 eq.) in DCM (0.5 mL) and the mixture was stirred at r.t. for 1 h. The reaction was concentrated under vacuum and the crude was used in the next step without further purification. Step 3 (R)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1- yl)prop-2-en-1-one A solution of (R)-N-(4,4-dimethylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (32 mg, 0.07 mmol, 1 eq.) and triethylamine (15 µL, 0.10 mmol, 1.4eq.) in dry DCM (0.8 mL) was bubbled with nitrogen for 5 min. The solution was cooled to 0 ºC, acryloyl chloride (5.60 µL, 0.07 mmol, 1eq.) in dry DCM (0.2 mL) was added at 0 ºC under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1h. The volatiles were concentrated under reduced pressure to give the crude title compound which was used without further purification. Step 4 (R)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one A mixture of trifluoroacetic acid (1.0 mL) and (R)-1-(3,3-dimethyl-4-((3-(tetrahydro-2H- pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (245 mg, 0.49 mmol, 1 eq.) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, 7 M ammonia in MeOH (3 mL) was added and the mixture was stirred at room temperature for 5 h. The solvent was removed under vacuum and the crude was purified by flash column chromatography, 0-100% heptane/EtOAc followed by purification by reverse phase chromatography (Phenomenex Gemini C1830x100mm 5μm Column; from 72% [25mM NH4HCO3] - 28% [ACN:MeOH (1:1)] to 36% [25mM NH4HCO3] - 64% [ACN:MeOH (1:1)], 230 nm) to yield the title compound (15 mg, 39.76 μmol, 8% yield) as a white solid. LCMS 1: RT = 1.85 min, m/z = 369 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 7.85 (dd, J = 5.7, 1.0 Hz, 1H), 6.93 (s, 1H), 6.60 (ddd, J = 19.3, 16.8, 10.5 Hz, 1H), 6.43 (dd, J = 8.3, 5.8 Hz, 1H), 6.29 (ddd, J =16.8, 4.4, 2.0 Hz, 1H), 5.76 (ddd, J = 13.5, 10.5, 2.0 Hz, 1H), 4.27 – 4.17 (m, 1H), 4.15 – 4.09 (m, 1H), 4.09 – 4.02 (m, 2H), 3.68 – 3.53 (m, 4H), 3.44 – 3.36 (m, 1H), 3.17 – 3.09 (m, 1H), 2.09 (d, J = 13.7 Hz, 1H), 1.98 (d, J = 13.4 Hz, 1H), 1.87 – 1.67 (m, 2H), 1.25 (s, 3H), 1.20 (d, J = 2.7 Hz, 3H) EXAMPLE 98 1-((2R,3R)-2-Methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-2-methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1- carboxylate In a sealed tube, a mixture of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (389 mg, 0.98 mmol, 1 eq.), tert- butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (237 mg, 1.20 mmol, 1.2 eq.) and cesium carbonate (405 mg, 1.20 mmol, 1.2 eq.) was dissolved in dry 1,4-dioxane (4 mL) previously purged with nitrogen for 10 min. Pd2(dba)3 (63 mg, 69.01 μmol, 0.14 eq.) and XantPhos® (68.45 mg, 118.30 μmol, 0.24 eq.) were added and the mixture was further bubbled with nitrogen for 5 min, the tube was sealed and the reaction mixture was stirred at 95 °C for 16 h. The crude was filtered over a pad of Celite® and rinsed with EtOAc. The reaction mixture was partitioned between EtOAc and water, the organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. The crude was purified by flash column chromatography 0-40% heptane/ EtOAc to yield the title compound (372 mg, 0.69 mmol, 70% yield) as a yellow gum. Step 2 N-((2R,3R)-2-Methylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 4 M hydrogen chloride in dioxane (3.90 mL, 15.60 mmol) was added to a solution of tert- butyl (2R,3R)-2-methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1- carboxylate (330 mg, 0.61 mmol) in DCM (13 mL) and the solution was stirred at room temperature for 1 h. The volatiles were concentrated under reduced pressure to give the title compound as a crude which was used in the next step without further purification. Step 3 1-((2R,3R)-2-Methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one A solution of N-((2R,3R)-2-methylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (328 mg, 0.70 mmol, 1 eq.) and triethylamine (0.29 mL, 2.11 mmol, 3 eq.) in DCM (10 mL) was bubbled with nitrogen for 5 min. The solution was cooled to 0 ºC and acryloyl chloride (68 μL, 0.84 mmol, 1.2 eq.) in DCM (6 mL) was added. The reaction mixture was stirred at room temperature for 1 h, TRIFLUOROACETIC ACID (5.30 mL, 69.95 mmol, 100 eq.) was added and the mixture was stirred at room temperature for an additional hour. The volatiles were removed under reduced pressure, 7 M ammonia in MeOH (19 mL, 133.00 mmol, 190 eq.) was added and the reaction mixture was stirred at room temperature for 0.5 h. The volatiles were concentrated in vacuo and the crude was purified by reverse phase (Phenomenex Gemini C1830x100mm 5μm Column; from 81% [25mM NH4HCO3] - 19% [ACN:MeOH (1:1)] to 45% [25mM NH4HCO3] - 55% [ACN:MeOH (1:1)]) to give the title compound (18 mg, 0.05 mmol, 7% yield) as a white solid. LCMS 1: RT = 1.50 min, m/z = 355 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 9.05 (s, 1H), 7.93 (d, J = 5.5 Hz, 1H), 6.91 (s, 1H), 6.65 – 6.54 (m, 1H), 6.34 (d, J = 5.2 Hz, 1H), 6.28 – 6.20 (m, 1H), 5.65 (dd, J = 10.3, 2.3 Hz, 1H), 4.83 – 4.76 (m, 1H), 4.57 (br b, 1H), 4.25 (br b, 1H), 4.05 – 3.98 (m, 2H), 3.58 (t, J = 11.7 Hz, 4H), 3.16 – 3.05 (m, 1H), 2.52 – 2.37 (m, 1H), 2.12 – 2.04 (m, 3H), 1.81 – 1.68 (m, 3H), 1.12 (d, J = 6.6 Hz, 3H) EXAMPLE 99 (R)-4-((1-Acryloyl-4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Step 1 Tert-butyl (R)-4-((5-cyano-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-3,3- dimethylpyrrolidine-1-carboxylate In a sealed tube, a mixture of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (342 mg, 0.83 mmol, 1 eq), tert-butyl (4R)-4-amino-3,3-dimethyl-pyrrolidine-1-carboxylate (355.27 mg, 1.66 mmol, 2 eq) and cesium carbonate (945.25 mg, 2.90 mmol, 3.4 eq.) was dissolved in dry toluene (3 mL) .The reaction mixture was bubbled with nitrogen for 5 min, and Pd(OAc)2 (15.25 mg, 0.067 mmol, 0.08 eq) and rac-BINAP (77.42 mg, 0.12 mmol, 0.14 eq.) were added. The mixture was further bubbled with nitrogen for 5 min. The reactor was sealed, and the reaction mixture was stirred at 120 °C for 18 h. The crude was filtered over a pad of Celite® and rinsing with EtOAc. The filtrate was concentrated, and the crude was purified by flash chromatography with heptane/EtOAc, 0-20%. The fractions were combined and concentrated to obtain tert-butyl (R)-4-((5-cyano-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-3,3- dimethylpyrrolidine-1-carboxylate (83 mg, 0.12 mmol, 14% yield) as a brown gum. Step 2 (R)-4-((4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile Tert-butyl (R)-4-((5-cyano-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-3,3- dimethylpyrrolidine-1-carboxylate (131 mg, 0.17 mmol, 1 eq.) was dissolved in trifluoroacetic acid (2.72 mL, 35.35 mmol, 200 eq.) and the mixture was stirred at 25 ºC for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved with 7N ammonia in MeOH (2.71 mL, 18.97 mmol, 110 eq.) and stirred at 25 ºC for 2 h. The solvent was removed under reduced pressure to obtain the title compound (196 mg, crude) as a white solid. This crude was used as such without purification in the next synthetic step. Step 3 (R)-4-((1-acryloyl-4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile Acrylic acid (17.82 μL, 0.260 μmol, 1.5 eq) was dissolved in dry DMF (1.43 mL) under nitrogen atmosphere. Diisopropylethylamine (137.44 μL, 0.79 mmol, 4.6 eq) and 50% T3P in DMF (154.68 μL, 0.260 mmol, 50 %, 1.5 eq) were added to the solution and was stirred at 25 ºC for 30 min. The solution was cooled to 0 ºC and (R)-4-((4,4-dimethylpyrrolidin-3- yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (196 mg, 0.17 mmol, 1eq ) in dry DMF (4.29 mL) and DIPEA (137.44 μL, 0.790 mmol, 4.6 eq) were added. The reaction mixture was stirred at 25 ºC for 18 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography with heptane/EtOAc, 0-100% and repurified by reverse phase obtain (R)-4-((1-acryloyl-4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile (17 mg, 42.69 μmol, 25% yield) as a white solid. LCMS 1: RT = 2.40 min, m/z = 394 [M+H]+, 97% 1H NMR (400 MHz, MeOD) δ 8.12 (s, 1H), 7.08 (s, 1H), 6.67 – 6.52 (m, 1H), 6.30 (dd, J = 16.9, 3.0 Hz, 1H), 5.81 – 5.72 (m, 1H), 4.92 (dt, J = 16.0, 5.5 Hz, 1H), 4.29 – 4.07 (m, 1H), 4.09 – 3.97 (m, 2H), 3.77 – 3.41 (m, 5H), 3.03 (t, J = 11.6 Hz, 1H), 2.03 – 1.90 (m, 2H), 1.85 – 1.71 (m, 2H), 1.27 (s, 6H). EXAMPLE 100 1-((2R,3R)-3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2- methylpyrrolidine-1-carboxylate A mixture of 4-chloro-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (525 mg, 136 mmol, 1 eq.), tert- butyl (2R,3R)-3-amino-2-methylpyrrolidine-1-carboxylate (600 mg, 2.9 mmol, 2.2 eq.), caesium carbonate (1.1 g, 1.34 mmol, 2.7 eq.), palladium diacetate (61 mg, 0.27 mmol, 0.2 eq.) and Xantphos® (237 mg, 0.41 mmol, 0.3 eq) in 1,4-dioxane (7.5 mL). The mixture was heated at 80 ºC for 16 h. Once at room temperature, the mixture was filtered through Celite®, washed with EtOAc and the solvents evaporated under reduced pressure. The resulting crude was purified by normal-phase chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to obtain the desired compound (756 mg, 1.32 mmol, 96% yield) as a yellow solid. LCMS 2: RT = 2.49 min, m/z = 549 [M+H]+, 97% Step 2 5-Fluoro-N-((2R,3R)-2-methylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine Tert-butyl (2R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpyrrolidine- 1-carboxylate (756 mg, 1.37 mmol, 1 eq.) was dissolved in DCM (2mL) and trifluoroacetic acid (6 mL, 77.8 mmol, 56 eq.) was added. The solution was stirred at room temperature for 2 h and concentrated under reduced pressure. 7M ammonia in MeOH (16 mL) was added and the mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo to give a crude which was used in the next synthetic step without further purification. LCMS 2: RT = 0.61 min, m/z = 319 [M+H]+, 96% Step 3 1-((2R,3R)-3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one Acryloyl chloride (69 μL, 0.849 mmol, 1.3 eq) was dropwise added to a solution of 5-fluoro- N-((2R,3R)-2-methylpyrrolidin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine (208 mg, 0.653 mmol, 1 eq) and N-ethyl-N-isopropylpropan-2-amine (342 μL, 1.96 mmol, 3 eq) in tetrahydrofuran (2.2 mL) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the crude was purified by preparative HPLC to give the title compound (57.5 mg, 0.154 mmol, 24% yield) as a beige powder. LCMS 1: RT = 1.90 min, m/z = 373 [M+H]+, 98% 1H NMR (400 MHz, MeOD) δ 7.88 (dd, J = 6.3, 3.4 Hz, 1H), 7.04 (s, 1H), 6.63 (ddd, J = 22.5, 16.7, 10.4 Hz, 1H), 6.41 – 6.20 (m, 1H), 5.76 (ddd, J = 10.4, 3.7, 2.0 Hz, 1H), 4.67 – 4.32 (m, 3H), 4.07 (d, J = 11.2 Hz, 2H), 3.82 (t, J = 9.3 Hz, 1H), 3.73 – 3.40 (m, 4H), 3.24 – 3.04 (m, 1H), 2.45 (dd, J = 11.4, 6.6 Hz, 1H), 2.20 – 1.94 (m, 3H), 1.91 – 1.65 (m, 2H), 1.22 (dd, J = 6.3, 4.6 Hz, 3H). EXAMPLE 101 1-((3S,5R)-3-Methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3R,5S)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)-5-methylpiperidine-1-carboxylate Sodium hydride (199 mg, 4.97 mmol, 60 mass%) was added to a solution of tert-butyl (3R,5S)-3-hydroxy-5-methylpiperidine-1-carboxylate (988 mg, 4.59 mmol, 1.2 eq.) in dimethyl sulfoxide (7.5 mL) at room temperature. The reaction was stirred for 30 minutes then 4-fluoro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.50 g, 3.80 mmol, 1 eq.) was added. The reaction was then stirred at r.t. for 1 h. The reaction was quenched with water (10 ml) and the product extracted with EtOAc (3 x 10 ml) and 3:1 CHCl3/IPA (2 x 10 ml). The organics were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography, 0-100% heptane/EtOAc. The relevant fractions were combined and concentrated in vacuo to afford the desired product (1.37 g, 2.19 mmol, 57% yield). LCMS 7: RT = 1.26 min, m/z = 589 [M+H]+, 94% Step 2 Tert-butyl (3S,5R)-3-methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1- carboxylate Tert-butyl (3R,5S)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)-5-methylpiperidine-1-carboxylate (1.50 g, 2.60 mmol, 1 eq.), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.21 g, 4.78 mmol, 1.8 eq.), (1,3- dioxoisoindolin-2-yl) 2-methyltetrahydropyran-4-carboxylate (960 mg, 3.32 mmol, 1.3 eq.) and sodium hydrogen carbonate (429 mg, 5.11 mmol, 2 eq.) were dissolved in N,N- dimethylacetamide (15 mL) and degassed via sonication for 5 min. To the reaction mixture was added NiBr2. dtbbpy (124 mg, 0.25 mmol, 0.1 eq.) and degassed for a further 5 mins under sonication. The reaction mixture was sealed and irradiated under 395 nm light for 20 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (2 x 50 mL) before being concentrated in vacuo to afford a yellow oil. The oil was purified by flash chromatography, 0-50% ethyl acetate in heptane followed by low pH reverse phase chromatography eluting with a gradient of 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid). The product containing fractions were combined and concentrated in vacuo to afford tert-butyl (3S,5R)-3-methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1- carboxylate (775 mg, 0.94 mmol, 37% yield) as a colourless oil. LCMS 7: RT = 1.32 min, m/z = 560 [M+H]+, 68% Step 3 4-(((3R,5S)-5-Methylpiperidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine Trifluoroacetic acid (2 mL, 26.12 mmol) was added to a solution of tert-butyl (3S,5R)-3- methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1-carboxylate (775 mg, 0.94 mmol, 68 mass%) in dichloromethane (5 mL) . The reaction mixture was stirred for 48 h and then concentrated in vacuo to afford a brown oil. The oil was dissolved in ammonia (in methanol) (10 mL, 70 mmol, 7 mol/L) and was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo to afford a yellow solid. The solid was loaded onto an SCX cartridge (20 g column) and the column was washed with MeOH (3 CV) and the product eluted with 7M ammonia in MeOH (3 CV). The methanolic ammonia flush was concentrated in vacuo to afford an orange oil identified as 4-(((3R,5S)-5- methylpiperidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine (440 mg, 0.81mmol, 61mass%, 87% yield). LCMS 8: RT = 0.81 min, m/z = 330 [M+H]+, 61% Step 4 1-((3S,5R)-3-Methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one A solution of 4-(((3R,5S)-5-methylpiperidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.67 mmol) and potassium phosphate (179 mg, 1.34 mmol) in tetrahydrofuran (6 mL) and water (2 mL). The reaction mixture was cooled to 0ºC and a solution of acryloyl chloride (60 μL, 0.74 mmol) was added. The reaction mixture was stirred at 0ºC for 1 h before analysis by LCMS, which showed less than 50% conversion. The reaction mixture was retreated with acryloyl chloride (60 μL, 0.74 mmol) and the reaction mixture was stirred at 0ºC for a further 1 h. The organics were removed in vacuo and the aqueous phase was diluted with water (3 mL) and ethyl acetate (3 x 5 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL) and the combined organics were concentrate in vacuo to afford a brown oil that was purified by HPLC (method P3E). The pure fractions were combined and concentrated in vacuo to afford a white solid identified as 1-((3S,5R)-3-methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)oxy)piperidin-1-yl)prop-2-en-1-one (19.7 mg, 0.05 mmol, 97 mass%, 7% yield). LCMS 4: RT = 1.96 min, m/z = 384 [M+H]+, 100% 1H NMR (500 MHz, DMSO) δ 11.23 (s, 1H), 8.04 – 8.00 (m, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.93 – 6.79 (m, 1H), 6.72 – 6.66 (m, 1H), 6.20 – 6.07 (m, 1H), 5.77 – 5.66 (m, 1H), 4.85 – 4.53 (m, 1H), 4.51 – 4.28 (m,1H), 4.07 – 2.98 (m, 5H), 2.82 – 2.22 (m, 3H), 1.99 – 1.91 (m, 1H), 1.87 – 1.81 (m, 1H), 1.80 – 1.68 (m, 1H), 1.62 – 1.51 (m, 1H), 1.38 – 1.23 (m, 2H), 1.16 – 1.11 (m, 3H), 0.95 (d, J = 6.5 Hz, 3H). EXAMPLE 102 and EXAMPLE 103 1-((3S,5R)-3-Methyl-5-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one The title compounds were separated from an isomeric mixture of 1-((3S,5R)-3-methyl-5-((3- (2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1- yl)prop-2-en-1-one, prepared as described in Example 100. Chiral separation of the two stereoisomers was done by preparative HPLC. Column: Chiralpak AD-H (4.6 x 250mm, 5 µm, Eluent A: CO2, Eluent B: iPrOH + 0.2% DEA, Flux: 4 mL/min. First eluting peak (Example 102): Obtained as a white solid (6 mg). Purity by LCMS 96%. LCMS 4: RT = 1.91 min, m/z = 384 [M+H]+, 96% 1H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 8.06 – 8.00 (m, 1H), 7.02 – 6.97 (m, 1H), 6.95 – 6.80 (m, 1H), 6.74 – 6.65 (m, 1H), 6.22 – 6.07 (m, 1H), 5.77 – 5.66 (m, 1H), 4.84 – 4.56 (m, 1H), 4.54 – 4.25 (m, 1H), 4.08 – 3.00 (m, 5H), 2.83 – 2.27 (m, 3H), 2.00 – 1.90 (m, 1H), 1.88 – 1.82 (m, 1H), 1.82 – 1.66 (m, 1H), 1.62 – 1.48 (m, 1H), 1.41 – 1.22 (m, 2H), 1.15 (d, J = 6.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). Second eluting peak (Example 103): Obtained as a white solid (8 mg). Purity by LCMS 98% LCMS 4: RT = 1.92 min, m/z = 384 [M+H]+, 98% 1H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 8.06 – 8.00 (m, 1H), 7.02 – 6.97 (m, 1H), 6.95 – 6.80 (m, 1H), 6.74 – 6.65 (m, 1H), 6.22 – 6.07 (m, 1H), 5.77 – 5.66 (m, 1H), 4.84 – 4.56 (m, 1H), 4.54 – 4.25 (m, 1H), 4.08 – 3.00 (m, 5H), 2.83 – 2.27 (m, 3H), 2.00 – 1.90 (m, 1H), 1.88 – 1.82 (m, 1H), 1.82 – 1.66 (m, 1H), 1.62 – 1.48 (m, 1H), 1.41 – 1.22 (m, 2H), 1.15 (d, J = 6.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). EXAMPLE 104 and EXAMPLE 105 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-2-methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1- carboxylate A mixture of 2-[[4-chloro-3-(2-methyltetrahydropyran-4-yl)pyrrolo[2,3-b]pyridin-1- yl]methoxy]ethyl-trimethyl-silane (200 mg, 525 mmol, 1 eq.), tert-butyl (2R,3R)-3-amino- 2-methyl-pyrrolidine-1-carboxylate (231 mg, 1.15 mmol, 2.2 eq.), caesium carbonate (428 mg, 1.31 mmol, 2.5 eq.), palladium diacetate (23.5 mg, 0.10 mmol, 0.2 eq.) and Xantphos® (91 mg, 0.16 mmol, 0.3 eq.) in 1,4-dioxane (3 mL). The mixture was heated at 80ºC for 16 h. Once at room temperature, the mixture was filtered through Celite®, washed with EtOAc and the solvents evaporated under reduced pressure. The resulting crude was purified by normal-phase chromatography, 0-100% hexane/EtOAc. The product tubes were collected, and the solvent was removed in vacuo to obtain the desired compound (251 mg, 0.46 mmol, 88% yield). LCMS 4: RT = 2.16 min, m/z = 545 [M+H]+, 100% Step 2 N-((2R,3R)-2-Methylpyrrolidin-3-yl)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine Tert-butyl (2R,3R)-2-methyl-3-[[3-(2-methyloxan-4-yl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]amino]pyrrolidine-1-carboxylate (251 mg, 0.45 mmol, 1 eq.) was dissolved in DCM (25 mL) and trifluoroacetic acid (3.2 mL, 41.5 mmol, 90 eq.) was added. The solution was stirred at room temperature for 150 min and concentrated under reduced pressure.7M ammonia in methanol (3 mL) was added and the mixture was stirred overnight at room temperature. The solvent was concentrated in vacuo to give the title compound as a crude which was used in the next synthetic step without further purification. LCMS 4: RT = 0.57 min, m/z = 315 [M+H]+, 100% Step 3 1-((2R,3R)-2-Methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one A solution of N-[(2R,3R)-2-methylpyrrolidin-3-yl]-3-(2-methyltetrahydropyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine (144 mg, 0.46 mmol) and diisopropylethylamine (0.24 mL, 1.38 mmol) in tetrahydrofuran (5.5 mL) was cooled to 0 ºC and a solution of acryloyl chloride (56 μL, 0.69 mmol) was added. Ice bath was removed, and the reaction mixture was stirred overnight at room temperature. The organics were removed in vacuo and the residue was purified by reverse phase chromatography eluting from 100% water to 100% 1:1 ACN/MeOH mixture to afford 83 mg of 1-((2R,3R)-2-methyl-3-((3-(2-methyltetrahydro- 2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Chiralpak IA 5µm, 250 x 30mm; Eluent A: Heptane; Eluent B: iPrOH; Flux: 20 ml / min First eluting peak (Example 104): Obtained as a white solid (19.8 mg). Purity by LCMS 90% LCMS 1: RT = 1.40 min, m/z = 369 [M+H]+, 90% 1H NMR (400 MHz, MeOD) δ 7.87 (dd, J = 5.8, 1.9 Hz, 1H), 6.93 (d, J = 0.9 Hz, 1H), 6.67 (ddd, J = 30.5, 16.8, 10.5 Hz, 1H), 6.43 (dd, J = 16.9, 5.8 Hz, 1H), 6.32 (ddd, J = 16.8, 13.1, 2.0 Hz, 1H), 5.77 (dt, J = 10.4, 1.9 Hz, 1H), 4.73 – 4.54 (m, 1H), 4.45 – 4.24 (m, 1H), 4.07 (ddd, J = 11.5, 4.4, 1.6 Hz, 1H), 3.85 (dd, J = 10.7, 8.9 Hz, 1H), 3.77 – 3.63 (m, 3H), 3.56 (ddd, J = 12.9, 10.7, 7.7 Hz, 1H), 3.27 – 3.16 (m, 1H), 2.48 (ddt, J = 18.6, 13.3, 7.0 Hz, 1H), 2.25 – 1.95 (m, 3H), 1.79 – 1.61 (m, 1H), 1.46 – 1.27 (m, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H). Second eluting peak (Example 105): Obtained as a white solid (19.4 mg). Purity by LCMS 100% LCMS 1: RT = 1.40 min, m/z = 369 [M+H]+, 93% 1H NMR (400 MHz, MeOD) δ 7.89 (dd, J = 5.8, 1.9 Hz, 1H), 6.93 (d, J = 0.9 Hz, 1H), 6.64 (ddd, J = 30.5, 16.8, 10.5 Hz, 1H), 6.43 (dd, J = 16.9, 5.8 Hz, 1H), 6.32 (ddd, J = 16.8, 13.1, 2.0 Hz, 1H), 5.70 (dt, J = 10.4, 1.9 Hz, 1H), 4.73 – 4.54 (m, 1H), 4.45 – 4.24 (m, 1H), 4.07 (ddd, J = 11.5, 4.4, 1.6 Hz, 1H), 3.85 (dd, J = 10.7, 8.9 Hz, 1H), 3.80 – 3.63 (m, 3H), 3.56 (ddd, J = 12.9, 10.7, 7.7 Hz, 1H), 3.27 – 3.16 (m, 1H), 2.50 (ddt, J = 18.6, 13.3, 7.0 Hz, 1H), 2.25 – 1.95 (m, 3H), 1.79 – 1.61 (m, 1H), 1.46 – 1.27 (m, 1H), 1.28 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H). EXAMPLE 106 and EXAMPLE 107 1-((2S,4R)-2-Methyl-4-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 1-((2S,4R)-2-Methyl-4-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2S,4R)-2-methyl-4-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidine-1- carboxylate Potassium tert-butoxide (264 mg, 2.35 mmol, 4 eq.) was added to a solution of tert-butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (237 mg, 1.18 mmol, 2 eq.) in 1,4- dioxane (4 mL) and the reaction mixture was stirred at r.t. for 30 min. 2-[[4-chloro-5-(2- methyltetrahydropyran-4-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methoxy]ethyl-trimethyl-silane (225 mg, 0.59 mmol, 1 eq.) was added and the mixture was stirred at RT for 5 h. Another solution consisting of potassium tert-butoxide (130 mg, 1.2 mmol, 2 eq.), tert-butyl (2S,4R)- 4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (120 mg, 0.60 mmol, 1 eq.) in 1,4-dioxane (1 mL) was prepared and poured into the reaction mixture and stirred overnight at r.t. The solvent was concentrated in vacuo to afford a yellow oil, which was partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer was extracted with ethyl acetate (3x25 mL). The combined organics were washed with brine (2 x 20 mL) and concentrated in vacuo. The crude was purified through a reversed phase column eluting from 100% water to 100% 1:1 ACN/MeOH mixture to give the title compound (165 mg, 0.30 mmol, 51% yield). LCMS 2: RT = 2.48 min, m/z = 547 [M+H]+, 96% Step 2 4-(((3R,5S)-5-Methylpyrrolidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine Tert-butyl (2S,4R)-2-methyl-4-[5-(2-methyltetrahydropyran-4-yl)-7-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]oxy-pyrrolidine-1-carboxylate (160 mg, 0.29 mmol, 1 eq) was dissolved in DCM (1.7 mL) and trifluoroacetic acid (1.7 mL, 22.1 mmol, 75 eq) was added. The solution was stirred at room temperature for 2 h and concentrated under reduced pressure.7 M ammonia in methanol (3 mL) was added and the mixture was stirred overnight at room temperature. The solvent was concentrated in vacuo to give the title compound as a crude which was used in the next synthetic step without further purification. LCMS 2: RT = 2.48 min, m/z = 547 [M+H]+, 96% Step 3 1-((2S,4R)-2-Methyl-4-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one A solution of 4-[(3R,5S)-5-methylpyrrolidin-3-yl]oxy-5-(2-methyltetrahydropyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (92 mg, 0.29 mmol) and diisopropylethylamine (0.15 mL, 0.86 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0 ºC and a solution of acryloyl chloride (37 μL, 0.45 mmol) was added. Ice bath was removed, and the reaction mixture was stirred overnight at room temperature. The organics were removed in vacuo and the residue was purified by reverse phase chromatography eluting from 100% water to 100% 1:1 ACN/MeOH mixture to afford 92 mg of 1-((2S,4R)-2-methyl-4-((5-(2-methyltetrahydro- 2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one. Chiral separation of the two stereoisomers was done by preparative HPLC. Column: Chiralpak IA 5µm, 250 x 30mm; Eluent A: Heptane; Eluent B: iPrOH; Flux: 20 ml / min. First eluting peak (Example 105): Obtained as a white solid (24 mg). Purity by LCMS 100% LCMS 1: RT = 2.00 min, m/z = 547 [M+H]+, 99% 1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 8.33 (s, 1H), 7.11 (dd, J = 2.4, 0.9 Hz, 1H), 6.62 (ddd, J = 42.1, 16.7, 10.3 Hz, 1H), 6.16 (td, J = 17.0, 2.5 Hz, 1H), 5.78 (dt, J = 22.9, 5.7 Hz, 1H), 5.67 (ddd, J = 20.9, 10.3, 2.5 Hz, 1H), 4.45 – 4.24 (m, 1H), 4.13 – 3.85 (m, 2H), 3.77 (pd, J = 6.1, 4.2 jHz, 0.5H), 3.65 (d, J = 14.5 Hz, 0.5H), 3.48 – 3.37 (m, 1H), 3.09 (t, J = 12.2 Hz, 1H), 2.08 (d, J = 14.2 Hz, 1H), 2.01 – 1.81 (m, 3H), 1.57 (qd, J = 12.5, 4.5 Hz, 1H), 1.44 – 1.25 (m, 2H), 1.10 (d, J = 6.2 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H). Second eluting peak (Example 106): Obtained as a white solid (24 mg). Purity by LCMS 100% LCMS 1: RT = 2.00 min, m/z = 547 [M+H]+, 100% 1H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 8.33 (s, 1H), 7.10 (dd, J = 2.4, 0.9 Hz, 1H), 6.62 (ddd, J = 38.8, 16.7, 10.3 Hz, 1H), 6.16 (td, J = 17.2, 2.5 Hz, 1H), 5.82 – 5.71 (m, 1H), 5.70 – 5.62 (m, 1H), 4.47 – 4.23 (m, 1H), 4.12 – 3.84 (m, 3H), 3.77 (pd, J = 6.1, 4.2 Hz, 0.5H), 3.66 (d, J = 14.5 Hz, 0.5H), 3.49 – 3.36 (m, 2H), 3.09 (t, J = 12.2 Hz, 1H), 2.02 (dt, J = 31.6, 15.4 Hz, 2H), 1.84 (d, J = 12.8 Hz, 1H), 1.58 (qd, J = 12.4, 4.5 Hz, 1H), 1.37 (dd, J = 8.4, 6.6 Hz, 1H), 1.25 (q, J = 12.0 Hz, 1H), 1.11 (d, J = 6.1 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H). EXAMPLE 108 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3S,4R)-4-fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate A suspension of 2-[[4-chloro-3-[(2R,4R)-2-methyltetrahydropyran-4-yl]pyrrolo[2,3- b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (400 mg, 1.05 mmol) , tert-butyl (3S,4R)-3- amino-4-fluoro-piperidine-1-carboxylate (298 mg, 1.37 mmol) and dicesium carbonate (855 mg, 2.62 mmol) in 1,2-dimethoxyethane (8 mL) was degassed with nitrogen for 5 minutes before the addition of BrettPhos-Pd-G3 (95 mg, 0.10 mmol) . The reaction mixture was degassed for a further 5 minutes before being heated to 80 ºC and stirred for 18 h. The reaction mixture was filtered and the solids washed with ethyl acetate (5 mL). The filtrate was concentrated in vacuo to afford an orange oil that was purified by column chromatography using a Biotage Isolera (10 g column) eluting with a gradient of 0-30% ethyl acetate in heptane. The product containing fractions were combined and concentrated in vacuo to afford a brown oil identified as tert-butyl (3S,4R)-4-fluoro-3-[[3-[(2R,4R)-2- methyltetrahydropyran-4-yl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4- yl]amino]piperidine-1-carboxylate (350 mg, 0.62 mmol, 59% yield). LCMS 7: RT = 0.95 min, m/z = 563 [M+H]+, 100% Step 2 N-((3S,4R)-4-Fluoropiperidin-3-yl)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine Trifluoroacetic acid (5 mL, 65.33 mmol) was added to a solution of tert-butyl (3S,4R)-4- fluoro-3-[[3-[(2R,4R)-2-methyltetrahydropyran-4-yl]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]amino]piperidine-1-carboxylate (350 mg, 0.62 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 6 h. The reaction mixture was concentrated in vacuo to afford a brown oil. The oil was dissolved in ammonia (in methanol) (1 mL, 7 mmol, 7 mol/L) and was stirred at RT for 18h. The reaction mixture was concentrated in vacuo to afford a yellow solid. The solid was loaded onto an SCX cartridge (10 g column) and the column was washed with MeOH (3 CV) and the product eluted with 7M ammonia in MeOH (3 CV). The methanolic ammonia flush was concentrated in vacuo to afford an orange oil identified as N-[(3S,4R)-4-fluoro-3-piperidyl]- 3-[(2R,4R)-2-methyltetrahydropyran-4-yl]-1H-pyrrolo[2,3-b]pyridin-4-amine (200 mg, 0.51 mmol, 85 mass%, 82% yield) LCMS 7: RT = 0.70 min, m/z = 333 [M+H]+, 69% Step 3 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one A solution of N-((3S,4R)-4-fluoropiperidin-3-yl)-3-(2-methyltetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine (200 mg, 0.51 mmol, 85 mass%) and potassium phosphate (161 mg, 1.20 mmol) in THF (15 mL) and water (2 mL). The reaction mixture was cooled to 0ºC and a solution of acryloyl chloride (54 μL, 0.66 mmol) in THF (5 mL) was added. The reaction mixture was stirred at 0ºC for 1 h. The organics were removed in vacuo and the aqueous was diluted with water (3 mL) and ethyl acetate (3 x 5 mL). The combined organics were concentrated in vacuo to afford a brown oil that was purified by preparative HPLC. The pure fractions were combined and concentrated in vacuo to afford a white solid identified as 1-((3S,4R)-4-fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (24.5 mg, 0.06 mmol, 95 mass%, 12% yield). LCMS 7: RT = 1.62 min, m/z = 387 [M+H]+, 98% EXAMPLE 109 and EXAMPLE 110 1-((3S,4R)-4-Fluoro-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one 1-((3S,4R)-4-Fluoro-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one The title compounds were separated from an isomeric mixture of 1-((3S,4R)-4-fluoro-3-((3- (2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one, prepared as described in Example 107. Chiral separation of the two stereoisomers was done by preparative HPLC. Column: Cellulose-4 (10 x 250mm, 5 µm, Eluent A: CO2, Eluent B: iPrOH + 0.2% DEA, Flux: 15 mL/min. First eluting peak (Example 109): Obtained as a white solid (7 mg). Purity by LCMS 100% LCMS 1: RT = 2.25 min, m/z = 387 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 7.90 – 7.84 (m, 1H), 6.93 – 6.89 (m, 1H), 6.89 – 6.64 (m, 1H), 6.51 – 6.33 (m, 1H), 6.33 – 6.13 (m, 1H), 5.90 – 5.62 (m, 1H), 5.22 – 5.02 (m, 1H), 4.78 – 3.76 (m, 4H), 3.73 – 2.97 (m, 5H), 2.30 – 1.85 (m, 4H), 1.79 – 1.64 (m, 1H), 1.41 – 1.28 (m, 1H), 1.22 (d, J = 6.2 Hz, 3H). Second eluting peak (Example 110): Obtained as a white solid (7 mg). Purity by LCMS 100% LCMS 1: RT = 2.25 min, m/z = 387 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 7.90 – 7.84 (m, 1H), 6.91 (s, 1H), 6.88 – 6.58 (m, 1H), 6.48 – 6.33 (m, 1H), 6.33 – 6.01 (m, 1H), 5.88 – 5.51 (m, 1H), 5.22 – 5.01 (m, 1H), 4.79 – 3.83 (m, 4H), 3.72 – 2.94 (m, 5H), 2.28– 1.82 (m, 4H), 1.72 – 1.58 (m, 1H), 1.50 – 1.35 (m, 1H), 1.24 (d, J = 6.2 Hz, 3H). EXAMPLE 111 and EXAMPLE 112 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (2R,3R)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate Sodium hydride (60%, 67 mg, 1.67 mmol, 1.3 eq) was added to a solution of tert-butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (307 mg, 1.53 mmol, 1.2 eq) in DMSO (8mL) and the mixture was stirred at room temperature for 30 min. A solution of 4- fluoro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.27 mmol, 1 eq) in DMSO (2mL) was added and the mixture was stirred at room temperature for 2 h. The reaction was partitioned between water and ethyl acetate. The combined organics layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent was concentrated under reduced pressure. The crude was purified by flash chromatography, 0-100% hexane/EtOAc to give the title compound (470 mg, 64%) as a colourless oil. LCMS 2: RT = 2.49 min, m/z = 574 [M+H]+, 99% Step 2 Tert-butyl (2R,3R)-2-methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidine-1- carboxylate Tert-butyl (2R,3R)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)-2-methylpyrrolidine-1-carboxylate (470 mg, 0.82 mmol, 1 eq), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (390 mg, 1.53 mmol, 1.8 eq), 1,3- dioxoisoindolin-2-yl 2-methyltetrahydro-2H-pyran-4-carboxylate (356 mg, 1.23 mmol, 1.5 eq) and sodium hydrogen carbonate (140 mg, 1.6 mmol, 2eq) were dissolved in N,N- dimethylacetamide (4 mL) and degassed for 15 min. To the reaction mixture was added NiBr2. dtbbpy (40 mg, 0.082 mmol, 0.1 eq) and degassed for a further 15 min. The reaction mixture was sealed and irradiated under 395 nm light (Photoreactor Peen) for 15 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine before being concentrated in vacuo to afford a yellow oil. The oil was purified by column chromatography with hexane/EtOAc, 0-100%. The fractions were combined and concentrated in vacuo to afford a colourless oil (260 mg, 58%). LCMS 2: RT 2.45 min, m/z 546 [M+H]+, 80%. Step 3 4-(((2R,3R)-2-Methylpyrrolidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine Trifluoroacetic acid (2 mL, 25.97 mmol, 39 eq.) was added to a solution of tert-butyl (2R,3R)-2-methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidine-1- carboxylate (360 mg, 0.66 mmol, 1.0 eq.) in dichloromethane (1 mL) and the solution was stirred at room temperature for 4 h. Solvents were evaporated under reduced pressure.7 M ammonia in MeOH (4 mL, 28 mmol, 42 eq.) was added to the residue and the mixture was stirred at room temperature for 4 h. The solvent was concentrated in vacuo to give the title compound as a crude which was used in the next synthetic step without further purification. LCMS 2: RT 0.59 min, m/z 316 [M+H]+, 90%. Step 4 1-((2R,3R)-2-Methyl-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one Acryloyl chloride (40 μL, 0.55 mmol, 1.4 eq.) was added to a solution of 4-(((2R,3R)-2- methylpyrrolidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine (510 mg, 25%, 0.40 mmol, 1 eq.) and diisopropylethylamine (0.3 mL, 1.72 mmol, 4 eq.) in tetrahydrofuran (2 mL) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under nitrogen and the crude was purified by basic reverse-phase. The fractions which contained the product were combined and concentrated under vacuum. Chiral separation of the two stereoisomers was done by preparative HPLC. Column: Daicel Chiralpak IA 5um (250x30 mm) , Eluent A: heptane, Eluent B: IPA, Flux: 20 mL/min. First eluting peak (Example 111): Obtained as a white solid (9 mg). Purity by LCMS 96%. LCMS 1: RT = 1.75 min, m/z = 370 [M+H]+, 96% 1H NMR (400 MHz, MeOD) δ 8.04 (dd, J = 5.7, 1.7 Hz, 1H), 7.00 (dd, J = 2.3, 0.9 Hz, 1H), 6.84 – 6.56 (m, 2H), 6.39 – 6.24 (m, 1H), 5.78 (ddd, J = 10.5, 4.1, 2.0 Hz, 1H), 5.24 (dq, J = 19.0, 6.6 Hz, 1H), 4.73 (p, J = 6.7 Hz, 1H), 4.62 (p, J = 6.5 Hz, 1H), 4.10 – 4.00 (m, 1H), 3.92 – 3.79 (m, 1H), 3.79 – 3.54 (m, 3H), 2.59 – 2.21 (m, 3H), 2.05 (d, J = 13.2 Hz, 1H), 1.98 (d, J = 13.1 Hz, 1H), 1.67 (qd, J = 12.5, 4.5 Hz, 1H), 1.43 (q, J = 12.1 Hz, 1H), 1.29 (dd, J = 24.4, 6.6 Hz, 3H), 1.21 (dd, J = 6.2, 3.5 Hz, 3H). Second eluting peak (Example 112): Obtained as a white solid (10 mg). Purity by LCMS 99%. LCMS 1: RT = 1.74 min, m/z = 370 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 8.04 (dd, J = 5.7, 1.6 Hz, 1H), 7.00 (t, J = 1.3 Hz, 1H), 6.87 – 6.53 (m, 2H), 6.32 (ddd, J = 16.9, 13.7, 2.0 Hz, 1H), 5.78 (ddd, J = 10.4, 3.4, 2.0 Hz, 1H), 5.23 (dq, J = 18.7, 6.5 Hz, 1H), 4.72 (p, J = 6.6 Hz, 1H), 4.62 (p, J = 6.5 Hz, 1H), 4.07 (dd, J = 11.4, 4.3 Hz, 1H), 3.93 – 3.51 (m, 4H), 2.60 – 2.19 (m, 2H), 2.08 (d, J = 13.0 Hz, 1H), 1.95 (d, J = 13.1 Hz, 1H), 1.74 (qt, J = 12.6, 4.5 Hz, 1H), 1.42-1.34 (m, 2H), 1.30 (dd, J = 24.2, 6.6 Hz, 3H), 1.20 (t, J = 5.8 Hz, 3H). EXAMPLE 113 and EXAMPLE 114 (R*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one (S*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one Step 1 Tert-butyl 4-((5-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2-azabicyclo[3.1.1]heptane-2-carboxylate Tert-butyl 4-[5-(3,6-dihydro-2H-pyran-4-yl)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- d]pyrimidin-4-yl]oxy-2-azabicyclo[3.1.1]heptane-2-carboxylate (286 mg, 0.53 mmol, 1 eq.) was dissolved in MeOH (5 mL). Three vacuum-argon cycles were performed and Pd/C 10% (29 mg) was added. The mixture was stirred under hydrogen atmosphere for 6.5 h. The hydrogen was removed by vacuum and the catalyst was filtered, washed with MeOH and concentrated to give the title compound (275mg, 0.51 mmol, 96% yield) as a colourless oil, which was used in the following step without further purification. LCMS 2: RT = 2.47 min, m/z = 545 [M+H]+, 100% Step 2 4-(2-Azabicyclo[3.1.1]heptan-4-yloxy)-5-tetrahydropyran-4-yl-7H-pyrrolo[2,3- d]pyrimidine Trifluoroacetic acid (2.8 mL, 36 mmol) was added to a solution of tert-butyl 4-[5- tetrahydropyran-4-yl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]oxy-2- azabicyclo[3.1.1]heptane-2-carboxylate (275 mg, 0.50 mmol, 1 eq.) in dichloromethane (2.8 mL). The reaction mixture was stirred for 2h 45 min. The reaction mixture was concentrated in vacuo to afford an oil, which was dissolved in 7 N ammonia in methanol (5.0 mL, 35 mmol, 70 eq.) and the solution was stirred at r.t. for 18h. The reaction mixture was concentrated in vacuo to afford a crude that was used without further purification. LCMS 2: RT = 0.91 min, m/z = 315 [M+H]+, 83% Step 3 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2- azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one A solution of 4-(2-azabicyclo[3.1.1]heptan-4-yloxy)-5-tetrahydropyran-4-yl-7H- pyrrolo[2,3-d]pyrimidine (158 mg, 0.50 mmol, 1 eq.) and diisopropylethylamine (0.26 mL, 1.49 mmol, 3 eq.) in tetrahydrofuran (4.5 mL) was cooled to 0 ºC and a solution of acryloyl chloride (61 μL, 0.75 mmol, 1.5 eq.) was added. Ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The organics were removed in vacuo and the crude was purified by reverse phase chromatography eluting from 100% water to 100% 1:1 ACN/MeOH mixture to afford 95 mg of 1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one as a racemic mixture. Chiral separation of the two enantiomers was done by preparative HPLC. Column: Chiralpak IA 5µm, 250 x 30mm; Eluent A: Heptane; Eluent B: iPrOH; Flux: 20 ml / min. First eluting peak (Example 113): Obtained as a white solid (24 mg). Purity by LCMS 100% LCMS 1: RT = 2.00 min, m/z = 371 [M+H]+, 100% 1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 8.33 (s, 1H), 7.11 (dd, J = 2.4, 0.9 Hz, 1H), 6.62 (ddd, J = 42.1, 16.7, 10.3 Hz, 1H), 6.16 (td, J = 17.0, 2.5 Hz, 1H), 5.78 (dt, J = 22.9, 5.7 Hz, 1H), 5.67 (ddd, J = 20.9, 10.3, 2.5 Hz, 1H), 4.45 – 4.24 (m, 1H), 4.13 – 3.85 (m, 2H), 3.77 (pd, J = 6.1, 4.2 jHz, 0.5H), 3.65 (d, J = 14.5 Hz, 0.5H), 3.48 – 3.37 (m, 1H), 3.09 (t, J = 12.2 Hz, 1H), 2.08 (d, J = 14.2 Hz, 1H), 2.01 – 1.81 (m, 3H), 1.57 (qd, J = 12.5, 4.5 Hz, 1H), 1.44 – 1.25 (m, 2H), 1.10 (d, J = 6.2 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H). Second eluting peak (Example 114): Obtained as a white solid (24 mg). Purity by LCMS 100% LCMS 1: RT = 2.00 min, m/z = 371 [M+H]+, 99% 1H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 8.33 (s, 1H), 7.10 (dd, J = 2.4, 0.9 Hz, 1H), 6.62 (ddd, J = 38.8, 16.7, 10.3 Hz, 1H), 6.16 (td, J = 17.2, 2.5 Hz, 1H), 5.82 – 5.71 (m, 1H), 5.70 – 5.62 (m, 1H), 4.47 – 4.23 (m, 1H), 4.12 – 3.84 (m, 3H), 3.77 (pd, J = 6.1, 4.2 Hz, 0.5H), 3.66 (d, J = 14.5 Hz, 0.5H), 3.49 – 3.36 (m, 2H), 3.09 (t, J = 12.2 Hz, 1H), 2.02 (dt, J = 31.6, 15.4 Hz, 2H), 1.84 (d, J = 12.8 Hz, 1H), 1.58 (qd, J = 12.4, 4.5 Hz, 1H), 1.37 (dd, J = 8.4, 6.6 Hz, 1H), 1.25 (q, J = 12.0 Hz, 1H), 1.11 (d, J = 6.1 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H). EXAMPLE 115 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3S,4R)-4-fluoro-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1-carboxylate Sodium hydride (51 mg, 1.27 mmol, 60 mass%, 1.67 eq.) was added to a solution of tert- butyl (3S,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate (279 mg, 1.27 mmol, 1.67 eq.) in dimethyl sulfoxide (2 mL) at r.t. The reaction was stirred for 30 minutes then 2-[(4-fluoro- 3-iodo-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (300 mg, 0.76 mmol, 1.0 eq.) was added and the reaction was stirred at r.t. for 4 h. Water (25 mL) was added and the mixture was extracted with EtOAc (25 mL). The organics were washed with water (25 mL) and brine (2 x 25 mL) and were concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of 0-40% ethyl acetate in heptane. The product containing fractions were combined and concentrated in vacuo to afford the title (287 mg, 0.48 mmol, 64% yield) as a colourless oil. LCMS 7: RT = 1.21 min, m/z = 592 [M+H]+, 84% Step 2 Tert-butyl (3S,4R)-4-fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1- carboxylate Tert-butyl (3S,4R)-4-fluoro-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1-carboxylate (565 mg, 0.95 mmol, 1.0 eq.), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (452 mg, 1.78 mmol, 1.8 eq.), 1,3-dioxoisoindolin-2-yl 2-methyltetrahydro-2H-pyran-4-carboxylate (359 mg, 1.24 mmol, 1.3 eq.) and sodium hydrogen carbonate (160 mg, 1.90 mmol, 2.0 eq.) were dissolved in N,N-dimethylacetamide (6 mL) and degassed via sonication for 5 mins. To the reaction mixture was added NiBr2. dtbbpy (47 mg, 0.095 mmol, 0.1 eq.), the reaction mixture was degassed for a further 5 mins under sonication, sealed and irradiated under 395 nm light for 20 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (2 x 50 mL) and concentrated in vacuo. The crude was purified by flash chromatography eluting with a gradient of 0-50% ethyl acetate in heptane to give the title compound (240 mg, 0.30 mmol, 31% yield). LCMS 7: RT = 1.18 min, m/z = 564 [M+H]+, 70% Step 3 4-(((3S,4R)-4-Fluoropiperidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine Trifluoroacetic acid (5 mL, 65.29 mmol, 130 eq.) was added to a solution of tert-butyl (3S,4R)-4-fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidine-1- carboxylate (150 mg, 0.30 mmol, 1 eq.) in dichloromethane (5 mL). The reaction mixture was stirred at r.t. for 6 h. The reaction mixture was concentrated in vacuo and dissolved in 7 M ammonia (in methanol) (10 mL, 70.00 mmol, 233 eq.) and was stirred at r.t. for 72 h. The reaction mixture was concentrated in vacuo to afford a yellow solid. The solid was loaded onto an SCX cartridge (10 g column) and the column was washed with MeOH (3 cv.) and the product eluted with 7M ammonia in MeOH (3 cv.). The methanolic ammonia flush was concentrated in vacuo to afford the title compound (150 mg, 0.30 mmol, 100 % yield). LCMS 8: RT = 0.74 min, m/z = 334 [M+H]+, 68% Step 4 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one A solution of 4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.30 mmol, 1.0 eq.) and potassium phosphate (82 mg, 0.61 mmol, 2.0 eq.) in THF (15 mL) and water (1.5 mL). The reaction mixture was cooled to 0 ºC and a solution of acryloyl chloride (27 μL, 0.33 mmol, 1.1 eq) in THF (5 mL) was added over the course of 2 minutes. The mixture was stirred at 0 ºC for 1 h, the organics were removed in vacuo and the aqueous phase was diluted with water (3 mL) and ethyl acetate (3 x 5 mL). The combined organics were concentrated in vacuo to afford a brown oil that was purified by preparative HPLC. The pure fractions were combined and concentrated in vacuo to afford the title compound (33 mg, 0.08 mmol, 27% yield). LCMS 5: RT = 2.12 min, m/z = 388 [M+H]+, 95% 1H NMR (500 MHz, DMSO) δ 11.27 – 11.21 (m, 1H), 8.06 – 8.01 (m, 1H), 7.00 – 6.95 (m, 1H), 6.92 – 6.34 (m, 2H), 6.12 – 5.79 (m, 1H), 5.76 – 5.28 (m, 1H), 5.21 – 4.90 (m, 2H), 4.31 – 3.80 (m, 3H), 3.75 – 2.98 (m, 5H), 2.23 – 1.66 (m, 4H), 1.62 – 1.40 (m, 1H), 1.40 – 1.16 (m, 1H), 1.16 – 1.02 (m, 3H). EXAMPLE 116 1-((3S,4R)-4-Fluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3S,4R)-4-fluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidine-1- carboxylate Potassium tert-butoxide (106 mg, 0.94 mmol, 1.2 eq.) was added to a solution of tert-butyl (3S,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate (207 mg, 0.94 mmol, 1.2 eq.) in 1,4- dioxane (3 mL) and the reaction mixture was stirred at r.t. for 30 min. 4-Chloro-5-(2- methyltetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (300 mg, 0.78 mmol, 1.0 eq.) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo and the resulting residue was partitioned between water (5 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL), the combined organics were washed with brine and concentrated in vacuo to afford the title compound (170 mg, 0.29 mmol, 38% yield) as a yellow oil. LCMS 7: RT = 1.26 min, m/z = 565 [M+H]+, 99% Step 2 4-(((3S,4R)-4-Fluoropiperidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine Trifluoroacetic acid (5 mL, 65.29 mmol, 217 eq.) was added to a solution of tert-butyl (3S,4R)-4-fluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidine-1- carboxylate (170 mg, 0.30 mmol, 1.0 eq.) in dichloromethane (5 mL) and the reaction mixture was stirred at r.t. for 6 h. The reaction mixture was concentrated in vacuo to afford a brown oil. The oil was dissolved in 7M ammonia in MeOH (10 mL, 70 mmol, 233 eq.) and the mixture was stirred at r.t. for 18 h before being concentrated in vacuo to afford a yellow solid. The solid was loaded onto an SCX cartridge (10 g column) and the column was washed with MeOH (3 cv.) and the product eluted with 7M ammonia in MeOH (3 cv.). The methanolic ammonia flush was concentrated in vacuo to afford the title compound (110 mg, 0.29 mmol, 96% yield) as a yellow oil. LCMS 8: RT = 1.26 min, m/z = 565 [M+H]+, 84% Step 3 1-((3S,4R)-4-Fluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one A solution of 4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg, 0.33 mmol, 1.0 eq.) and potassium phosphate (88 mg, 0.66 mmol, 2.0 eq. ) in THF (15 mL) and water (1 mL). The reaction mixture was cooled to 0 ºC and a solution of acryloyl chloride (29 μL, 0.35 mmol, 1.05 eq.) in THF (5 mL) was added over the course of 2 minutes. The reaction mixture was stirred at 0 ºC for 1 h, the organics were removed in vacuo and the aqueous phase was diluted with water (3 mL) and ethyl acetate (3 x 5 mL). The combined organics were concentrated in vacuo to afford a brown oil which was purified by preparative HPLC to give the title compound (39 mg, 0.10 mmol, 30% yield). LCMS 7: RT = 2.29 min, m/z = 389 [M+H]+, 95% 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 8.33 – 8.29 (m, 1H), 7.11 – 7.05 (m, 1H), 6.97 – 6.30 (m, 1H), 6.07 – 5.80 (m, 1H), 5.79 – 5.24 (m, 2H), 5.18 – 5.00 (m, 1H), 4.56 – 3.96 (m, 2H), 3.94 – 3.88 (m, 1H), 3.68 – 2.88 (m, 5H), 2.26 – 1.90 (m, 3H), 1.81 – 1.39 (m, 3H), 1.39 – 1.16 (m, 1H), 1.15 – 1.04 (m, 3H). EXAMPLE 117 and EXAMPLE 118 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one 4-(((2R,3R)-2-Methylpyrrolidin-3-yl)oxy)-3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine (175 mg, 0.55 mmol, 1 eq., synthesis described in Examples 111 and 112, Step 3) was dissolved in DMF (2 mL). Propiolic acid (58 mg, 0.83 mmol, 1.5 eq), HATU (320 mg, 0.84 mmol, 1.5 eq.) and diisopropylethylamine (0.39 mL, 2.24 mmol, 4 eq.) were added and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. Chiral separation was done by preparative HPLC. Column: Daicel Chiralpak IA 5um (250x30 mm), Eluent A: heptane, Eluent B: IPA, Flux: 20 mL/min. to obtain the two title compounds. First eluting peak (Example 117): LMCS 1: RT = 1.23 min, m/z = 368 [M+H]+, 80% 1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.04 (dd, J = 5.7, 4.4 Hz, 1H), 7.01 (dd, J = 2.6, 0.9 Hz, 1H), 6.74 (dd, J = 15.2, 5.8 Hz, 1H), 5.32 – 5.20 (m, 1H), 4.75 (t, J = 6.7 Hz, 1H), 4.54 (dt, J = 12.8, 6.6 Hz, 1H), 4.12 – 4.01 (m, 1H), 3.95 – 3.80 (m, 1H), 3.68 – 3.55 (m, 2H), 2.63 – 2.22 (m, 3H), 2.12 – 1.90 (m, 2H), 1.66 (qt, J = 12.6, 4.1 Hz, 1H), 1.52 – 1.38 (m, 2H), 1.35 (dd, J = 14.9, 6.6 Hz, 3H), 1.22 (dd, J = 6.2, 1.4 Hz, 3H). Second eluting peak (Example 118): LMCS 1: RT = 1.22 min, m/z = 368 [M+H]+, 85% 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.05 (dd, J = 5.7, 3.9 Hz, 1H), 7.01 (dd, J = 2.3, 0.9 Hz, 1H), 6.74 (dd, J = 15.6, 5.8 Hz, 1H), 5.33 – 5.21 (m, 1H), 4.75 (t, J = 6.6 Hz, 1H), 4.58 (s, 1H), 4.55 – 4.46 (m, 1H), 4.08 (dd, J = 11.3, 4.3 Hz, 1H), 3.99 – 3.81 (m, 3H), 2.57 – 2.26 (m, 2H), 2.13 – 2.05 (m, 1H), 1.95 (d, J = 13.3 Hz, 1H), 1.83 – 1.66 (m, 1H), 1.35 (dd, J = 14.9, 6.6 Hz, 3H), 1.22 (dd, J = 6.2, 1.4 Hz, 3H). EXAMPLE 119, EXAMPLE 120, EXAMPLE 121 and EXAMPLE 122 1-((3S,5R)-3-Methyl-5-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((5-((2R*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-((3S,5R)-3-Methyl-5-((5-((2S*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one Step 1 Tert-butyl (3R,5S)-3-((5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)-5-methylpiperidine-1-carboxylate Tert-butyl (3R,5S)-3-hydroxy-5-methylpiperidine-1-carboxylate (200 mg, 0.93 mmol, 1.2 eq.) was dissolved in 1,4-dioxane (4 mL). Potassium tert-butoxide (165 mg, 1.47 mmol, 2 eq.) was added and the solution was stirred at room temperature, under argon atmosphere, for 30 min. 4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (300 mg, 0.73 mmol, 1 eq.) was added and the mixture was stirred at room temperature overnight. The reaction was poured into water, extracted with ethyl acetate (x 3), the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude (400 mg, 80% yield) was used in the next step without further purification. LMCS 2: RT = 2.57 min, m/z = 589 [M+H]+, 87% Step 2 Tert-Butyl (3S,5R)-3-methyl-5-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidine-1- carboxylate Tert-butyl (3R,5S)-3-((5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)-5-methylpiperidine-1-carboxylate (400 mg, 0.68 mmol, 1 eq), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (321 mg, 1.23 mmol, 1.8 eq), 1,3- dioxoisoindolin-2-yl 2-methyltetrahydro-2H-pyran-4-carboxylate (295 mg, 1.02 mmol, 1.5 eq) and sodium hydrogen carbonate (115 mg, 1.34 mmol, 2 eq.) were dissolved in N,N- dimethylacetamide (12 mL) and degassed for 30 min. To the reaction mixture was added NiBr2. dtbbpy (33 mg, 0.067 mmol, 0.09 eq) and degassed for a further 30 min. The reaction mixture was sealed and irradiated under 395 nm light (Photoreactor Peen) for 15 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine before being concentrated in vacuo to afford a yellow oil. The oil was purified by column chromatography with hexane/EtOAc, 0-100%. The fractions were combined and concentrated in vacuo to afford a colourless oil (260 mg, 68%). LMCS 2: RT = 2.55 min, m/z = 561 [M+H]+, 70% Step 3 4-(((3R,5S)-5-Methylpiperidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine Tert-butyl (3S,5R)-3-methyl-5-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidine-1- carboxylate (260 mg, 0.46 mmol, 1 eq.) was dissolved in DCM (2 mL) and trifluoroacetic acid (3 mL, 38.9 mmol, 84 eq.) was added at 0 ºC. The solution was stirred at room temperature for 3 h and concentrated under reduced pressure. 7 M ammonia in MeOH (3 mL, 21 mmol, 45 eq.) was added to the residue and the mixture was stirred at room temperature for 4 h. The solvent was concentrated in vacuo to give the title compound as a crude which was used in the next synthetic step without further purification. LMCS 2: RT = 0.94 min, m/z = 331 [M+H]+, 70% Step 4 1-((3S,5R)-3-Methyl-5-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one Acryloyl chloride (74 μL, 0.91 mmol, 1.5 eq.) was added to a solution of 4-(((3R,5S)-5- methylpiperidin-3-yl)oxy)-5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidine (1g, 20%, 0.65 mmol, 1 eq.) and diisopropylethylamine (0.32 mL, 1.83 mmol, 3 eq.) in tetrahydrofuran (4 mL) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under nitrogen and the crude was purified by basic reverse-phase. The fractions which contained the product were combined and concentrated under vacuum. Chiral separation was done by preparative HPLC. Column: Daicel Chiralpak IA 5um (250x30 mm), Eluent A: heptane, Eluent B: IPA, Flux: 20 mL/min. to obtain the four title compounds. First eluting peak (Example 119): Obtained as a white solid (14 mg). Purity by LCMS 98%. LCMS 4: RT =2.67 min, m/z = 385 [M+H]+, 98% 1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 16.8, 10.7 Hz, 1H), 6.23 (dd, J = 16.8, 1.9 Hz, 1H), 5.77 (dt, J = 10.7, 1.9 Hz, 1H), 5.28 (dtt, J = 14.4, 9.7, 4.5 Hz, 1H), 4.57 (dd, J = 13.0, 4.5 Hz, 1H), 4.45 (dd, J = 13.1, 4.2 Hz, 1H), 4.13 – 3.92 (m, 2H), 3.63 (ddd, J = 13.7, 9.8, 2.2 Hz, 2H), 3.24 – 3.08 (m, 2H), 2.88 (dt, J = 13.5, 10.4 Hz, 1H), 2.58 – 2.32 (m, 2H), 2.06 – 1.78 (m, 2H), 1.71 (ddt, J = 12.6, 8.3, 4.1 Hz, 1H), 1.61 – 1.41 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 1.06 (dd, J = 6.8, 3.6 Hz, 3H). Second eluting peak (Example 120): Obtained as a white solid (6 mg). Purity by LCMS 99%. LCMS 4: RT = 2.62 min, m/z = 385 [M+H]+, 98% 1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.93 – 6.75 (m, 1H), 6.23 (dq, J = 17.0, 2.0 Hz, 1H), 5.77 (dd, J = 10.6, 1.9 Hz, 1H), 5.27 (tq, J = 10.4, 5.4 Hz, 1H), 4.59 (d, J = 12.9 Hz, 1H), 4.47 (d, J = 12.9 Hz, 1H), 4.08 – 3.91 (m, 2H), 3.91 – 3.81 (m, 1H), 3.81 – 3.68 (m, 1H), 3.53 (p, J = 5.7 Hz, 1H), 3.12 (dd, J = 12.9, 10.1 Hz, 1H), 2.85 (t, J = 10.7 Hz, 1H), 2.55 – 2.34 (m, 2H), 2.02 (dtd, J = 10.0, 7.3, 3.8 Hz, 2H), 1.95 – 1.74 (m, 3H), 1.49 (dt, J = 28.2, 11.5 Hz, 1H), 1.27 (d, J = 6.5 Hz, 3H), 1.05 (dd, J = 6.8, 2.8 Hz, 3H). Third eluting peak (Example 121): Obtained as a white solid (10 mg). Purity by LCMS 99%. LCMS 4: RT = 2.67 min, m/z = 385 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 9.3 Hz, 1H), 7.01 (s, 1H), 6.84 (dd, J = 16.8, 10.6 Hz, 1H), 6.23 (dt, J = 16.9, 2.1 Hz, 1H), 5.77 (dd, J = 10.7, 1.9 Hz, 1H), 5.28 (ddp, J = 14.6, 9.8, 4.4 Hz, 1H), 4.69 – 4.51 (m, 1H), 4.51 – 4.36 (m, 1H), 4.14 – 3.89 (m, 2H), 3.75 – 3.53 (m, 2H), 3.15 (tq, J = 10.0, 3.0 Hz, 2H), 2.90 (td, J = 13.5, 10.5 Hz, 1H), 2.59 – 2.34 (m, 2H), 2.02 (t, J = 10.5 Hz, 1H), 1.95 – 1.77 (m, 2H), 1.72 (qd, J = 12.2, 4.2 Hz, 1H), 1.46 (ddt, J = 28.0, 24.0, 11.9 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.06 (dd, J = 6.8, 2.3 Hz, 3H). Fourth eluting peak (Example 122): Obtained as a white solid (5 mg). Purity by LCMS 97%. LCMS 4: RT = 2.63 min, m/z = 385 [M+H]+, 97% 1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 8.5 Hz, 1H), 7.10 (s, 1H), 6.84 (ddd, J = 17.1, 10.7, 2.5 Hz, 1H), 6.29 – 6.15 (m, 1H), 5.77 (dd, J = 10.7, 2.0 Hz, 1H), 5.27 (ddt, J = 14.8, 10.3, 5.2 Hz, 1H), 4.58 (d, J = 12.7 Hz, 1H), 4.46 (d, J = 12.8 Hz, 1H), 4.07 – 3.94 (m, 2H), 3.86 (ddd, J = 11.7, 6.2, 4.1 Hz, 1H), 3.76 (td, J = 8.2, 4.1 Hz, 1H), 3.53 (p, J = 5.6 Hz, 1H), 3.19 – 3.05 (m, 1H), 2.87 (td, J = 11.5, 5.5 Hz, 1H), 2.57 – 2.33 (m, 2H), 2.02 (dd, J = 8.4, 4.3 Hz, 2H), 1.95 – 1.75 (m, 2H), 1.58 – 1.41 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H). The following compounds have also been synthesized using analogous procedures to those described herein or using variations thereof known to those skilled in the art: EXAMPLE 123 1-(3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 5: RT = 2.01 min, m/z = 382 [M+H]+, 96% 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 8.09 (s, 1H), 6.93 (s, 1H), 6.65 – 6.48 (m, 1H), 6.22 – 6.04 (m, 1H), 5.77 – 5.60 (m, 1H), 3.95 – 3.83 (m, 4H), 3.74 – 3.64 (m, 2H), 3.63 – 3.55 (m, 1H), 3.54 – 3.49 (m, 2H), 3.48 – 3.40 (m, 3H), 3.15 – 3.04 (m, 1H), 2.69 – 2.54 (m, 1H), 1.98 – 1.86 (m, 2H), 1.56 – 1.37 (m, 2H), 1.20 (d, J = 4.5 Hz, 3H). EXAMPLE 124 1-((3aS*,6aR*)-3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 5: RT = 2.06 min, m/z = 382 [M+H]+, 92% 1H NMR (400 MHz, DMSO) δ 11.54 – 11.49 (m, 1H), 8.09 (s, 1H), 6.96 – 6.91 (m, 1H), 6.62 – 6.49 (m, 1H), 6.18 – 6.08 (m, 1H), 5.71 – 5.63 (m, 1H), 3.97 – 3.82 (m, 4H), 3.75 – 3.63 (m, 2H), 3.63 – 3.56 (m, 1H), 3.55 – 3.49 (m, 2H), 3.49 – 3.38 (m, 3H), 3.14 – 3.04 (m, 1H), 2.64 (m, 1H), 1.91 (m, 2H), 1.57 – 1.38 (m, 2H), 1.23 – 1.18 (m, 3H). EXAMPLE 125 1-((3aR*,6aS*)-3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 5: RT = 2.06 min, m/z = 382 [M+H]+, 96% 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 8.09 (s, 1H), 6.96 – 6.91 (m, 1H), 6.62 – 6.49 (m, 1H), 6.17 – 6.09 (m, 1H), 5.70 – 5.63 (m, 1H), 3.96 – 3.80 (m, 4H), 3.75 – 3.64 (m, 2H), 3.64 – 3.56 (m, 1H), 3.54 – 3.39 (m, 5H), 3.14 – 3.04 (m, 1H), 2.68 – 2.62 (m, 1H), 1.95 – 1.87 (m, 2H), 1.57 – 1.42 (m, 2H), 1.23 – 1.18 (m, 3H). EXAMPLE 126 1-((1R*,4R*,7R*)-7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 4: RT = 1.39 min, m/z = 368 [M+H]+, 91% 1H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 8.23 – 8.13 (m, 1H), 6.97 – 6.84 (m, 1H), 6.67 – 6.38 (m, 1H), 6.21 – 6.09 (m, 1H), 6.03 (s, 1H), 5.73 – 5.62 (m, 1H), 4.80 – 4.59 (m, 1H), 4.15 – 4.00 (m, 1H), 4.00 – 3.86 (m, 2H), 3.77 – 3.12 (m, 5H), 2.87 – 2.74 (m, 1H), 1.93 – 1.37 (m, 8H). EXAMPLE 127 1-((1S*,4S*,7S*)-7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 4: RT = 1.39 min, m/z = 368 [M+H]+, 98% 1H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 8.21 – 8.11 (m, 1H), 6.97 – 6.85 (m, 1H), 6.65 – 6.39 (m, 1H), 6.24 – 6.09 (m, 1H), 6.09 – 5.95 (m, 1H), 5.74 – 5.59 (m, 1H), 4.77 – 4.57 (m, 1H), 4.17 – 4.01 (m, 1H), 4.01 – 3.84 (m, 2H), 3.76 – 3.11 (m, 5H), 2.89 – 2.70 (m, 1H), 1.92 – 1.32 (m, 8H). EXAMPLE 128 (R)-1-(3,3-Dimethyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT = 2.17 min, m/z = 370 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 8.17 – 8.11 (m, 1H), 6.98 – 6.92 (m, 1H), 6.69 – 6.53 (m, 1H), 6.34 – 6.25 (m, 1H), 5.81 – 5.71 (m, 1H), 4.83 – 4.74 (m, 1H), 4.29 – 3.33 (m, 8H), 3.23 – 3.09 (m, 1H), 2.12 – 2.00 (m, 1H), 2.00 – 1.91 (m, 1H), 1.91 – 1.76 (m, 1H), 1.75 – 1.60 (m, 1H), 1.22 (s, 3H), 1.19 – 1.15 (m, 3H). EXAMPLE 129 1-((3aR,6aS)-3a,6a-dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 5: RT = 2.06 min, m/z = 396 [M+H]+, 98% 1H NMR (500 MHz, DMSO) δ 11.57 – 11.48 (m, 1H), 8.08 (s, 1H), 6.96 – 6.90 (m, 1H), 6.57 – 6.48 (m, 1H), 6.19 – 6.10 (m, 1H), 5.71 – 5.62 (m, 1H), 3.92 – 3.83 (m, 2H), 3.80 – 3.69 (m, 3H), 3.61 – 3.46 (m, 4H), 3.46 – 3.37 (m, 2H), 3.35 – 3.31 (m, 1H), 3.13 – 3.05 (m, 1H), 1.96 – 1.86 (m, 2H), 1.54 – 1.41 (m, 2H), 1.13 – 1.04 (m, 6H). EXAMPLE 130 1-(1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one LCMS 1: RT = 1.20 min, m/z = 354 [M+H]+, 92% 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.55 (td, J = 16.8, 10.3 Hz, 1H), 6.12 (ddd, J = 16.8, 5.6, 2.4 Hz, 1H), 5.66 (ddd, J = 12.8, 10.3, 2.4 Hz, 1H), 4.10 – 4.01 (m, 1H), 3.91 (td, J = 10.9, 5.6 Hz, 3H), 3.76 (d, J = 9.9 Hz, 1H), 3.73 – 3.62 (m, 1H), 3.53 (dt, J = 22.6, 11.8 Hz, 3H), 1.88 – 1.70 (m, 3H), 1.65 – 1.45 (m, 2H), 1.21 – 1.07 (m, 1H), 0.77 (td, J = 5.3, 2.1 Hz, 1H). EXAMPLE 131 1-((1S*,5R*)-1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one LCMS 2: RT = 0.92 min, m/z = 354 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.07 (d, J = 10.1 Hz, 1H), 6.57 (ddd, J = 16.8, 14.9, 10.5 Hz, 1H), 6.27 (ddd, J = 16.8, 3.6, 2.0 Hz, 1H), 5.75 (td, J = 10.2, 2.0 Hz, 1H), 4.28 (d, J = 10.7 Hz, 1H), 4.03 (q, J = 9.3 Hz, 3H), 3.89 – 3.75 (m, 2H), 3.73 – 3.58 (m, 3H), 3.24 (ddt, J = 11.5, 7.7, 4.3 Hz, 1H), 2.12 – 1.82 (m, 3H), 1.83 – 1.59 (m, 1H), 1.01 (dt, J = 18.2, 5.5 Hz, 1H), 0.90 (td, J = 7.3, 5.1 Hz, 1H). EXAMPLE 132 1-((1R*,5S*)-1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one LCMS 2: RT = 0.92 min, m/z = 354 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 2.2 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.57 (ddd, J = 16.8, 13.1, 10.5 Hz, 1H), 6.28 (ddd, J = 16.8, 3.0, 1.9 Hz, 1H), 5.76 (ddd, J = 10.9, 9.2, 2.0 Hz, 1H), 4.37 – 4.27 (m, 1H), 4.08 – 3.97 (m, 3H), 3.91 – 3.73 (m, 2H), 3.73 – 3.57 (m, 2H), 2.04 (ddt, J = 28.6, 9.1, 4.6 Hz, 1H), 1.97 – 1.85 (m, 3H), 1.83 – 1.60 (m, 2H), 1.06 (dt, J = 18.8, 5.5 Hz, 1H), 0.95 – 0.83 (m, 1H). EXAMPLE 133 1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 5: RT = 1.97 min, m/z = 374 [M+H]+, 100% 1H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 8.17 – 8.11 (m, 1H), 7.37 – 7.28 (m, 1H), 7.24 – 7.16 (m, 1H), 7.11 – 7.03 (m, 1H), 6.97 – 6.92 (m, 1H), 6.91 – 6.73 (m, 1H), 6.25 – 6.11 (m, 1H), 6.02 – 5.85 (m, 1H), 5.81 – 5.63 (m, 1H), 5.20 – 4.90 (m, 1H), 4.52 – 4.30 (m, 1H), 4.16 – 4.04 (m, 1H), 3.90 – 3.81 (m, 1H), 3.66 – 3.13 (m, 3H), 3.12 – 3.01 (m, 1H), 2.21 – 2.00 (m, 1H), 1.92 – 1.34 (m, 5H). EXAMPLE 134 1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-on LCMS 4: RT = 1.72 min, m/z = 384 [M+H]+, 99% 1H NMR (500 MHz, DMSO) δ 11.38 (s, 1H), 8.15 – 8.08 (m, 1H), 6.97 – 6.75 (m, 2H), 6.18 – 6.10 (m, 1H), 5.74 – 5.63 (m, 1H), 4.67 – 4.20 (m, 2H), 4.20 – 3.62 (m, 3H), 3.62 – 3.47 (m, 2H), 3.28 – 3.22 (m, 1H), 2.97 – 2.90 (m, 1H), 2.78 – 2.47 (m, 1H), 1.88 – 1.81 (m, 2H), 1.76 – 1.47 (m, 4H), 1.02 – 0.96 (m, 3H), 0.94 – 0.89 (m, 3H). EXAMPLE 135 (S*)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT = 1.72 min, m/z = 384 [M+H]+, 99% 1H NMR (500 MHz, DMSO) δ 11.38 (s, 1H), 8.15 – 8.08 (m, 1H), 6.93 – 6.87 (m, 1H), 6.87 – 6.79 (m, 1H), 6.18 – 6.10 (m, 1H), 5.74 – 5.63 (m, 1H), 4.62 – 4.22 (m, 2H), 4.15 – 3.63 (m, 3H), 3.62 – 3.49 (m, 2H), 3.27 – 3.18 (m, 1H), 2.97 – 2.90 (m, 1H), 2.79 – 2.49 (m, 1H), 1.88 – 1.81 (m, 2H), 1.79 – 1.44 (m, 4H), 0.99 (d, J = 12.8 Hz, 3H), 0.92 (d, J = 7.8 Hz, 3H). EXAMPLE 136 (R*)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT = 1.72 min, m/z = 384 [M+H]+, 99% 1H NMR (500 MHz, DMSO) δ 11.38 (s, 1H), 8.21 – 7.98 (m, 1H), 6.95 – 6.87 (m, 1H), 6.87 – 6.79 (m, 1H), 6.18 – 6.10 (m, 1H), 5.74 – 5.63 (m, 1H), 4.61 – 4.22 (m, 2H), 4.15 – 3.63 (m, 3H), 3.60 – 3.47 (m, 2H), 3.28 – 3.19 (m, 1H), 2.96 – 2.90 (m, 1H), 2.73 (t, J = 11.2 Hz, 1H), 1.88 – 1.78 (m, 2H), 1.77 – 1.44 (m, 4H), 0.99 (d, J = 12.7 Hz, 3H), 0.92 (d, J = 7.8 Hz, 3H). EXAMPLE 137 1-((3R,5R)-3-Fluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-on LCMS 5: RT = 1.91 min, m/z = 374 [M+H]+, 96% 1H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.24 – 8.04 (m, 1H), 6.94 – 6.87 (m, 1H), 6.86 – 6.75 (m, 1H), 6.18 – 6.08 (m, 1H), 5.90 – 5.79 (m, 1H), 5.75 – 5.65 (m, 1H), 5.13 – 4.90 (m, 1H), 4.57 – 4.40 (m, 2H), 4.29 – 4.16 (m, 1H), 3.97 – 3.83 (m, 2H), 3.64 – 3.02 (m, 4H), 3.02 – 1.94 (m, 3H), 1.91 – 1.80 (m, 2H), 1.65 – 1.44 (m, 2H). EXAMPLE 138 1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT = 2.10 min, m/z = 379 [M+H]+, 98% 1H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 7.16 (s, 1H), 6.74 – 6.62 (m, 1H), 6.49 – 6.37 (m, 1H), 6.16 (ddd, J = 7.7, 4.9, 2.9 Hz, 1H), 5.96 – 5.81 (m, 1H), 4.42 – 4.31 (m, 1H), 4.22 – 4.02 (m, 5H), 3.64 – 3.52 (m, 2H), 3.23 – 3.09 (m, 1H), 2.03 – 1.79 (m, 4H) EXAMPLE 139 (S*)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT = 2.20 min, m/z = 379 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.09 (s, 1H), 6.61 (ddd, J = 16.9, 10.4, 6.5 Hz, 1H), 6.35 (ddd, J = 16.8, 11.1, 1.8 Hz, 1H), 6.12 – 6.06 (m,1H), 5.82 (ddd, J = 21.5, 10.4, 1.8 Hz, 1H), 4.33 – 4.28 (m, 1H), 4.21 – 3.85 (m, 5H), 3.56 – 3.48 (m, 2H), 3.13 – 3.05 (m, 1H), 1.93 – 1.74 (m, 4H). EXAMPLE 140 (R*)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT = 2.20 min, m/z = 379 [M+H]+, 100% 1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.09 (s, 1H), 6.61 (ddd, J = 16.8, 10.4, 6.5 Hz, 1H), 6.35 (ddd, J = 16.8, 11.1, 1.8 Hz, 1H), 6.12 – 6.06 (m,1H), 5.82 (ddd, J = 21.5, 10.4, 1.8 Hz, 1H), 4.33 – 4.28 (m, 1H), 4.26 – 3.83 (m, 5H), 3.56 – 3.48 (m, 2H), 3.13 – 3.05 (m, 1H), 1.94 – 1.74 (m, 4H). EXAMPLE 141 1-((3R,5R)-3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-(trifluoromethyl)piperidin-1-yl)prop-2-en-1-one LCMS 5: RT = 2.38 min, m/z = 424 [M+H]+, 98% 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.19 – 8.11 (m, 1H), 6.97 – 6.45 (m, 2H), 6.24 – 5.91 (m, 1H), 5.87 – 5.37 (m, 2H), 4.59 – 4.39 (m, 1H), 4.38 – 4.20 (m, 1H), 4.20 – 4.00 (m, 1H), 3.98 – 3.77 (m, 2H), 3.63 – 3.36 (m, 4H), 3.25 – 2.98 (m, 2H), 2.94 – 2.69 (m, 1H), 2.46 – 2.25 (m, 1H), 2.04 – 1.91 (m, 1H), 1.83 – 1.74 (m, 1H), 1.68 – 1.58 (m, 1H), 1.47 – 1.34 (m, 1H). EXAMPLE 142 (S)-1-(4,4-Difluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT = 1.84 min, m/z = 391 [M+H]+, 99% 1H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.26 – 8.05 (m, 1H), 6.97 (s, 1H), 6.94 – 6.72 (m, 1H), 6.31 – 6.10 (m, 1H), 5.85 – 5.50 (m, 2H), 4.92 (s, 1H), 4.48 – 4.02 (m, 2H), 4.02 – 3.77 (m, 2H), 3.64 – 3.35 (m, 3H), 3.29 – 3.07 (m, 2H), 2.31 – 2.02 (m, 2H), 2.01 – 1.88 (m, 1H), 1.88 – 1.67 (m, 2H), 1.53 – 1.31 (m, 1H). EXAMPLE 143 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT = 2.10 min, m/z = 370 [M+H]+, 97% H NMR (400 MHz, MeOD) δ 8.20 – 8.14 (m, 1H), 6.94 – 6.90 (m, 1H), 6.75 – 6.58 (m, 1H), 6.37 – 6.27 (m, 1H), 5.81 – 5.73 (m, 1H), 4.81 – 4.66 (m, 2H), 4.66 – 4.47 (m, 2H), 4.16 – 4.00 (m, 1H), 3.90 – 3.51 (m, 4H), 3.29 – 3.20 (m, 1H), 2.50 – 2.32 (m, 1H), 2.32 – 2.14 (m, 1H), 2.14 – 1.93 (m, 2H), 1.77 – 1.57 (m, 1H), 1.48 – 1.28 (m, 1H), 1.26 – 1.18 (m, 3H), 1.17 – 1.09 (m, 3H). EXAMPLE 144 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT = 2.04 min, m/z = 370 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 8.19 – 8.15 (m, 1H), 6.95 – 6.90 (m, 1H), 6.74 – 6.59 (m, 1H), 6.39 – 6.25 (m, 1H), 5.80 – 5.74 (m, 1H), 4.79 – 4.62 (m, 2H), 4.09 – 4.00 (m, 1H), 3.90 – 3.52 (m, 4H), 3.29 – 3.18 (m, 1H), 2.54 – 2.35 (m, 1H), 2.33 – 2.12 (m, 1H), 2.12 – 1.96 (m, 2H), 1.72 – 1.52 (m, 1H), 1.52 – 1.33 (m, 1H), 1.24 (d, J = 6.2 Hz, 3H), 1.19 – 1.04 (m, 3H). EXAMPLE 145 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT = 2.02 min, m/z = 370 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 8.23 – 8.17 (m, 1H), 7.01 – 6.88 (m, 1H), 6.76 – 6.61 (m, 1H), 6.40 – 6.29 (m, 1H), 5.82 – 5.74 (m, 1H), 4.83 – 4.68 (m, 2H), 4.16 – 4.03 (m, 1H), 3.92 – 3.54 (m, 4H), 3.30 – 3.19 (m,1H), 2.53 – 2.35 (m, 1H), 2.35 – 2.15 (m, 1H), 2.14 – 1.94 (m, 2H), 1.80 – 1.65 (m, 1H), 1.42 – 1.30 (m, 1H), 1.23 (d, J = 6.2 Hz, 3H), 1.19 – 1.11 (m, 3H). EXAMPLE 146 1-((2R,3R)-2-Methyl-3-((5-(oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT = 1.58 min, m/z = 370 [M+H]+, 93% 1H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 8.16 – 8.07 (m, 1H), 6.95 – 6.89 (m, 1H), 6.68 – 6.53 (m, 1H), 6.22 – 6.12 (m, 1H), 5.84 – 5.73 (m, 1H), 5.72 – 5.64 (m, 1H), 4.72 – 4.47 (m, 2H), 3.85 – 3.73 (m, 2H), 3.73 – 3.60 (m, 2H), 3.60 – 3.47 (m, 1H), 3.45 – 3.35 (m, 1H), 2.30 – 2.09 (m, 1H), 2.03 (s, 4H), 1.93 – 1.75 (m, 3H), 1.74 – 1.53 (m, 1H), 1.03 – 0.92 (m, 3H). EXAMPLE 147 1-((2S,5R)-2-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 1: m/z = 369 [M+H]+, 95% 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 5.5 Hz, 1H), 6.84 – 6.71 (m, 1H), 6.38 (s, 1H), 6.21 (m, 1H), 5.76 (m, 1H), 4.11 – 3.98 (m, 2H), 3.73 – 3.61 (m, J = 11.9, 5.5, 2.0 Hz, 2H), 3.57 – 3.45 (m, J = 16.5 Hz, 1H), 3.28 – 3.16 (m, 2H), 2.83 – 2.67 (m, J = 33.1 Hz, 1H), 2.13 – 1.97 (m, 3H), 1.91 – 1.56 (m, 6H), 1.41 – 1.25 (m, 3H). EXAMPLE 148 1-((3aR,6aS)-5-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 1: RT = 1.20 min, m/z = 367 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 7.94 (d, J = 5.5 Hz, 1H), 7.06 (s, 1H), 6.73 – 6.61 (m, 2H), 6.31 (dd, J = 16.8, 1.9 Hz, 1H), 5.78 (dd, J = 10.4, 1.9 Hz, 1H), 4.04 – 3.91 (m, 3H), 3.87 (dd, J = 13.1, 8.3 Hz, 1H), 3.71 (dd, J = 11.1, 4.6 Hz, 1H), 3.64 (dd, J = 13.1, 4.5 Hz, 1H), 3.57 – 3.40 (m, 4H), 3.36 – 3.33 (m, 1H), 3.30 – 3.27 (m, 1H), 3.27 – 3.17 (m, 2H), 3.17 – 3.07 (m, 1H), 2.05 (dd, J = 13.2, 1.4 Hz, 2H), 1.64 (quintd, J = 11.9, 4.4 Hz, 2H). EXAMPLE 149 4-(((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT = 2.00 min, m/z = 398 [M+H]+, 98% 1H NMR (400 MHz, MeOD) δ 8.14 (s, 1H), 7.08 (s, 1H), 7.02 – 6.63 (m, 1H), 6.31 – 6.05 (m, 1H), 5.85 – 5.60 (m, 1H), 5.10 – 4.88 (m, 1H), 4.74 – 4.48 (m, 2H), 4.47 – 4.12 (m, 1H), 4.12 – 3.94 (m, 2H), 3.72 – 3.53 (m, 2H), 3.23 – 2.92 (m, 2H), 2.68 – 2.44 (m, 1H), 2.10 – 1.86 (m, 4H), 1.84 – 1.67 (m, 2H). EXAMPLE 150 4-((3aR,6aS)-5-Acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT = 2.20 min, m/z = 391 [M+H]+, 95% 1H NMR (400 MHz, MeOD) δ 11.388.29 (s, 1H), 7.27 (s, 1H), 6.68 (dd, J = 16.8, 10.5 Hz, 1H), 6.31 (dd, J = 16.8, 2.0 Hz, 1H), 5.78 (dd, J = 10.5, 2.0 Hz, 1H), 4.03 – 3.95 (m, 3H), 3.95 – 3.87 (m, 2H), 3.88 – 3.82 (m, 1H), 3.77 (dd, J = 11.2, 4.5 Hz, 1H), 3.66 (dd, J = 13.0, 4.5 Hz, 1H), 3.58 – 3.45 (m, 4H), 3.30 – 3.25 (m, 1H), 3.25 – 3.16 (m, 2H), 2.01 – 1.89 (m, J = 13.4 Hz, 2H), 1.76 – 1.64 (m, 2H). EXAMPLE 151 4-(((3R,6S)-1-Acryloyl-6-methylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT = 2.20 min, m/z = 391 [M+H]+, 95% 1H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 7.36 (s, 1H), 7.16 (dd, J = 16.8, 10.8 Hz, 1H), 6.47 (dd, J = 16.9, 1.7 Hz, 1H), 6.03 (dd, J = 10.8, 1.8 Hz, 1H), 4.91 (br b, 2H), 4.69 – 4.57 (m, 1H), 4.45 – 4.31 (m, 2H), 3.98 (t, J = 11.7 Hz, 2H), 3.55 (tt, J = 11.6, 3.3 Hz, 1H), 3.33 (br b, 1H), 2.56 – 2.48 (m, 1H), 2.34 (d, J = 13.2 Hz, 2H), 2.27 – 2.01 (m, 5H), 1.62 (d, J = 6.9 Hz, 3H). EXAMPLE 152 4-(((3R,5S)-1-Acryloyl-5-methylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT = 2.50 min, m/z = 394 [M+H]+, 99% 1H NMR (400 MHz, MeOD) δ 8.10 (s, 1H), 7.04 (s, 1H), 6.83 (br b, 1H), 6.17 (d, J = 17.0 Hz, 1H), 5.72 (d, J = 10.9 Hz, 1H), 4.85 (br s, 1H), 4.41 (br b, 1H), 4.05 (d, J = 11.6 Hz, 2H), 3.65 (t, J = 11.8 Hz, 2H), 3.17 (tt, J = 12.4, 3.4 Hz, 1H), 2.97 (s, J = 73.6 Hz, 1H), 2.72 (br b, 1H), 2.40 (d, J = 13.0 Hz, 1H), 2.28 (br b, 1H), 2.01 (d, J = 13.4 Hz, 2H), 1.84 – 1.70 (m, 3H), 1.29 (q, J = 11.8 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H). EXAMPLE 153 1-((3S,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)piperidin-1-yl)prop-2-en-1-one LCMS 1: RT = 2.70 min, m/z = 371 [M+H]+, 97% 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 7.11 (s, 1H), 6.94 – 6.78 (m, 1H), 6.13 (d, J = 16.6 Hz, 1H), 5.71 (dd, J = 10.5, 2.4 Hz, 1H), 5.16 (s, 1H), 4.69 (d, J = 12.2 Hz, 1H), 4.36 (dd, J = 48.5, 12.8 Hz, 1H), 4.03 – 3.88 (m, 3H), 3.44 (t, J = 11.6 Hz, 2H), 3.14 – 2.98 (m, 1H), 2.88 – 2.74 (m, 1H), 2.36 – 2.22 (m, 1H), 1.86 (d, J = 12.9 Hz, 2H), 1.81 – 1.57 (m, 4H), 1.38 (d, J = 10.8 Hz, 1H), 0.98 (d, J = 6.6 Hz, 3H). EXAMPLE 154 (S)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 3-yl)acrylamide LCMS 4: RT 1.11 min, m/z 342 [M+H]+, 97%. 1H NMR (400 MHz, DMSO) δ 11.59 – 11.45 (m, 1H), 8.40 – 8.27 (m, 1H), 8.10 (s, 1H), 7.02 – 6.90 (m, 1H), 6.28 – 6.17 (m, 1H), 6.15 – 6.02 (m, 1H), 5.66 – 5.54 (m, 1H), 4.44 – 4.28 (m, 1H), 3.98 – 3.85 (m, 3H), 3.85 – 3.74 (m, 1H), 3.74 – 3.63 (m, 1H), 3.57 – 3.40 (m, 3H), 3.16 – 3.00 (m, 1H), 2.24 – 2.05 (m, 1H), 1.99 – 1.79 (m, 3H), 1.63 – 1.39 (m, 2H). EXAMPLE 155 (R)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin- 3-yl)acrylamide LCMS 4: RT 1.43 min, m/z 356 [M+H]+, 100%. 1H NMR (400 MHz, DMSO) δ 11.78 – 11.58 (m, 1H), 8.28 (s, 1H), 8.17 – 8.03 (m, 1H), 7.18 – 7.05 (m, 1H), 6.30 – 6.16 (m, 1H), 6.16 – 6.01 (m, 1H), 5.67 – 5.53 (m, 1H), 4.02 – 3.86 (m, 3H), 3.86 – 3.76 (m, 1H), 3.75 – 3.65 (m, 1H), 3.65 – 3.49 (m, 2H), 3.18 – 3.00 (m, 1H), 2.93 – 2.78 (m, 1H), 2.74 – 2.61 (m, 1H), 2.10 – 1.76 (m, 4H), 1.76 – 1.35 (m, 4H). EXAMPLE 156 (S)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)acrylamide LCMS 4: RT 1.43 min, m/z 356 [M+H]+, 98% 1H NMR (400 MHz, DMSO) δ 11.79 – 11.58 (m, 1H), 8.28 (s, 1H), 8.15 – 8.06 (m, 1H), 7.17 – 7.03 (m, 1H), 6.32 – 6.15 (m, 1H), 6.15 – 6.02 (m, 1H), 5.64 – 5.53 (m, 1H), 4.06 – 3.87 (m, 3H), 3.87 – 3.76 (m, 1H), 3.73 – 3.64 (m, 1H), 3.64 – 3.50 (m, 2H), 3.16 – 3.00 (m, 1H), 2.94 – 2.77 (m, 1H), 2.74 – 2.59 (m, 1H), 2.11 – 1.79 (m, 4H), 1.79 – 1.32 (m, 4H). EXAMPLE 157 1-((1R*,4R*)-4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 4: RT 1.69 min, m/z 368 [M+H]+, 99%. 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.21 – 8.06 (m, 1H), 6.92 (s, 1H), 6.75 – 6.38 (m, 1H), 6.20 – 6.04 (m, 2H), 5.74 – 5.57 (m, 1H), 4.54 – 4.34 (m, 1H), 4.02 – 3.88 (m, 2H), 3.88 – 3.72 (m, 1H), 3.64 – 3.43 (m, 3H), 2.37 – 1.82 (m, 8H), 1.74 – 1.43 (m, 3H). EXAMPLE 158 1-((1S*,4S*)-4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 4: RT 1.69 min, m/z 368 [M+H]+, 100%. 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.17 – 8.07 (m, 1H), 6.92 (s, 1H), 6.76 – 6.38 (m, 1H), 6.23 – 6.06 (m, 2H), 5.73 – 5.60 (m, 1H), 4.57 – 4.36 (m, 1H), 4.01 – 3.89 (m, 2H), 3.89 – 3.74 (m, 1H), 3.65 – 3.42 (m, 3H), 2.36 – 1.74 (m, 8H), 1.74 – 1.46 (m, 3H). EXAMPLE 159 1-(4-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazin-1-yl)prop-2-en-1-one LCMS 1: RT 1.41 min, m/z 359 [M+H]+, 100%. 1H NMR (400 MHz, MeOD) δ 8.02 (d, J = 5.2 Hz, 1H), 7.24 (s, 1H), 6.84 (dd, J = 16.8, 10.6 Hz, 1H), 6.27 (dd, J = 16.8, 2.0 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 4.07 (dd, J = 11.0, 3.6 Hz, 2H), 3.65 (td, J = 12.1, 1.8 Hz, 3H), 3.48 – 3.36 (m, 7H), 2.06 (d, J = 12.9 Hz, 2H), 1.76 (qd, J = 12.3, 4.3 Hz, 2H), 1.28 (m, 1H). EXAMPLE 160 1-(5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one LCMS 5: RT 1.74 min, m/z 354 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.18 – 8.12 (m, 1H), 6.98 – 6.93 (m, 1H), 6.76 – 6.56 (m, 1H), 6.39 – 6.30 (m, 1H), 5.86 – 5.73 (m, 1H), 5.05 – 4.87 (m, 1H), 4.13 – 4.00 (m, 2H), 3.95 – 3.84 (m, 1H), 3.79 – 3.58 (m, 4H), 3.43 – 3.31 (m, 1H), 3.21 – 3.09 (m, 1H), 2.85 – 2.70 (m, 1H), 2.12 – 1.97 (m, 2H), 1.87 – 1.60 (m, 3H). EXAMPLE 161 1-((1R*,4R*,5R*)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one LCMS 5: RT 1.84 min, m/z 354 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.18 – 8.12 (m, 1H), 6.98 – 6.93 (m, 1H), 6.76 – 6.56 (m, 1H), 6.39 – 6.30 (m, 1H), 5.86 – 5.73 (m, 1H), 5.03 – 4.88 (m, 1H), 4.10 – 4.02 (m, 2H), 3.95 – 3.84 (m, 2H), 3.79 – 3.58 (m, 4H), 3.22 – 3.09 (m, 1H), 2.84 – 2.70 (m, 1H), 2.07 – 1.99 (m, 2H), 1.87 – 1.60 (m, 3H). EXAMPLE 162 1-((1S*,4S*,5S*)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one LCMS 5: RT 1.85 min, m/z 354 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.18 – 8.12 (m, 1H), 6.98 – 6.93 (m, 1H), 6.76 – 6.56 (m, 1H), 6.39 – 6.30 (m, 1H), 5.79 (m, 1H), 5.03 – 4.90 (m, 1H), 4.10 – 4.01 (m, 2H), 3.95 – 3.84 (m, 2H), 3.79 – 3.58 (m, 4H), 3.22 – 3.12 (m, 1H), 2.85 – 2.70 (m, 1H), 2.02 (d, J = 8.6 Hz, 2H), 1.87 – 1.60 (m, 3H) EXAMPLE 163 1-((1R*,4R*)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one LCMS 4: RT 1.46 min, m/z 368 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 8.17 (s, 1H), 7.08 – 6.95 (m, 1H), 6.87 – 6.48 (m, 1H), 6.25 – 6.01 (m, 1H), 5.76 – 5.61 (m, 1H), 4.72 – 4.38 (m, 2H), 4.03 – 3.68 (m, 5H), 3.59 – 3.39 (m, 3H), 3.10 – 2.95 (m, 1H), 2.24 – 2.07 (m, 1H), 2.05 – 1.70 (m, 5H), 1.65 – 1.39 (m, 2H). EXAMPLE 164 1-((1S*,4S*)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one LCMS 4: RT 1.45 min, m/z 368 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 8.16 (s, 1H), 7.03 – 6.98 (m, 1H), 6.83 – 6.53 (m, 1H), 6.21 – 6.07 (m, 1H), 5.74 – 5.62 (m, 1H), 4.70 – 4.37 (m, 2H), 4.00 – 3.68 (m, 5H), 3.58 – 3.41 (m, 3H), 3.07 – 2.96 (m, 1H), 2.22 – 2.09 (m, 1H), 2.00 – 1.74 (m, 5H), 1.57 – 1.42 (m, 2H). EXAMPLE 165 N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4- yl)cyanamide LCMS 4: RT 1.29 min, m/z 327 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.72 – 11.67 (m, 1H), 8.27 (s, 1H), 7.14 – 7.09 (m, 1H), 7.06 – 7.01 (m, 1H), 3.99 – 3.91 (m, 2H), 3.79 – 3.73 (m, 2H), 3.52 – 3.45 (m, 2H), 3.34 – 3.21 (m, 1H), 3.06 – 2.92 (m, 3H), 2.02 – 1.94 (m, 4H), 1.67 – 1.48 (m, 4H). EXAMPLE 166 (R)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)prop-2-en-1-one LCMS 5: RT 2.1 min, m/z 370 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 8.08 (s, 1H), 6.87 – 6.72 (m, 2H), 6.20 – 6.10 (m, 1H), 5.76 – 5.64 (m, 2H), 4.36 – 4.21 (m, 1H), 3.94 – 3.86 (m, 2H), 3.83 – 3.15 (m, 7H), 2.19 – 1.98 (m, 1H), 1.96 – 1.62 (m, 7H), 1.62 – 1.47 (m, 2H). EXAMPLE 167 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-oxa-2,8- diazaspiro[3.5]nonan-8-yl)prop-2-en-1-one LCMS 5: RT 1.9 min, m/z 384 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 8.17 (s, 1H), 6.99 – 6.95 (m, 1H), 6.94 – 6.67 (m, 1H), 6.28 – 6.12 (m, 1H), 5.77 – 5.71 (m, 1H), 4.16 – 4.00 (m, 4H), 3.97 – 3.87 (m, 2H), 3.88 – 3.76 (m, 2H), 3.69 – 3.54 (m, 4H), 3.52 – 3.39 (m, 2H), 2.98 – 2.85 (m, 1H), 1.96 – 1.88 (m, 2H), 1.59 – 1.46 (m, 2H). EXAMPLE 168 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.9 min, m/z 342 [M+H]+, 98%; 1H NMR (400 MHz, DMSO_100ºC) δ 7.82 (s, 1H), 7.55 (d, J = 2.5 Hz, 1H), 6.66 – 6.45 (m, 2H), 6.25 (br, 1H), 6.14 (dd, J = 16.8, 2.1 Hz, 1H), 5.71 – 5.57 (m, 1H), 4.81 (br, 1H), 3.92 (d, J = 10.8 Hz, 3H), 3.78 – 3.46 (m, 5H), 3.39 – 3.28 (m, 1H), 2.25 (d, J = 60.6 Hz, 2H), 1.84 – 1.65 (m, 4H). EXAMPLE 169 (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 1: RT 2.10 min, m/z 356 [M+H]+, 100%; 1H NMR (400 MHz, DMSO_100ºC) δ 7.82 (s, 1H), 7.55 (d, J = 2.5 Hz, 1H), 6.66 – 6.45 (m, 2H), 6.25 (br, 1H), 6.14 (dd, J = 16.8, 2.1 Hz, 1H), 5.71 – 5.57 (m, 1H), 4.81 (br, 1H), 3.92 (d, J = 10.8 Hz, 3H), 3.78 – 3.46 (m, 5H), 3.39 – 3.28 (m, 1H), 2.25 (d, J = 60.6 Hz, 2H), 1.84 – 1.65 (m, 6H). EXAMPLE 170 (R)-1-(3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.05 min, m/z 359 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 7.88 (dd, J = 6.3, 1.9 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.62 (ddd, J = 20.0, 16.8, 10.4 Hz, 1H), 6.38 – 6.22 (m, 1H), 5.76 (ddd, J = 15.5, 10.4, 2.0 Hz, 1H), 4.76 – 4.56 (m, 1H), 4.08 – 3.95 (m, 2H), 3.90 (dd, J = 11.1, 5.2 Hz, 1H), 3.84 – 3.70 (m, 2H), 3.70 – 3.42 (m, 3H), 3.11 (ddd, J = 11.7, 7.5, 3.0 Hz, 1H), 2.50 – 2.10 (m, 3H), 2.01 – 1.84 (m, 2H), 1.77 – 1.60 (m, 2H), 1.31 (d, J = 17.8 Hz, 1H). EXAMPLE 171 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 1: RT 1.80 min, m/z 371 [M+H]+, 94%; 1H NMR (400 MHz, DMSO) δ 11.48 (d, J = 3.0 Hz, 1H), 8.06 (dd, J = 5.1, 1.9 Hz, 1H), 7.24 (t, J = 2.6 Hz, 1H), 6.81 (dd, J = 16.7, 10.3 Hz, 1H), 6.48 (dd, J = 16.8, 10.2 Hz, 1H), 6.21 (dt, J = 16.7, 2.2 Hz, 1H), 5.71 (ddd, J = 10.3, 3.8, 2.5 Hz, 1H), 4.89 (d, J = 56.3 Hz, 1H), 4.21 (d, J = 17.4 Hz, 1H), 4.04 – 3.92 (m, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.68 (d, J = 8.8 Hz, 1H), 3.61 (d, J = 8.9 Hz, 1H), 3.57 – 3.46 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 3.08 (s, 1H), 2.15 (d, J = 9.8 Hz, 1H), 2.11 – 2.03 (m, 1H), 2.03 – 1.90 (m, 2H), 1.82 (q, J = 6.3 Hz, 2H), 1.36 (qd, J = 12.3, 4.3 Hz, 1H). EXAMPLE 172 1-((1R,4R)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 1: RT 1.8 min, m/z 371 [M+H]+, 95%; 1H NMR (400 MHz, MeOD) δ 8.09 (d, J = 5.4 Hz, 1H), 7.28 (s, 1H), 6.89 (dd, J = 16.7, 10.5 Hz, 1H), 6.61 (dd, J = 16.8, 10.2 Hz, 1H), 6.50 – 6.39 (m, 1H), 5.97 – 5.83 (m, 1H), 5.58 (s, 1H), 4.40 (d, J = 12.6 Hz, 1H), 4.18 (d, J = 11.9 Hz, 1H), 4.07 (d, J = 11.2 Hz, 1H), 3.98 (d, J = 9.1 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H), 3.76 – 3.59 (m, 3H), 3.55 – 3.47 (m, 1H), 3.37 – 3.25 (m, 1H), 2.39 (dd, J = 21.8, 10.0 Hz, 1H), 2.17 (d, J = 11.7 Hz, 1H), 2.03 (p, J = 3.3 Hz, 1H), 1.81 (m, 2H), 1.64 – 1.49 (m, 1H), 1.46 (dd, J = 6.7, 3.5 Hz, 2H), 1.11 (t, J = 7.0 Hz, 1H). EXAMPLE 173 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one LCMS 5: RT 1.90 min, 368 m/z [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.10 (s, 1H), 6.99 – 6.94 (m, 1H), 6.92 – 6.62 (m, 1H), 6.15 – 6.05 (m, 1H), 5.74 – 5.61 (m, 1H), 5.35 – 4.91 (m, 1H), 4.91 – 4.83 (m, 1H), 4.28 – 3.82 (m, 4H), 3.78 – 3.67 (m, 1H), 3.56 – 3.44 (m, 2H), 3.19 – 3.07 (m, 1H), 3.07 – 2.55 (m, 1H), 2.22 – 2.14 (m, 1H), 2.04 – 1.85 (m, 3H), 1.82 – 1.51 (m, 3H), 1.50 – 1.37 (m, 1H). EXAMPLE 174 1-((1S*,5R*)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one LCMS 5: RT 1.92 min, 368 m/z [M+H]+, 93%; 1H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.92 – 6.64 (m, 1H), 6.15 – 6.05 (m, 1H), 5.74 – 5.61 (m, 1H), 5.33 – 5.26 (m, 1H), 4.91 – 4.84 (m, 1H), 4.25 – 4.15 (m, 1H), 3.97 – 3.83 (m, 4H), 3.78 – 3.67 (m, 1H), 3.56 – 3.44 (m, 2H), 3.16 – 3.07 (m, 1H), 2.21 – 2.14 (m, 1H), 2.02 – 1.84 (m, 3H), 1.81 – 1.53 (m, 3H), 1.50 – 1.37 (m, 1H). EXAMPLE 175 1-((1R*,5S*)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one LCMS 5: RT 1.91 min, 368 m/z [M+H]+, 95%; 1H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.13 – 8.06 (m, 1H), 6.99 – 6.94 (m, 1H), 6.92 – 6.64 (m, 1H), 6.15 – 6.05 (m, 1H), 5.74 – 5.61 (m, 1H), 5.32 – 4.92 (m, 1H), 4.88 (s, 1H), 4.25 – 4.15 (m, 1H), 3.96 – 3.82 (m, 4H), 3.78 – 3.67 (m, 1H), 3.56 – 3.44 (m, 2H), 3.16 – 3.07 (m, 1H), 3.06 – 2.96 (m, 1H), 2.21 – 2.14 (m, 1H), 2.02 – 1.84 (m, 3H), 1.80 – 1.52 (m, 2H), 1.50 – 1.37 (m, 1H). EXAMPLE 176 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-oxa-2,5- diazaspiro[3.5]nonan-5-yl)prop-2-en-1-one LCMS 4: RT 1.26 min, 384 m/z [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.00 – 6.95 (m, 1H), 6.72 – 6.61 (m, 1H), 6.31 – 6.22 (m, 1H), 5.81 – 5.73 (m, 1H), 4.49 – 4.42 (m, 2H), 4.38 – 4.31 (m, 2H), 4.09 – 4.00 (m, 2H), 3.92 (s, 2H), 3.72 – 3.59 (m, 6H), 3.16 – 2.99 (m, 1H), 2.11 – 2.03 (m, 2H), 1.74 – 1.59 (m, 2H). EXAMPLE 177 4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine- 1-carbonitrile LCMS 5: RT 1.94 min, m/z 327 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.40 – 11.30 (m, 1H), 8.07 (s, 1H), 6.85 (d, J = 2.3 Hz, 1H), 5.82 (d, J = 8.0 Hz, 1H), 4.32 – 4.18 (m, 1H), 3.94 – 3.86 (m, 2H), 3.61 – 3.50 (m, 2H), 3.46 – 3.37 (m, 3H), 3.22 – 3.11 (m, 2H), 1.96 – 1.89 (m, 2H), 1.87 – 1.81 (m, 2H), 1.81 – 1.70 (m, 2H), 1.61 – 1.46 (m, 2H). EXAMPLE 178 (R)-4-((1-Acryloylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.35 min, 359 m/z [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.10 (s, 1H), 7.04 (s, 1H), 6.86 (dd, J = 16.8, 10.6 Hz, 1H), 6.68 (dd, J = 16.7, 10.7 Hz, 1H), 6.24 (d, J = 16.7 Hz, 1H), 6.03 (d, J = 17.1 Hz, 1H), 5.80 (d, J = 11.1 Hz, 1H), 5.53 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 26.5 Hz, 1H), 4.13 – 3.70 (m, 4H), 3.70 – 3.51 (m, 2H), 3.05 (s, 1H), 2.20 (td, J = 8.7, 4.3 Hz, 1H), 1.98 (d, J = 13.5 Hz, 4H), 1.77 (d, J = 4.7 Hz, 4H). EXAMPLE 179 (R)-4-((1-Acryloylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.23 min, 413 m/z [M+H]+, 99.6%; 1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.64 (ddd, J = 16.8, 10.4, 8.5 Hz, 2H), 6.33 (dd, J = 10.3, 1.9 Hz, 1H), 5.79 (ddd, J = 10.0, 7.8, 1.9 Hz, 1H), 5.18 – 5.07 (m, 1H), 5.07 – 4.98 (m, 1H), 4.14 – 3.92 (m, 2H), 3.92 – 3.75 (m, 2H), 3.73 – 3.63 (m, 1H), 3.63 – 3.42 (m, 2H), 3.11 (t, J = 12.0 Hz, 2H), 2.44 (dddd, J = 35.9, 14.2, 12.1, 6.9 Hz, 1H), 2.25 (d, J = 5.2 Hz, 1H), 1.92 (t, J = 10.5 Hz, 2H), 1.80 – 1.59 (m, 2H). EXAMPLE 180 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-yn-1-one LCMS 1: RT 1.32 min, m/z 369 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.03 (dd, J = 5.4, 4.1 Hz, 1H), 7.20 (s, 1H), 4.30 (s, 1H), 4.15 – 4.05 (m, 1H), 4.04 – 3.95 (m, 2H), 3.94 – 3.73 (m, 2H), 3.67 – 3.52 (m, 4H), 3.48 – 3.32 (m, 2H), 3.27 – 3.18 (m, 1H), 2.31 (dd, J = 16.1, 10.0 Hz, 1H), 2.21 – 2.04 (m, 2H), 2.01 – 1.88 (m, 2H), 1.53 – 1.42 (m, 2H). EXAMPLE 181 1-((3R,5R)-3-Methoxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 5: RT 1.97 min, 386 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.37 (m, 1H), 8.15 – 8.07 (m, 1H), 6.88 (s, 1H), 6.86 – 6.61 (m, 1H), 6.15 – 6.02 (m, 1H), 5.74 – 5.55 (m, 2H), 4.49 – 4.38 (m, 1H), 4.25 – 3.82 (m, 4H), 3.60 – 3.47 (m, 3H), 3.37 (d, J = 0.9 Hz, 1H), 3.28 – 3.26 (m, 3H), 3.24 – 3.11 (m, 2H), 2.13 – 1.94 (m, 2H), 1.87 – 1.79 (m, 2H), 1.61 – 1.47 (m, 2H). EXAMPLE 182 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one LCMS 5: RT 2.05 min, 354 m/z [M+H]+, 97%; 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.12 (s, 1H), 6.95 – 6.90 (m, 1H), 6.79 – 6.45 (m, 2H), 6.22 – 6.12 (m, 1H), 5.72 – 5.62 (m, 1H), 4.73 – 4.70 (m, 1H), 4.66 – 4.62 (m, 1H), 3.95 – 3.87 (m, 2H), 3.86 – 3.62 (m, 2H), 3.59 – 3.49 (m, 2H), 2.39 – 2.33 (m, 1H), 2.23 – 2.15 (m, 1H), 2.00 – 1.92 (m, 2H), 1.92 – 1.82 (m, 2H), 1.63 – 1.48 (m, 2H). EXAMPLE 183 1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.5]octan-5-yl)prop-2-en-1-one LCMS 5: RT 2.24 min, 382 m/z [M+H]+, 93%; 1H NMR (400 MHz, DMSO) δ 11.43 – 11.36 (m, 1H), 8.11 (d, J = 15.3 Hz, 1H), 6.94 – 6.89 (m, 1H), 6.87 – 6.50 (m, 1H), 6.20 – 5.96 (m, 1H), 5.77 – 5.39 (m, 2H), 4.60 – 4.42 (m, 1H), 4.04 – 3.67 (m, 5H), 3.58 – 3.25 (m, 1H), 3.06 – 2.96 (m, 1H), 1.97 – 1.45 (m, 8H), 0.65 – 0.24 (m, 4H). EXAMPLE 184 (R*)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.5]octan-5-yl)prop-2-en-1-one LCMS 4: RT 1.53 min, 382 m/z [M+H]+, 95%; 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.11 (d, J = 15.3 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 6.87 – 6.54 (m, 1H), 6.23 – 5.98 (m, 1H), 5.76 – 5.48 (m, 2H), 4.57 – 4.38 (m, 1H), 3.94 – 3.69 (m, 4H), 3.60 – 3.39 (m, 4H), 3.08 – 2.97 (m, 1H), 1.95 – 1.44 (m, 3H), 0.67 – 0.18 (m, 4H). EXAMPLE 185 (S*)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5- azaspiro[2.5]octan-5-yl)prop-2-en-1-one LCMS 4: RT 1.53 min, 382 m/z [M+H]+, 95%; 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.11 (d, J = 15.3 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 6.87 – 6.54 (m, 1H), 6.23 – 5.98 (m, 1H), 5.76 – 5.48 (m, 2H), 4.57 – 4.38 (m, 1H), 3.94 – 3.69 (m, 4H), 3.60 – 3.39 (m, 4H), 3.08 – 2.97 (m, 1H), 1.95 – 1.44 (m, 6H), 0.67 – 0.18 (m, 4H). EXAMPLE 186 1-((3aR,6aR)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)prop-2-en-1-one LCMS 5: RT 1.99 min, 368 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.64 – 11.55 (m, 1H), 8.17 – 8.10 (m, 1H), 7.06 – 6.98 (m, 1H), 6.71 – 6.52 (m, 1H), 6.22 – 6.08 (m, 1H), 5.74 – 5.63 (m, 1H), 4.69 – 4.27 (m, 1H), 3.95 – 3.78 (m, 4H), 3.72 – 3.62 (m, 3H), 3.62 – 3.50 (m, 1H), 3.50 – 3.38 (m, 2H), 3.12 – 2.89 (m, 2H), 2.18 – 1.70 (m, 4H), 1.65 – 1.35 (m, 2H). EXAMPLE 187 1-((3aS,6aS)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)prop-2-en-1-one LCMS 5: RT 1.94 min, 368 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.64 – 11.55 (m, 1H), 8.17 – 8.10 (m, 1H), 7.06 – 6.98 (m, 1H), 6.71 – 6.52 (m, 1H), 6.22 – 6.08 (m, 1H), 5.74 – 5.63 (m, 1H), 4.83 – 4.32 (m, 1H), 4.00 – 3.77 (m, 4H), 3.77 – 3.61 (m, 3H), 3.61 – 3.48 (m, 1H), 3.48 – 3.36 (m, 2H), 3.09 – 2.91 (m, 2H), 2.15 – 1.70 (m, 4H), 1.62 – 1.41 (m, 2H). EXAMPLE 188 1-(7-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one LCMS 4: RT 1.14 min, 384 m/z [M+H]+, 93%; 1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.18 (s, 1H), 7.08 – 7.02 (m, 1H), 6.88 – 6.77 (m, 1H), 6.25 – 6.16 (m, 1H), 5.80 – 5.73 (m, 1H), 4.51 (s, 1H), 4.32 (s, 1H), 4.26 (d, J = 13.0 Hz, 2H), 3.95 (d, J = 11.3 Hz, 2H), 3.92 – 3.83 (m, 2H), 3.67 – 3.54 (m, 2H), 3.54 – 3.45 (m, 3H), 3.45 – 3.37 (m, 1H), 3.20 – 3.08 (m, 1H), 1.98 – 1.94 (m, 2H), 1.57 – 1.41 (m, 2H). EXAMPLE 189 1-((3R,4R)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.7 min, m/z 372 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.16 (s, 1H), 6.89 (td, J = 2.4, 0.9 Hz, 1H), 6.60 (ddd, J = 16.7, 10.3, 7.3 Hz, 1H), 6.15 (ddd, J = 16.8, 4.6, 2.4 Hz, 1H), 5.94 (dd, J = 10.2, 5.9 Hz, 1H), 5.68 (td, J = 10.3, 2.4 Hz, 1H), 4.69 (dt, J = 38.8, 3.5 Hz, 1H), 4.21 – 4.00 (m, 2H), 3.89 (ddd, J = 27.5, 11.3, 5.8 Hz, 2H), 3.80 – 3.57 (m, 3H), 3.52 – 3.40 (m, 2H), 3.38 (d, J = 5.4 Hz, 3H), 3.17 (d, J = 5.3 Hz, 1H), 1.81 (t, J = 14.7 Hz, 2H), 1.60 (q, J = 12.0 Hz, 1H), 1.52 – 1.37 (m, 1H). EXAMPLE 190 1-((3S,4S)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.35 min, 372 m/z [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 11.46 – 11.40 (m, 1H), 8.16 (s, 1H), 6.94 – 6.86 (m, 1H), 6.67 – 6.53 (m, 1H), 6.20 – 6.10 (m, 1H), 5.98 – 5.90 (m, 1H), 5.73 – 5.63 (m, 1H), 4.82 – 4.61 (m, 1H), 4.23 – 4.05 (m, 1H), 3.97 – 3.80 (m, 3H), 3.79 – 3.40 (m, 5H), 3.40 – 3.35 (m, 3H), 3.31 – 3.23 (m, 1H), 1.90 – 1.73 (m, 2H), 1.66 – 1.54 (m, 1H), 1.52 – 1.38 (m, 1H). EXAMPLE 191 1-((3S,4S)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.5 min, 370 m/z [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.46 – 11.40 (m, 1H), 8.16 (s, 1H), 6.94 – 6.86 (m, 1H), 6.67 – 6.53 (m, 1H), 6.20 – 6.10 (m, 1H), 5.98 – 5.90 (m, 1H), 5.73 – 5.63 (m, 1H), 4.82 – 4.61 (m, 1H), 4.23 – 4.05 (m, 1H), 3.97 – 3.80 (m, 3H), 3.79 – 3.40 (m, 5H), 3.40 – 3.35 (m, 3H), 3.31 – 3.23 (m, 1H), 1.90 – 1.73 (m, 2H), 1.66 – 1.54 (m, 1H), 1.52 – 1.38 (m, 1H). EXAMPLE 192 (R)-1-(3-(Methyl(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.4 min, m/z 356 [M+H]+, 93%; 1H NMR (400 MHz, DMSO_100ºC) δ 10.99 (bs, 1H), 8.31 (s, 1H), 7.06 (s, 1H), 6.59 – 6.48 (m, 1H), 6.10 (dd, J = 16.8, 2.3 Hz, 1H), 5.62 (d, J = 10.9 Hz, 1H), 4.51 (bs, 1H), 3.93 (td, J = 11.8, 1.9 Hz, 2H), 3.88 – 3.77 (m, 1H), 3.75 – 3.62 (m, 1H), 3.56 – 3.44 (m, 4H), 3.17 – 3.05 (m, 1H), 2.96 (s, 3H), 2.24 (bs, 1H), 2.14 (bs, 1H), 1.96 (d, J = 12.8 Hz, 2H), 1.67 – 1.47 (m, 2H). EXAMPLE 193 1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azetidin-1-yl)prop-2-en-1-one. LCMS 1: RT 1.2 min, m/z 328 [M+H]+, 86%; 1H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 8.12 (s, 1H), 6.92 (s, 1H), 6.72 (d, J = 6.6 Hz, 1H), 6.37 (dd, J = 17.0, 10.3 Hz, 1H), 6.12 (dd, J = 17.0, 2.3 Hz, 1H), 5.67 (dd, J = 10.3, 2.3 Hz, 1H), 4.91 (s, 1H), 4.57 (t, J = 8.3 Hz, 1H), 4.30 – 4.21 (m, 1H), 4.21 – 4.13 (m, 2H), 4.01 – 3.91 (m, 1H), 3.57 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.8 Hz, 3H), 1.55 (d, J = 12.4 Hz, 3H). EXAMPLE 194 (R)-1-(3-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-en-1-one LCMS 1: RT 1.19 min, 356 m/z [M+H]+, 99.5%; 1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 7.12 (s, 1H), 6.92 – 6.73 (m, 1H), 6.27 (d, J = 16.7 Hz, 1H), 5.79 (dd, J = 10.6, 2.0 Hz, 1H), 4.19 (d, J = 6.5 Hz, 2H), 4.14 – 3.94 (m, 3H), 3.82 (m, 2H), 3.70 – 3.56 (m, 3H), 3.56 – 3.41 (m, 3H), 3.12 (t, J = 11.5 Hz, 1H), 2.19 (d, J = 12.7 Hz, 1H), 2.02 (d, J = 12.2 Hz, 1H), 1.84 (qd, J = 12.0, 4.3 Hz, 1H), 1.54 (dq, J = 21.1, 6.4 Hz, 1H), 1.12 (t, J = 6.6 Hz, 3H). EXAMPLE 195 rac-1-((1R,4R,6R)-6-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 5: RT 1.82 min, 368 m/z [M+H]+, 93%; 1H NMR (400 MHz, DMSO) δ 11.49 – 11.41 (m, 1H), 8.04 (s, 1H), 7.91 (d, J = 6.8 Hz, 1H), 6.98 – 6.93 (m, 1H), 6.11 – 6.00 (m, 1H), 5.96 – 5.86 (m, 1H), 5.46 – 5.39 (m, 1H), 5.06 – 5.01 (m, 1H), 4.31 – 4.20 (m, 1H), 3.91 – 3.81 (m, 2H), 3.64 – 3.38 (m, 4H), 3.14 – 3.04 (m, 1H), 2.63 – 2.58 (m, 1H), 2.19 – 2.05 (m, 1H), 2.03 – 1.95 (m, 1H), 1.82 – 1.73 (m, 1H), 1.71 – 1.56 (m, 2H), 1.53 – 1.37 (m, 2H), 1.26 – 1.17 (m, 1H). EXAMPLE 196 rac-1-((1R,4R,6S)-6-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one LCMS 5: RT 1.68 min, 368 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 6.91 – 6.84 (m, 1H), 6.63 – 6.52 (m, 1H), 6.28 – 6.14 (m, 1H), 5.97 – 5.88 (m, 1H), 5.85 – 5.75 (m, 1H), 5.29 – 5.19 (m, 1H), 4.73 – 4.43 (m, 2H), 3.93 – 3.70 (m, 2H), 3.63 – 3.32 (m, 3H), 3.14 – 3.09 (m, 1H), 2.66 – 2.54 (m, 1H), 1.84 – 1.65 (m, 4H), 1.65 – 1.31 (m, 2H), 1.25 – 1.12 (m, 1H). EXAMPLE 197 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- azabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one LCMS 4: RT 1.70 min, 382 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.13 – 8.06 (m, 1H), 6.92 – 6.87 (m, 1H), 6.79 – 6.48 (m, 1H), 6.21 – 6.06 (m, 1H), 5.73 – 5.58 (m, 1H), 5.32 – 5.25 (m, 1H), 4.48 – 4.06 (m, 2H), 4.00 – 3.86 (m, 3H), 3.65 – 3.41 (m, 2H), 3.22 – 3.10 (m, 1H), 2.45 – 2.24 (m, 2H), 1.99 – 1.77 (m, 8H), 1.66 – 1.51 (m, 2H). EXAMPLE 198 (R)-1-(3-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.6 min, 370 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 8.09 (d, J = 23.1 Hz, 1H), 6.97 – 6.47 (m, 2H), 6.25 – 5.79 (m, 1H), 5.79 – 5.27 (m, 1H), 5.27 – 5.03 (m, 1H), 4.81 – 4.43 (m, 1H), 4.18 – 3.70 (m, 3H), 3.62 – 2.81 (m, 6H), 2.29 – 1.29 (m, 10H). EXAMPLE 199 1-((3R,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.8 min, m/z 357 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 1.2 Hz, 1H), 7.04 (dd, J = 2.3, 0.8 Hz, 1H), 6.67 (dd, J = 16.8, 10.4 Hz, 0.5H), 6.51 (dd, J = 16.8, 10.4 Hz, 0.5H), 6.27 (ddd, J = 16.8, 14.9, 2.0 Hz, 1H), 5.99 (t, J = 3.8 Hz, 1H), 5.74 (ddd, J = 34.2, 10.5, 2.0 Hz, 1H), 4.09 – 3.86 (m, 4H), 3.77 (dd, J = 14.1, 3.7 Hz, 1H), 3.61 – 3.45 (m, 3H), 3.41 – 3.33 (m, 1H), 3.09 (dtd, J = 11.3, 7.5, 3.7 Hz, 1H), 2.73 (dddd, J = 39.1, 14.9, 8.0, 3.9 Hz, 1H), 1.98 – 1.61 (m, 4H), 1.23 (dd, J = 6.8, 2.8 Hz, 3H). EXAMPLE 200 1-((3S,4S)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT 1.79 min, 360 m/z [M+H]+, 97%; 1H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 8.19 (s, 1H), 6.92 (m, 1H), 6.71 – 6.57 (m, 1H), 6.27 – 6.14 (m, 1H), 6.10 – 5.98 (m, 1H), 5.77 – 5.70 (m, 1H), 5.51 – 5.27 (m, 1H), 4.79 (m, 1H), 4.07 – 3.58 (m, 6H), 3.54 – 3.38 (m, 2H), 1.89 – 1.77 (m, 2H), 1.66 – 1.38 (m, 2H). EXAMPLE 201 4-(4-Acryloylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine-5-carbonitrile LCMS 1: RT 1.31 min, 366 m/z [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 12.11 (s, 1H), 8.38 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 16.7, 10.4 Hz, 1H), 6.18 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H), 3.95 (dd, J = 11.2, 3.3 Hz, 2H), 3.79 (s, 2H), 3.51 (t, J = 11.1 Hz, 2H), 3.32 (s, 7H), 1.92 (d, J = 14.1 Hz, 2H), 1.63 (qd, J = 12.5, 4.2 Hz, 2H). EXAMPLE 202 1-((3R,5R)-3-Hydroxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.0 min, m/z 372 [M+H]+, 90%; 1H NMR (400 MHz, MeOD) δ 8.15 (d, J = 12.9 Hz, 1H), 6.90 (s, 1H), 6.84 (dd, J = 16.8, 10.6 Hz, 0.5H), 6.52 (dd, J = 16.8, 10.6 Hz, 0.5H), 6.30 – 6.21 (m, 0.5H), 6.03 (dd, J = 16.7, 1.9 Hz, 0.5H), 5.80 (dd, J = 10.6, 2.0 Hz, 0.5H), 5.49 – 5.42 (m, 0.5H), 4.62 (d, J = 19.9 Hz, 1H), 4.19 – 3.79 (m, 5H), 3.78 – 3.44 (m, 3H), 3.27 – 3.17 (m, 1H), 3.16 – 2.97 (m, 1H), 2.23 (d, J = 15.9 Hz, 1H), 2.04 – 1.84 (m, 3H), 1.82 – 1.55 (m, 1H), 1.42 – 1.26 (m, 1H). EXAMPLE 203 1-((R)-3-((5-((2R*,4R*)-2-Methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.44 min, 370 m/z [M+H]+, 96%; 1H NMR (400 MHz, MeOD) δ 8.18 – 8.10 (m, 1H), 6.89 (s, 1H), 6.88 – 6.43 (m, 1H), 6.32 – 5.95 (m, 1H), 5.87 – 5.38 (m, 1H), 4.48 – 4.28 (m, 1H), 4.12 – 3.98 (m, 1H), 3.97 – 3.44 (m, 6H), 3.18 – 3.02 (m, 1H), 2.17 – 1.58 (m, 7H), 1.41 – 1.16 (m, 4H). EXAMPLE 204 1-((R)-3-((5-((2S*,4S*)-2-Methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.47 min, m/z 370 [M+H]+, 98%; 1H NMR (400 MHz, DMSO, 353K) δ 11.37 (s, 1H), 8.11 (d, J = 12.0 Hz, 1H), 6.92 – 6.59 (m, 2H), 6.16 – 6.01 (m, 1H), 5.73 – 5.50 (m, 2H), 4.37 – 4.12 (m, 1H), 3.94 – 3.85 (m, 2H), 3.75 – 3.44 (m, 5H), 3.43 – 3.31 (m, 1H), 3.21 – 3.06 (m, 1H), 2.02 – 1.38 (m, 6H), 1.30 – 1.14 (m, 1H), 1.11 (d, J = 6.1 Hz, 3H). EXAMPLE 205 1-((3R,4R)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.49 min, 370 m/z [M+H]+, 96%; 1H NMR (400 MHz, DMSO) δ 11.51 – 11.34 (m, 1H), 8.11 (m, 1H), 7.00 – 6.43 (m, 2H), 6.17 – 5.93 (m, 1H), 5.80 – 5.36 (m, 1H), 5.07 – 4.79 (m, 1H), 4.69 – 4.51 (m, 1H), 4.50 – 4.06 (m, 2H), 3.98 – 3.82 (m, 2H), 3.49 – 3.33 (m, 2H), 3.23 – 2.87 (m, 1H), 2.88 – 2.70 (m, 1H), 2.10 (m, 1H), 1.83 (m, 1H), 1.80 – 1.53 (m, 4H), 1.35 – 1.12 (m, 1H), 0.99 – 0.89 (m, 3H). EXAMPLE 206 1-((3S,4S)-3-Hydroxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.1 min, m/z 358 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 8.15 (s, 1H), 6.89 (s, 1H), 6.59 (dd, J = 16.7, 10.3 Hz, 1H), 6.14 (ddd, J = 16.7, 5.9, 2.4 Hz, 1H), 5.81 (d, J = 5.5 Hz, 1H), 5.67 (td, J = 10.7, 2.4 Hz, 1H), 4.59 – 4.31 (m, 2H), 4.02 – 3.58 (m, 6H), 3.52 – 3.38 (m, 4H), 1.81 (dd, J = 23.3, 13.3 Hz, 2H), 1.42 – 1.59 (m, 2H). EXAMPLE 207 1-((2R,5R)-2-Isopropyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.88 min, 398 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.11 (s, 1H), 6.90 – 6.85 (m, 1H), 6.80 (dd, J = 16.8, 10.6 Hz, 1H), 6.08 (dd, J = 16.8, 2.4 Hz, 1H), 5.66 (dd, J = 10.6, 2.4 Hz, 1H), 5.61 (d, J = 7.9 Hz, 1H), 4.77 – 4.21 (m, 2H), 4.21 – 4.02 (m, 1H), 4.00 – 3.87 (m, 2H), 3.65 – 3.53 (m, 2H), 3.31 – 3.16 (m, 1H), 3.00 – 2.69 (m, 1H), 2.37 – 2.22 (m, 1H), 2.01 – 1.78 (m, 5H), 1.73 – 1.48 (m, 3H), 1.07 – 0.75 (m, 6H). EXAMPLE 208 1-((1S,5R,6R)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1-one LCMS 5: RT 2.04 min, 368 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.50 – 11.29 (m, 1H), 8.20 – 8.08 (m, 1H), 6.94 – 6.88 (m, 1H), 6.87 – 6.35 (m, 1H), 6.22 – 5.98 (m, 1H), 5.95 – 5.73 (m, 1H), 5.58 – 5.18 (m, 1H), 4.73 – 4.54 (m, 1H), 4.09 – 4.01 (m, 1H), 4.00 – 3.85 (m, 3H), 3.75 – 3.50 (m, 3H), 3.51 – 3.14 (m, 1H), 3.10 – 2.89 (m, 1H), 1.93 – 1.76 (m, 2H), 1.76 – 1.49 (m, 3H), 1.47 – 1.21 (m, 1H), 0.73 – 0.43 (m, 1H), 0.43 – 0.02 (m, 1H). EXAMPLE 209 1-((3S,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT 2.12 min, 357 m/z [M+H]+, 95%; 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.32 (s, 1H), 7.11 – 7.06 (m, 1H), 6.67 – 6.51 (m, 1H), 6.20 – 6.09 (m, 1H), 5.76 – 5.60 (m, 1H), 5.49 – 5.37 (m, 1H), 4.16 – 3.18 (m, 8H), 3.01 – 2.91 (m, 1H), 2.72 – 2.47 (m, 1H), 1.84 – 1.73 (m, 2H), 1.71 – 1.57 (m, 2H), 1.14 – 1.06 (m, 3H). EXAMPLE 210 1-((3R,5R)-3-((5-((S*)-3,3-Difluorotetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.66 min, 406 m/z [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 8.23 – 8.05 (m, 1H), 7.18 – 7.06 (m, 1H), 6.99 – 6.32 (m, 1H), 6.23 – 5.84 (m, 1H), 5.83 – 5.37 (m, 2H), 4.45 – 4.15 (m, 2H), 4.11 – 3.81 (m, 4H), 3.68 – 3.42 (m, 2H), 3.32 – 3.19 (m, 1H), 3.06 – 2.72 (m, 1H), 2.41 – 2.27 (m, 1H), 2.27 – 2.08 (m, 1H), 2.04 – 1.73 (m, 2H), 1.68 – 1.36 (m, 1H), 1.03 – 0.75 (m, 3H). EXAMPLE 211 1-((3R,5R)-3-((5-((R*)-3,3-Difluorotetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.74 min, 406 m/z [M+H]+, 87%; 1H NMR (400 MHz, DMSO) δ 11.77 – 11.58 (m, 1H), 8.22 – 8.07 (m, 1H), 7.22 – 7.07 (m, 1H), 6.98 – 6.64 (m, 1H), 6.27 – 6.06 (m, 1H), 5.87 – 5.34 (m, 2H), 4.58 – 4.12 (m, 2H), 4.10 – 3.84 (m, 3H), 3.77 – 3.46 (m, 3H), 3.32 – 2.89 (m, 2H), 2.29 – 2.08 (m, 1H), 2.08 – 1.66 (m, 3H), 1.66 – 1.36 (m, 1H), 1.01 – 0.76 (m, 3H). EXAMPLE 212 rac-1-((3R,4R)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 2.1 min, m/z 361 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.05 (s, 1H), 6.73 – 6.55 (m, 1H), 6.45 – 6.25 (m, 1H), 6.10 – 5.92 (m, 1H), 5.88 – 5.72 (m, 1H), 5.60 – 5.41 (m, 1H), 4.21 – 3.85 (m, 6H), 3.55 – 3.43 (m, 2H), 3.08 – 2.96 (m, 1H), 1.90 – 1.66 (m, 4H). EXAMPLE 213 1-((3S*,4S*)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.9 min, m/z 361 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.05 (s, 1H), 6.72 – 6.55 (m, 1H), 6.41 – 6.24 (m, 1H), 6.03 – 5.92 (m, 1H), 5.87 – 5.73 (m, 1H), 5.60 – 5.36 (m, 1H), 4.19 – 3.83 (m, 6H), 3.56 – 3.42 (m, 2H), 3.09 – 2.87 (m, 1H), 1.90 – 1.68 (m, 4H). EXAMPLE 214 1-((3R*,4R*)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 4: RT 2.5 min, m/z 361 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.05 (s, 1H), 6.73 – 6.55 (m, 1H), 6.40 – 6.27 (m, 1H), 6.04 – 5.92 (m, 1H), 5.87 – 5.75 (m, 1H), 5.61 – 5.37 (m, 1H), 4.19 – 3.83 (m, 6H), 3.54 – 3.41 (m, 2H), 3.07 – 2.93 (m, 1H), 1.88 – 1.68 (m, 4H). EXAMPLE 215 1-(9-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,9- diazabicyclo[3.3.1]nonan-3-yl)prop-2-en-1-one LCMS 4: RT 1.73 min, 382 m/z [M+H]+, 93%; 1H NMR (400 MHz, DMSO) δ 11.72-11.71 (m, 1H), 8.26 (s, 1H), 7.18 – 7.06 (m, 1H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 4.47 (d, J = 13.3 Hz, 1H), 4.22 (s, 2H), 4.14 (d, J = 13.1 Hz, 1H), 4.02 – 3.86 (m, 2H), 3.69 – 3.55 (m, 1H), 3.54 – 3.40 (m, 2H), 3.21 – 3.07 (m, 1H), 2.96 – 2.77 (m, 1H), 2.16 – 1.66 (m, 7H), 1.66 – 1.43 (m, 3H). EXAMPLE 216 (S)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazin-1-yl)prop-2-yn-1-one LCMS 1: RT 1.6 min, m/z 354 [M+H]+, 84%; 1H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 8.30 (s, 1H), 7.16 (s, 1H), 4.67 (s, 1H), 4.62 (d, J = 6.4 Hz, 1H), 4.33 – 4.18 (m, 1H), 4.04 – 3.82 (m, 3H), 3.79 – 3.60 (m, 1H), 3.52 (td, J = 12.2, 6.6 Hz, 2H), 3.15 (dd, J = 13.1, 3.9 Hz, 2H), 3.02 (d, J = 10.9 Hz, 1H), 2.85 – 3.00 (m, 1H), 1.99 (dd, J = 24.8, 13.1 Hz, 2H), 1.76 (q, J = 10.9 Hz, 1H), 1.36 (qd, J = 12.4, 4.3 Hz, 1H), 1.23 (d, J = 6.7 Hz, 2H), 1.13 (d, J = 6.8 Hz, 1H). EXAMPLE 217 1-((3R,4S)-3-Hydroxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.1 min, m/z 358 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 1.1 Hz, 1H), 6.92 (d, J = 1.1 Hz, 1H), 6.60 (ddd, J = 16.8, 10.5, 1.2 Hz, 1H), 6.29 (ddd, J = 16.8, 3.7, 2.0 Hz, 1H), 5.76 (ddd, J = 11.4, 10.4, 2.0 Hz, 1H), 4.82 – 4.68 (m, 1H), 4.48 (dtd, J = 20.8, 4.4, 1.8 Hz, 1H), 4.27 (dd, J = 10.2, 7.6 Hz, 1H), 4.05 (dd, J = 11.4, 4.1 Hz, 3H), 3.94 (dd, J = 11.7, 4.4 Hz, 1H), 3.78 – 3.66 (m, 2H), 3.62 (tt, J = 11.7, 1.8 Hz, 2H), 3.55 – 3.47 (m, 1H), 3.05 (ddt, J = 11.7, 8.0, 3.5 Hz, 1H), 2.09 – 1.95 (m, 3H), 1.76 (qt, J = 12.2, 4.1 Hz, 2H). EXAMPLE 218 1-(8-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6,8- diazabicyclo[3.2.2]nonan-6-yl)prop-2-en-1-one LCMS 4: RT 1.41 min, 382 m/z [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 8.15 – 8.06 (m, 1H), 7.04 – 6.90 (m, 1H), 6.83 – 6.65 (m, 1H), 6.28 – 6.13 (m, 1H), 5.79 – 5.69 (m, 1H), 4.76 – 4.49 (m, 2H), 4.17 – 3.99 (m, 1H), 3.99 – 3.87 (m, 3H), 3.87 – 3.73 (m, 2H), 3.59 – 3.40 (m, 2H), 3.16 – 3.03 (m, 1H), 2.64 – 2.53 (m, 1H), 2.04 – 1.93 (m, 1H), 1.90 – 1.79 (m, 1H), 1.79 – 1.52 (m, 4H), 1.46 – 1.18 (m, 2H), 1.16 – 0.88 (m, 1H). EXAMPLE 219 1-((3S,4S)-4-Methoxy-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 5: RT 1.89 min, 386 m/z [M+H]+, 98%; 1H NMR (400 MHz, MeOD) δ 8.20 – 8.13 (m, 1H), 6.92 (s, 1H), 6.89 – 6.69 (m, 1H), 6.36 – 6.15 (m, 1H), 5.88 – 5.62 (m, 1H), 4.34 – 3.89 (m, 5H), 3.84 – 3.51 (m, 5H), 3.51 – 3.44 (m, 3H), 3.10 – 2.96 (m, 1H), 2.16 – 1.89 (m, 3H), 1.87 – 1.59 (m, 3H). EXAMPLE 220 1-((3R,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- yl)oxy)piperidin-1-yl)prop-2-en-1-one LCMS 1: RT 2.2 min, m/z 371 [M+H]+, 92%; 1H NMR (400 MHz, MeOD) δ 8.19 (s, 1H), 6.94 – 6.87 (m, 1H), 6.78 (dd, J = 16.7, 10.6 Hz, 1H), 6.20 (dd, J = 16.8, 10.6 Hz, 1H), 6.01 (dd, J = 16.7, 2.0 Hz, 1H), 5.76 (dd, J = 16.8, 2.0 Hz, 1H), 5.70 – 5.58 (m, 1H), 5.54 (t, J = 2.4 Hz, 1H), 5.39 (s, 1H), 5.16 (dd, J = 10.6, 2.0 Hz, 1H), 4.57 – 4.34 (m, 1H), 3.96 – 3.82 (m, 2H), 3.48 – 3.30 (m, 2H), 3.01 – 2.87 (m, 2H), 2.79 (dd, J = 13.6, 11.3 Hz, 1H), 2.36 (dd, J = 12.8, 11.5 Hz, 1H), 2.19 – 2.01 (m, 2H), 1.87 – 1.46 (m, 5H). EXAMPLE 221 1-((2R,3R)-2-Methyl-3-((5-((S*)-oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT 2.09 min, 370 m/z [M+H]+, 98%; 1H NMR (400 MHz, CDCl3) δ 10.73 – 10.16 (m, 1H), 8.37 – 8.27 (m, 1H), 6.89 (s, 1H), 6.58 – 5.67 (m, 3H), 5.55 – 5.46 (m, 1H), 4.97 – 4.61 (m, 2H), 3.98 – 3.56 (m, 6H), 3.11 – 3.01 (m, 1H), 2.52 – 1.23 (m, 8H), 1.20 – 1.06 (m, 3H). EXAMPLE 222 1-((2R,3R)-2-Methyl-3-((5-((R*)-oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT 2.08 min, 370 m/z [M+H]+, 100%; 1H NMR (400 MHz, CDCl3) δ 10.80 – 10.09 (m, 1H), 8.35 – 8.29 (m, 1H), 6.93 – 6.88 (m, 1H), 6.62 – 5.66 (m, 3H), 5.61 – 5.46 (m, 1H), 4.95 – 4.61 (m, 2H), 4.00 – 3.55 (m, 7H), 3.05 (s, 1H), 2.54 – 1.21 (m, 7H), 1.21 – 1.04 (m, 3H). EXAMPLE 223 1-((3S,5R)-3-Methoxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 5: RT 1.82 min, 386 m/z [M+H]+, 97%; 1H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 8.17 – 8.04 (m, 1H), 6.92 – 6.87 (m, 1H), 6.87 – 6.32 (m, 1H), 6.28 – 6.11 (m, 1H), 6.10 – 5.89 (m, 1H), 5.53 (m, 1H), 4.72 – 4.40 (m, 2H), 4.24 – 4.05 (m, 1H), 3.97 – 3.72 (m, 2H), 3.67 – 3.55 (m, 1H), 3.49 – 3.36 (m, 6H), 3.07 – 2.93 (m, 1H), 2.84 – 2.73 (m, 1H), 2.17 – 1.30 (m, 6H). EXAMPLE 224 1-(1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3- azabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one LCMS 5: RT 2.16 min, 368 m/z [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.14 – 8.05 (m, 1H), 6.92 – 6.86 (m, 1H), 6.83 – 6.65 (m, 1H), 6.35 – 6.25 (m, 1H), 5.81 – 5.70 (m, 1H), 4.26 – 3.98 (m, 4H), 3.87 – 3.82 (m, 1H), 3.72 – 3.61 (m, 3H), 3.26 – 3.17 (m, 1H), 2.69 – 2.57 (m, 1H), 2.39 – 2.24 (m, 2H), 2.21 – 2.11 (m, 2H), 2.04 – 1.95 (m, 2H), 1.79 – 1.64 (m, 2H). EXAMPLE 225 1-((2R,3R)-2-Isopropyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.68 min, 384 m/z [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.55 – 11.37 (m, 1H), 8.24 – 8.12 (m, 1H), 7.00 – 6.89 (m, 1H), 6.71 – 6.57 (m, 1H), 6.28 – 6.11 (m, 1H), 6.00 – 5.84 (m, 1H), 5.77 – 5.63 (m, 1H), 4.73 – 4.51 (m, 1H), 4.51 – 4.21 (m,1H), 3.99 – 3.83 (m, 2H), 3.74 – 3.48 (m, 4H), 3.42 – 3.35 (m, 1H), 2.33 – 2.09 (m, 2H), 2.04 – 1.77 (m, 3H), 1.74 – 1.60 (m, 1H), 1.60 – 1.43 (m, 1H), 0.88 – 0.67 (m, 6H). EXAMPLE 226 1-((2S,5R)-5-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.27 min, 387 m/z [M+H]+, 95%; 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 7.92 (d, J = 5.6 Hz, 1H), 7.03 (s, 1H), 6.76 (s, 1H), 6.07 (dd, J = 16.7, 2.3 Hz, 1H), 5.67 (d, J = 10.5 Hz, 1H), 4.96 (m, 1H), 4.77 (m, 1H), 4.57 (m, 1H), 4.33 (m, 1H), 3.93 (t, J = 12.3 Hz, 2H), 3.54 (t, J = 10.0 Hz, 2H), 3.25 (m, 1H), 2.01 – 1.74 (m, 4H), 1.58 (m, 4H), 1.20 (bs, 3H). EXAMPLE 227 1-((2R,3R)-2-Isopropyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 5: RT 2.46 min, 386 m/z [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.37 – 8.31 (m, 1H), 7.11 – 7.06 (m, 1H), 6.77 – 6.64 (m, 1H), 6.41 – 6.24 (m, 1H), 5.92 – 5.83 (m, 1H), 5.83 – 5.75 (m, 1H), 4.67 – 4.51 (m, 1H), 4.11 – 4.00 (m, 2H), 3.87 – 3.74 (m, 2H), 3.63 – 3.52 (m, 2H), 3.26 – 3.15 (m, 1H), 2.63 – 2.44 (m, 1H), 2.41 – 2.12 (m, 2H), 2.06 – 1.92 (m, 2H), 1.92 – 1.70 (m, 2H), 1.01 – 0.90 (m, 6H). EXAMPLE 228 (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-5- azaspiro[2.4]heptan-5-yl)prop-2-en-1-one LCMS 1: RT 2.4 min, m/z 369 [M+H]+, 93%; 1H NMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.02 (dd, J = 1.8, 0.9 Hz, 1H), 6.61 (ddd, J = 16.8, 13.5, 10.4 Hz, 1H), 6.29 (ddd, J = 16.8, 11.4, 2.0 Hz, 1H), 5.76 (ddd, J = 20.7, 10.5, 2.0 Hz, 1H), 5.42 (dd, J = 6.3, 3.8 Hz, 1H), 4.27 – 4.13 (m, 1H), 4.14 – 3.90 (m, 6H), 3.60 – 3.47 (m, 3H), 3.09 (ddq, J = 11.6, 7.8, 4.3 Hz, 1H), 2.05 – 1.69 (m, 3H), 1.15 – 1.04 (m, 1H), 1.00 (tt, J = 9.4, 4.5 Hz, 1H), 0.93 – 0.73 (m, 2H). EXAMPLE 229 (R)-1-(3,3-Dimethyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one LCMS 1: RT 2.6 min, m/z [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 7.12 (dt, J = 2.0, 0.9 Hz, 1H), 6.56 (ddd, J = 36.3, 16.7, 10.3 Hz, 1H), 6.13 (ddd, J = 16.8, 8.1, 2.4 Hz, 1H), 5.66 (ddd, J = 31.1, 10.3, 2.4 Hz, 1H), 5.47 (ddd, J = 17.0, 4.7, 2.0 Hz, 1H), 4.19 (dd, J = 12.1, 4.8 Hz, 1H), 3.98 – 3.83 (m, 3H), 3.70 – 3.51 (m, 2H), 3.48 – 3.34 (m, 3H), 3.17 (d, J = 5.2 Hz, 1H), 3.01 (t, J = 12.0 Hz, 1H), 1.89 – 1.52 (m, 3H), 1.17 (dd, J = 11.7, 5.5 Hz, 6H). EXAMPLE 230 1-((3R,5S)-3-((5-((3R*,4R*)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.36 min, m/z 386 [M+H]+, 94%; 1H NMR (400 MHz, MeOD) δ 8.16 – 8.04 (m, 1H), 6.99 – 6.94 (m, 1H), 6.96 – 6.77 (m, 1H), 6.28 – 6.16 (m, 1H), 5.81 – 5.72 (m, 1H), 4.87 – 3.95 (m, 5H), 3.56 – 3.40 (m, 2H), 3.28 – 3.18 (m, 1H), 2.99 – 2.64 (m, 2H), 2.59 – 2.32 (m, 1H), 2.25 – 2.01 (m, 2H), 1.92 – 1.85 (m, 1H), 1.82 – 1.72 (m, 1H), 1.37 – 1.10 (m, 1H), 1.05 – 0.96 (m, 3H). EXAMPLE 231 1-((3R,5S)-3-((5-((3S*,4S*)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one LCMS 4: RT 1.46 min, m/z 386 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.18 – 8.06 (m, 1H), 6.97 (s, 1H), 6.90 – 6.76 (m, 1H), 6.28 – 6.14 (m, 1H), 5.81 – 5.71 (m, 1H), 4.89 – 3.94 (m, 5H), 3.56 – 3.41 (m, 2H), 3.29 – 3.18 (m, 1H), 2.98 – 2.87 (m, 1H), 2.74 – 2.61 (m, 1H), 2.43 – 2.21 (m, 2H), 2.15 – 2.00 (m, 1H), 1.94 – 1.85 (m, 1H), 1.82 – 1.71 (m, 1H), 1.34 – 1.18 (m, 1H), 1.07 – 0.99 (m, 3H). EXAMPLE 232 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one LCMS 1: RT 1.4 min, m/z 380 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.11 (s, 1H), 6.97 (s, 1H), 4.05 – 3.89 (m, 5H), 3.74 – 3.66 (m, 4H), 3.65 – 3.55 (m, 2H), 3.50 – 3.40 (m, 1H), 3.25 – 3.16 (m, 1H), 3.15 – 3.05 (m, 2H), 2.11 – 1.97 (m, 5H), 1.70 – 1.55 (m, 2H). EXAMPLE 233 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-yn-1-one LCMS 1: RT 2.2 min, m/z 402 [M+H]+, 99%; 1H NMR (400 MHz, CD3CN) δ 9.65 (s, 1H), 8.21 (s, 1H), 7.00 (s, 1H), 4.33 – 4.02 (m, 6H), 4.00 – 3.89 (m, 3H), 3.89 – 3.75 (m, 1H), 3.59 – 3.49 (m, 3H), 3.16 – 3.07 (m, 1H), 2.01 (d, J = 11.7 Hz, 2H), 1.65 – 1.49 (m, 2H). EXAMPLE 234 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one LCMS 1: RT 2.4 min, m/z 416 [M+H]+, 99%; 1H NMR (400 MHz, CD3CN) δ 8.27 – 8.21 (m, 1H), 7.04 – 7.01 (m, 1H), 4.32 – 4.01 (m, 7H), 3.99 – 3.79 (m, 4H), 3.60 – 3.52 (m, 2H), 3.18 – 3.10 (m, 1H), 2.05 (s, 1H), 1.99 (s, 3H), 1.67 – 1.57 (m, 2H). EXAMPLE 235 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-yn-1-one LCMS 4: RT 1.67 min, m/z 366 [M+H]+, 97%; 1H NMR (400 MHz, CD3CN) δ 8.16 (s, 1H), 6.93 (s, 1H), 4.02 – 3.84 (m, 5H), 3.74 – 3.61 (m, 4H), 3.57 – 3.46 (m, 2H), 3.46 – 3.39 (m, 1H), 3.26 – 3.12 (m, 1H), 3.11 – 2.67 (m, 2H), 2.10 – 1.99 (m, 4H), 1.68 – 1.51 (m, 2H). EXAMPLE 236 (E)-1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-en-1-one LCMS 1: RT 1.0 min, m/z 366 [M+H]+, 82%; 1H NMR (400 MHz, CD3CN) δ 9.59 (br, 1H), 8.20 (s, 1H), 6.99 (d, J = 1.0 Hz, 1H), 6.89 – 6.69 (m, 1H), 6.15 (dq, J = 15.0, 1.7 Hz, 1H), 4.28 – 3.79 (m, 10H), 3.65 – 3.44 (m, 2H), 3.20 – 3.04 (m, 1H), 2.04 – 1.97 (m, 2H), 1.86 (dd, J = 6.9, 1.7 Hz, 3H), 1.66 – 1.47 (m, 2H). EXAMPLE 237 (Z)-1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-en-1-one LCMS 1: RT 2.0 min, m/z 418 [M+H]+, 100%; 1H NMR (400 MHz, CD3CN) δ 9.59 (s, 1H), 8.20 (s, 1H), 6.99 (s, 1H), 6.22 – 6.07 (m, 1H), 6.02 – 5.86 (m, 1H), 4.31 – 3.74 (m, 11H), 3.52 (t, J = 11.9 Hz, 2H), 3.21 – 3.07 (m, 1H), 2.05 – 1.96 (m, 3H), 1.86 (dd, J = 6.9, 1.7 Hz, 1H), 1.65 – 1.49 (m, 2H). Shows 10% of trans isomer. EXAMPLE 238 (Z)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.25 min, m/z 388 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.15 (s, 1H), 6.93 (s, 1H), 6.24 – 5.92 (m, 2H), 4.48 (m, 1H), 4.31 – 3.85 (m, 4H), 3.85 – 3.53 (m, 4H), 3.53 – 3.37 (m, 2H), 3.13 (m, 2H), 2.30 – 1.54 (m, 9H). EXAMPLE 239 1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-yn-1-one LCMS 1: RT 1.6 min, m/z 386 [M+H]+, 88%; 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 8.14 (dd, J = 17.9, 1.0 Hz, 1H), 6.93 (t, J = 3.2 Hz, 1H), 5.81 – 5.77 (m, 1H), 5.75 (d, J = 1.1 Hz, 1H), 4.40 (s, 2H), 4.25 (d, J = 13.3 Hz, 1H), 4.14 – 3.78 (m, 4H), 3.72 – 3.40 (m, 4H), 3.25 – 3.07 (m, 1H), 2.06 (d, J = 1.0 Hz, 2H), 1.86 (s, 3H), 1.67 (td, J = 12.1, 4.1 Hz, 1H), 1.48 (dt, J = 12.4, 6.8 Hz, 1H). EXAMPLE 240 2-Fluoro-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one LCMS 1: RT 1.7 min, m/z 392 [M+H]+, 87%; 1H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 8.12 (s, 1H), 6.93 (d, J = 2.3 Hz, 1H), 5.92 (s, 1H), 5.41 – 5.21 (m, 2H), 5.16 – 4.98 (m, 1H), 4.45 (s, 1H), 4.13 (d, J = 13.3 Hz, 1H), 3.98 – 3.81 (m, 3H), 3.55 (t, J = 11.4 Hz, 3H), 3.32 – 3.20 (m, 3H), 3.21 (s, 2H), 2.29 – 2.12 (m, 1H), 1.86 (t, J = 14.2 Hz, 3H), 1.66 (d, J = 11.8 Hz, 1H), 1.47 (d, J = 12.5 Hz, 1H). EXAMPLE 241 (E)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.7 min, m/z 388 [M+H]+, 94%; 1H NMR (400 MHz, MeOD) δ 8.45 – 8.05 (m, 2H), 6.93 (s, 2H), 6.86 – 6.70 (m, 1H), 6.58 (d, J = 14.9 Hz, 1H), 6.42 (d, J = 15.0 Hz, 1H), 5.08 (d, J = 47.2 Hz, 1H), 4.49 (d, J = 24.6 Hz, 1H), 4.15 (t, J = 18.5 Hz, 1H), 4.08 – 3.91 (m, 2H), 3.91 – 3.51 (m, 4H), 3.12 – 2.96 (m, 1H), 2.18 – 1.83 (m, 5H), 1.83 – 1.56 (m, 4H). EXAMPLE 242 1-((3aR,6aS)-5-(3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 1: RT 1.2 min, m/z 381 [M+H]+, 90%; EXAMPLE 243 1-((3aR,6aS)-5-(3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one LCMS 1: RT 1.2 min, m/z 381 [M+H]+, 80%; EXAMPLE 244 (E)-4-(Dimethylamino)-1-((3S,4R)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.3 min, m/z 431 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 8.15 (s, 1H), 6.94 – 6.89 (m, 1H), 6.65 – 6.47 (m, 2H), 5.40 (d, J = 7.8 Hz, 1H), 5.24 – 5.14 (m, 1H), 5.10 – 5.03 (m, 1H), 4.53 (d, J = 25.2 Hz, 1H), 4.12 (s, 1H), 4.01 – 3.79 (m, 2H), 3.56 – 3.34 (m, 2H), 3.05 – 2.94 (m, 3H), 2.12 (s, 6H), 2.05 – 1.83 (m, 4H), 1.74 – 1.56 (m, 2H). EXAMPLE 245 (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.0 min, m/z 431 [M+H]+, 99%; H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 6.93 – 6.87 (m, 1H), 6.72 – 6.53 (m, 2H), 5.63 – 5.48 (m, 1H), 5.20 – 4.96 (m, 1H), 4.51 – 4.38 (m, 1H), 4.08 – 3.98 (m, 1H), 3.96 – 3.87 (m, 2H), 3.87 – 3.77 (m, 1H), 3.67 – 3.42 (m, 4H), 3.04 – 2.98 (m, 3H), 2.15 (s, 6H), 2.12 – 2.01 (m, 1H), 1.95 – 1.75 (m, 3H), 1.73 – 1.49 (m, 2H). EXAMPLE 246 (E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.4 min, m/z 441 [M+H]+, 99%; 1H NMR (400 MHz, MeOD) δ 8.15 (d, J = 17.5 Hz, 1H), 6.91 (d, J = 5.2 Hz, 1H), 6.87 – 6.64 (m, 2H), 4.67 – 4.36 (m, 2H), 4.11 – 3.98 (m, 3H), 3.76 – 3.58 (m, 3H), 3.21 – 2.74 (m, 5H), 2.26 (d, J = 24.7 Hz, 6H), 2.02 – 1.83 (m, 3H), 1.83 – 1.60 (m, 3H), 1.12 – 1.01 (m, 6H). EXAMPLE 247 (S*,E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.8 min, m/z 441 [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 11.39 (d, J = 9.7 Hz, 1H), 8.11 (d, J = 11.3 Hz, 1H), 6.89 (s, 1H), 6.70 – 6.54 (m, 2H), 5.75 – 5.62 (m, 1H), 4.57 – 4.24 (m, 2H), 4.11 – 3.86 (m, 3H), 3.68 – 3.48 (m, 3H), 3.26 (s, 1H), 3.13 – 2.72 (m, 3H), 2.14 (d, J = 9.9 Hz, 6H), 1.90 – 1.79 (m, 2H), 1.77 – 1.46 (m, 4H), 1.00 (d, J = 10.4 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H). EXAMPLE 248 (R*,E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.8 min, m/z 441 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.15 (d, J = 17.4 Hz, 1H), 6.91 (d, J = 5.7 Hz, 1H), 6.87 – 6.67 (m, 2H), 4.69 – 4.36 (m, 2H), 4.13 – 3.98 (m, 3H), 3.75 – 3.59 (m, 3H), 3.25 – 2.70 (m, 4H), 2.36 (d, J = 17.1 Hz, 6H), 2.01 – 1.85 (m, 3H), 1.83 – 1.60 (m, 3H), 1.12 – 1.00 (m, 6H). EXAMPLE 249 (S,E)-1-(4,4-Difluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.60 min, m/z 449 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 8.16 (s, 1H), 6.96 – 6.91 (m, 1H), 6.75 – 6.54 (m, 2H), 5.53 – 5.32 (m, 1H), 4.87 (m, 1H), 4.28 – 4.13 (m, 1H), 4.07 – 3.89 (m, 3H), 3.55 – 3.38 (m, 4H), 3.04 – 3.00 (m,2H), 2.29 – 2.06 (m, 7H), 1.98 – 1.81 (m, 2H), 1.81 – 1.65 (m, 1H), 1.60 – 1.45 (m, 1H). EXAMPLE 250 (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.0 min, m/z 481 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.11 (s, 1H), 6.91 (s, 1H), 6.74 – 6.55 (m, 2H), 6.04 – 5.83 (m, 1H), 4.76 – 4.59 (m, 1H), 4.42 – 4.11 (m, 2H), 3.97 – 3.88 (m, 2H), 3.63 – 3.52 (m, 2H), 3.31 – 3.26 (m, 2H), 3.15 – 3.03 (m, 2H), 3.03 – 2.91 (m, 1H), 2.89 – 2.60 (m, 2H), 2.20 – 2.12 (m, 6H), 2.04 – 1.78 (m, 3H), 1.73 – 1.38 (m, 2H). EXAMPLE 251 (E)-4-(Dimethylamino)-1-((3R,4S)-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.80 min, m/z 481 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 8.12 (s, 1H), 6.94 – 6.88 (m, 1H), 6.68 – 6.54 (m, 2H), 5.84 (d, J = 8.4 Hz, 1H), 4.58 – 4.45 (m, 1H), 4.41 – 4.19 (m, 2H), 4.00 – 3.93 (m, 1H), 3.92 – 3.84 (m, 1H), 3.64 –3.52 (m, 2H), 3.27 – 3.11 (m, 3H), 3.03 (d, J = 5.3 Hz, 2H), 2.16 (s, 6H), 2.13 – 2.03 (m, 1H), 1.92 – 1.83 (m, 2H), 1.78 – 1.65 (m, 1H), 1.64 – 1.40 (m, 2H). EXAMPLE 252 4-(((3S,4S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-4-fluoropiperidin-3-yl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.80 min, m/z 455 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.09 (s, 1H), 6.68 – 6.58 (m, 2H), 5.07 – 4.87 (m, 1H), 4.63 – 4.53 (m, 1H), 4.11 – 4.01 (m, 1H), 3.96 – 3.87 (m, 2H), 3.86 – 3.75 (m, 1H), 3.74 – 3.59 (m, 1H), 3.59 – 3.43 (m, 3H), 3.18 – 3.07 (m, 1H), 3.01 – 2.97 (m, 2H), 2.13 (s, 6H), 2.11 – 1.99 (m, 1H), 1.94 – 1.78 (m, 3H), 1.69 (m, 1H), 1.62 – 1.48 (m, 1H). EXAMPLE 253 (S,E)-4-((1-(4-(Dimethylamino)but-2-enoyl)-4,4-difluoropiperidin-3-yl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.9 min, m/z 473 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.66 (bs, 1H), 8.16 (s, 1H), 7.14 (m, 1H), 6.73 – 6.61 (m, 2H), 5.66 – 5.23 (m, 1H), 4.91 – 4.73 (m, 1H), 4.43 – 4.27 (m, 1H), 4.15 – 4.03 (m, 1H), 4.04 – 3.89 (m, 2H), 3.63 – 3.31 (m, 4H), 3.04 – 3.00 (m, 3H), 2.30 – 2.06 (m, 8H), 1.97 – 1.83 (m, 2H), 1.83 – 1.70 (m, 1H), 1.64 – 1.52 (m, 1H). EXAMPLE 254 (E)-4-(Diethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.3 min, m/z 459 [M+H]+, 95%; 1H NMR (400 MHz, DMSO) δ 11.53 – 11.35 (m, 1H), 8.13 (s, 1H), 6.93 (s, 1H), 6.79 – 6.53 (m, 2H), 5.88 – 5.71 (m, 1H), 5.19 – 4.90 (m, 1H), 4.49 – 4.25 (m, 1H), 4.12 – 3.69 (m, 5H), 3.68 – 3.39 (m, 4H), 3.30 – 2.96 (m, 3H), 2.48 – 2.29 (m, 2H), 2.22 – 1.97 (m, 1H), 1.97 – 1.57 (m, 5H), 1.57 – 1.37 (m, 1H), 1.07 – 0.93 (m, 3H), 0.93 – 0.76 (m, 3H). EXAMPLE 255 (E)-1-((3S)-4,4-Difluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 2.3 min, m/z 463 [M+H]+, 97%; 1H NMR (500 MHz, MeOD) δ 8.25 – 8.14 (m, 1H), 6.94 (s, 1H), 6.89 – 6.68 (m, 1H), 6.68 – 6.53 (m, 1H), 5.01 – 4.70 (m, 1H), 4.69 – 4.46 (m, 1H), 4.31 – 3.97 (m, 3H), 3.85 – 3.39 (m, 3H), 3.29 – 3.19 (m, 1H), 3.19 – 2.92 (m, 3H), 2.40 – 2.08 (m, 8H), 2.08 – 1.87 (m, 1H), 1.78 (d, J = 13.6 Hz, 1H), 1.65 – 1.40 (m, 1H), 1.27 – 1.23 (m, 2H), 1.22 – 1.12 (m, 2H). EXAMPLE 256 (E)-1-((S)-4,4-Difluoro-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 2.0 min, m/z 463 [M+H]+, 100%; H NMR (400 MHz, MeOD) δ 8.26 – 8.12 (m, 1H), 6.99 – 6.91 (m, 1H), 6.90 – 6.67 (m, 1H), 6.62 (d, J = 15.3 Hz, 1H), 4.80 – 4.54 (m, 2H), 4.27 – 4.15 (m, 1H), 4.15 – 4.05 (m, 1H), 3.80 – 3.58 (m, 3H), 3.58 – 3.43 (m, 1H), 3.25 – 2.95 (m, 3H), 2.36 – 2.21 (m, 4H), 2.21 – 2.09 (m, 6H), 2.00 – 1.90 (m, 1H), 1.85 – 1.71 (m, 1H), 1.34 – 1.22 (m, 1H), 1.21 – 1.15 (m, 3H). EXAMPLE 257 (E)-1-((S)-4,4-Difluoro-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.90 min, m/z 463 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.26 – 8.13 (m, 1H), 7.00 – 6.92 (m, 1H), 6.90 – 6.65 (m, 1H), 6.65 – 6.49 (m, 1H), 4.80 – 4.47 (m, 2H), 4.19 – 3.97 (m, 3H), 3.89 – 3.75 (m, 1H), 3.71 – 3.53 (m, 2H), 3.23 – 2.85 (m, 3H), 2.37 – 2.18 (m, 4H), 2.18 – 2.09 (m, 4H), 2.09 – 1.92 (m, 2H), 1.67 – 1.38 (m, 2H), 1.32 – 1.28 (m, 1H), 1.26 (m, 3H). EXAMPLE 258 (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one LCMS 1: RT 1.3 min, m/z 413 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.16 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 5.2 Hz, 1H), 6.90 – 6.73 (m, 2H), 4.84 – 4.64 (m, 2H), 4.10 – 3.97 (m, 2H), 3.87 (d, J = 4.9 Hz, 2H), 3.66 (ddt, J = 19.6, 14.2, 7.3 Hz, 4H), 3.28 – 3.16 (m, 1H), 2.43 (ddd, J = 19.2, 13.0, 6.3 Hz, 1H), 2.23 (dt, J = 22.8, 11.6 Hz, 1H), 2.07 – 1.93 (m, 2H), 1.89 – 1.58 (m, 6H), 1.18 (dd, J = 17.9, 7.1 Hz, 1H), 1.12 (dd, J = 6.3, 3.8 Hz, 2H), 1.00 (t, J = 7.0 Hz, 3H). EXAMPLE 259 rac-(E)-1-((2R,3R,5S)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 2.4 min, m/z 441 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.38 (d, J = 10.6 Hz, 1H), 8.09 (d, J = 9.9 Hz, 1H), 6.93 – 6.85 (m, 1H), 6.68 – 6.50 (m, 2H), 5.83 (t, J = 8.9 Hz, 1H), 4.58 (ddd, J = 37.9, 12.3, 5.3 Hz, 1H), 4.21 – 4.01 (m, 2H), 4.00 – 3.84 (m, 2H), 3.64 – 3.50 (m, 2H), 3.02 (q, J = 5.4 Hz, 2H), 3.02 – 2.92 (m, 0.5H), 2.71 – 2.64 (m, 0.5H), 2.67 (q, J = 1.9 Hz, 1H), 2.15 (s, 3H), 2.14 (s, 3H), 1.91 – 1.83 (m, 2H), 1.81 – 1.60 (m, 4H), 1.55 – 1.37 (m, 1H), 1.09 (dd, J = 25.5, 6.9 Hz, 3H), 0.91 (dd, J = 6.7, 5.3 Hz, 3H). EXAMPLE 260 (E)-1-((2S*,3S*,5R*)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.8 min, m/z 441 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.41 – 11.34 (m, 1H), 8.12 – 8.05 (m, 1H), 6.92 – 6.85 (m, 1H), 6.68 – 6.51 (m, 2H), 5.87 – 5.78 (m, 1H), 4.70 – 4.48 (m, 1H), 4.24 – 4.01 (m, 3H), 3.98 – 3.86 (m, 2H), 3.62 – 3.51 (m, 2H), 3.06 – 2.92 (m, 3H), 2.70 – 2.65 (m, 1H), 2.17 – 2.12 (m, 7H), 1.91 – 1.84 (m, 2H), 1.84 – 1.36 (m, 3H), 1.16 – 1.03 (m, 3H), 0.94 – 0.87 (m, 3H). EXAMPLE 261 (E)-1-((2R*,3R*,5S*)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.9 min, m/z 441 [M+H]+, 97%; 1H NMR (400 MHz, DMSO) δ 11.41 – 11.34 (m, 1H), 8.12 – 8.05 (m, 1H), 6.92 – 6.85 (m, 1H), 6.68 – 6.51 (m, 2H), 5.87 – 5.78 (m, 1H), 4.70 – 4.48 (m, 1H), 4.24 – 4.01 (m, 3H), 3.98 – 3.86 (m, 2H), 3.62 – 3.51 (m, 2H), 3.06 – 2.92 (m, 3H), 2.70 – 2.65 (m, 1H), 2.17 – 2.12 (m, 7H), 1.91 – 1.84 (m, 2H), 1.84 – 1.36 (m, 3H), 1.16 – 1.03 (m, 3H), 0.94 – 0.87 (m, 3H). EXAMPLE 262 4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one LCMS 1: RT 1.9 min, m/z 429 [M+H]+, 98%; 1H NMR (400 MHz, MeOD) δ 8.24 – 8.14 (m, 1H), 7.00 – 6.94 (m, 1H), 5.23 – 4.96 (m, 1H), 4.73 – 4.53 (m, 1H), 4.18 – 4.10 (m, 2H), 4.10 – 4.02 (m, 2H), 3.97 – 3.83 (m, 1H), 3.82 – 3.70 (m, 1H), 3.70 – 3.57 (m, 3H), 3.21 – 3.02 (m, 2H), 2.41 (s, 3H), 2.09 (s, 4H), 2.05 – 1.90 (m, 3H), 1.88 – 1.61 (m, 2H). EXAMPLE 263 (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.2 min, m/z 427 [M+H]+, 99%; 1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 13.0 Hz, 1H), 6.91 (s, 1H), 6.79 – 6.65 (m, 2H), 4.56 – 4.47 (m, 1H), 4.32 – 4.17 (m, 1H), 4.09 – 3.99 (m, 2H), 3.72 – 3.61 (m, 2H), 3.26 – 3.13 (m, 3H), 2.98 – 2.60 (m, 1H), 2.40 – 2.14 (m, 8H), 2.02 – 1.93 (m, 2H), 1.83 – 1.62 (m, 3H), 1.48 – 1.33 (m, 1H), 1.07 – 0.99 (m, 3H). EXAMPLE 264 (E)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one LCMS 1: RT 1.9 min, m/z 459 [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 8.13 (s, 1H), 6.93 (s, 1H), 6.77 – 6.44 (m, 2H), 5.89 – 5.76 (m, 1H), 5.20 – 4.92 (m, 1H), 4.52 – 4.27 (m, 1H), 4.15 – 3.68 (m, 4H), 3.68 – 3.38 (m, 4H), 3.27 – 2.92 (m, 3H), 2.87 – 2.70 (m, 1H), 2.20 – 1.93 (m, 4H), 1.93 – 1.56 (m, 4H), 1.51 (d, J = 13.3 Hz, 1H), 1.06 – 0.75 (m, 6H). EXAMPLE 265 (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.3 min, m/z 426 [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.07 (d, J = 6.9 Hz, 1H), 7.42 – 6.92 (m, 2H), 6.75 – 6.58 (m, 2H), 6.43 (d, J = 8.3 Hz, 1H), 4.83 (s, 2H), 4.66 (d, J = 12.6 Hz, 1H), 4.22 – 3.83 (m, 2H), 3.64 – 3.27 (m, 5H), 2.78 (d, J = 7.2 Hz, 2H), 2.71 (t, J = 11.9 Hz, 2H), 2.09 (d, J = 12.1 Hz, 2H), 1.87 (d, J = 12.8 Hz, 3H), 1.78 – 1.45 (m, 6H), 0.96 (d, J = 6.5 Hz, 3H). EXAMPLE 266 (R,E)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one LCMS 1: RT 1.2 min, m/z 426 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 7.85 (dd, J = 5.7, 2.3 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.89 – 6.75 (m, 1H), 6.51 – 6.39 (m, 2H), 4.29 – 4.09 (m, 2H), 4.09 – 4.02 (m, 2H), 3.68 – 3.51 (m, 4H), 3.44 – 3.34 (m, 1H), 3.22 – 3.17 (m, 1H), 3.17 – 3.08 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.14 – 1.95 (m,2H), 1.91 – 1.66 (m, 2H), 1.25 (s, 3H), 1.20 (s, 3H). EXAMPLE 267 (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)but-2-en-1-one LCMS 1: RT 1.6 min, m/z 414 [M+H]+, 75%; 1H NMR (400 MHz, MeOD) δ 8.31 (d, J = 1.1 Hz, 1H), 7.94 (s, 1H), 7.17 (s, 1H), 7.07 (d, J = 3.9 Hz, 1H), 6.91 – 6.60 (m, 2H), 5.92 – 5.70 (m, 2H), 5.49 (s, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.94 – 3.84 (m, 1H), 3.71 (dd, J = 6.6, 3.0 Hz, 2H), 3.61 – 3.52 (m, 2H), 3.22 – 3.11 (m, 2H), 2.71 (s, 6H), 2.02 – 1.92 (m, 2H), 1.92 – 1.74 (m, 3H), 1.37 (dd, J = 7.0, 2.0 Hz, 3H). EXAMPLE 268 (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.0 min, m/z 428 [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 8.28 (s, 1H), 7.10 (s, 1H), 6.67 – 6.56 (m, 2H), 5.17 – 5.10 (m, 1H), 4.74 – 2.73 (m, 10H), 2.28 (s, 1H), 2.14 (d, J = 13.0 Hz, 6H), 1.90 – 1.81 (m, 2H), 1.78 – 1.59 (m, 4H), 1.39 (p, J = 11.5 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H). EXAMPLE 269 (R,E)-4-((1-(4-(Dimethylamino)but-2-enoyl)-4,4-dimethylpyrrolidin-3-yl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.8 min, m/z 451 [M+H]+, 99%; 1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 3.8 Hz, 1H), 7.11 (dd, J = 4.1, 0.9 Hz, 1H), 6.90 (ddt, J = 15.2, 9.8, 6.5 Hz, 1H), 6.49 (ddt, J = 16.9, 15.2, 1.5 Hz, 1H), 5.01 – 4.90 (m, 1H), 4.27 (dd, J = 11.3, 6.3 Hz, 1H), 4.16 – 3.99 (m, 3H), 3.79 (dd, J = 11.3, 5.1 Hz, 1H), 3.71 – 3.42 (m, 5H), 3.26 – 3.13 (m, 2H), 3.07 (tt, J = 11.7, 3.6 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.07 – 1.89 (m, 2H), 1.89 – 1.71 (m, 2H), 1.29 (t, J = 2.7 Hz, 6H). EXAMPLE 270 (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one LCMS 1: RT 0.9 min, m/z 412 [M+H]+, 99%; 1H NMR (400 MHz, MeOD) δ 7.89 (dd, J = 5.6, 4.1 Hz, 1H), 6.99 – 6.77 (m, 2H), 6.67 – 6.33 (m, 2H), 4.69 (t, J = 6.7 Hz, 1H), 4.37 (dt, J = 12.8, 6.8 Hz, 1H), 4.28 (dt, J = 12.7, 6.8 Hz, 1H), 4.14 – 4.01 (m, 2H), 3.86 (t, J = 9.7 Hz, 1H), 3.76 – 3.46 (m, 4H), 3.21 (dt, J = 6.6, 1.8 Hz, 3H), 2.50 (ddt, J = 19.3, 12.4, 7.0 Hz, 1H), 2.31 (s, 6H), 2.26 – 1.94 (m, 3H), 1.86 – 1.70 (m, 2H), 1.16 (dd, J = 6.6, 1.8 Hz, 3H). EXAMPLE 271 (E)-4-(Dimethylamino)-1-((2R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpyrrolidin-1-yl)but-2-en-1-one LCMS 1: RT 1.2 min, m/z 430 [M+H]+, 100%; 1H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.04 (d, J = 2.9 Hz, 1H), 6.82 (ddd, J = 20.8, 13.8, 6.8 Hz, 1H), 6.61 (dd, J = 28.3, 15.2 Hz, 1H), 4.70 – 4.36 (m, 3H), 4.07 (d, J = 11.2 Hz, 2H), 3.83 (t, J = 9.2 Hz, 1H), 3.73 – 3.42 (m, 6H), 3.14 (dd, J = 7.3, 3.6 Hz, 1H), 2.45 (dt, J = 13.2, 7.3 Hz, 1H), 2.26 – 1.97 (m, 4H), 1.88 – 1.65 (m, 4H), 1.22 (t, J = 6.4 Hz, 3H). EXAMPLE 272 4-(((3R,5S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-5-methylpiperidin-3-yl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.9 min, m/z 451 [M+H]+, 99%; 1H NMR (400 MHz, MeOD) δ 7.89 (dd, J = 5.6, 4.1 Hz, 1H), 6.99 – 6.77 (m, 2H), 6.67 – 6.33 (m, 2H), 4.69 (t, J = 6.7 Hz, 1H), 4.37 (dt, J = 12.8, 6.8 Hz, 1H), 4.28 (dt, J = 12.7, 6.8 Hz, 1H), 4.14 – 4.01 (m, 2H), 3.86 (t, J = 9.7 Hz, 1H), 3.76 – 3.46 (m, 4H), 3.21 (dt, J = 6.6, 1.8 Hz, 3H), 2.50 (ddt, J = 19.3, 12.4, 7.0 Hz, 1H), 2.31 (s, 6H), 2.26 – 1.94 (m, 4H), 1.86 – 1.70 (m, 2H), 1.16 (dd, J = 6.6, 1.8 Hz, 3H). EXAMPLE 273 (E)-4-(Dimethylamino)-1-((2S,5R)-5-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.6 min, m/z 444 [M+H]+, 97%; 1H NMR (400 MHz, MeOD) δ 8.49 (bs, 1H), 7.88 (s, 2H), 7.02 (bs, 1H), 6.70 (s, 1H), 4.04 (m, 2H), 3.77 – 3.61 (m, 2H), 3.47 (m, 2H), 3.21 (m, 1H), 2.53 (s, 6H), 2.03 (m, 4H), 1.80 (m, 3H), 1.68 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H), 1.30 (m, 4H). EXAMPLE 274 (R,E)-4-(Dimethylamino)-1-(7-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)but-2-en-1-one 1H NMR (400 MHz, MeOD) δ 8.45 (s, 2H), 7.88 (s, 1H), 6.96 (dd, J = 5.3, 0.9 Hz, 1H), 6.77 (ddt, J = 24.5, 15.2, 6.8 Hz, 1H), 6.66 – 6.55 (m, 1H), 6.34 (dd, J = 12.4, 5.7 Hz, 1H), 4.18 – 3.82 (m, 5H), 3.67 – 3.52 (m, 4H), 3.35 (s, 6H), 3.20 – 3.02 (m, 2H), 1.98 (dd, J = 32.2, 10.8 Hz, 2H), 1.87 – 1.65 (m, 2H), 1.03 – 0.93 (m, 2H), 0.92 – 0.79 (m, 2H). EXAMPLE 275 (E)-4-(Diisopropylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.7 min, m/z 487 [M+H]+, 98%; 1H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 8.13 (s, 1H), 6.93 (s, 1H), 6.80 – 6.54 (m, 2H), 5.87 – 5.73 (m, 1H), 5.26 – 4.87 (m, 1H), 4.52 – 4.28 (m, 1H), 4.10 – 3.67 (m, 4H), 3.67 – 3.37 (m, 4H), 3.29 – 2.77 (m, 5H), 2.17 – 1.93 (m, 1H), 1.93 – 1.37 (m, 5H), 1.08 – 0.71 (m, 12H). EXAMPLE 276 (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.2 min, m/z 427 [M+H]+, 100%; 1H NMR (400 MHz, CD3CN, 25ºC) δ 7.78 (s, J = 8.1 Hz, 1H), 7.47 (s, 1H), 6.75 – 6.48 (m, 3H), 5.51 (br s, 1H), 4.84 – 3.87 (m, 5H), 3.67 – 3.50 (m, 2H), 3.22 – 3.09 (m, 1H), 3.03 (d, J = 5.3 Hz, 2H), 2.90 – 2.65 (m, 1H), 2.65 – 2.22 (m, 1H), 2.19 (s, 6H), 1.93 – 1.63 (m, 6H), 1.48 – 1.34 (m, 1H), 0.99 (d, J = 5.2 Hz, 3H). EXAMPLE 277 (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.0 min, m/z 431 [M+H]+, 99%; 1H NMR (400 MHz, CD3CN) δ 7.70 (s, 1H), 7.41 (d, J = 2.8 Hz, 1H), 6.85 – 6.36 (m, 3H), 5.82 (s, 1H), 4.96 (t, J = 53.9 Hz, 1H), 4.39 (q, J = 6.2 Hz, 1H), 4.04 (d, J = 15.2 Hz, 1H), 3.93 – 3.33 (m, 4H), 3.08 – 2.81 (m, 3H), 2.08 (s, 6H), 1.85 (p, J = 2.6 Hz, 5H), 1.68 (d, J = 21.9 Hz, 4H). EXAMPLE 278 (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)-5-methylpiperidin-1-yl)but-2-en-1-one LCMS 1: RT 2.1 min, m/z 445 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.49 (s, 1H), 8.13 (s, 1H), 7.24 – 7.13 (m, 1H), 6.67 – 6.49 (m, 2H), 4.89 – 4.49 (m, 1H), 4.45 – 4.28 (m, 1H), 3.99 – 3.91 (m, 3H), 3.54 – 3.44 (m, 2H), 3.15 – 3.07 (m, 1H), 3.04 – 2.97 (m, 2H), 2.76 – 2.61 (m, 1H), 2.28 – 2.21 (m, 1H), 2.16 – 2.07 (m, 7H), 1.90 (d, J = 12.2 Hz, 2H), 1.70 – 1.51 (m, 3H), 1.35 – 1.20 (m, 1H), 0.97 – 0.91 (m, 3H). EXAMPLE 279 (E)-4-(Dimethylamino)-1-((1R*,5S*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1-one LCMS 1: RT 0.77 min, m/z 411 [M+H]+, 100%; 1H NMR (400 MHz, CD3CN) δ 9.58 (s, 1H), 8.19 (s, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.76 – 6.56 (m, 1H), 6.29 (m, 1H), 5.95 (m, 1H), 4.11 – 4.04 (m, 1H), 4.00 – 3.90 (m, 2H), 3.84 – 3.48 (m, 5H), 3.09 – 2.97 (m, 3H), 2.18 (d, J = 3.2 Hz, 3H), 2.16 (s, 3H), 1.89 (d, J = 12.9 Hz, 2H), 1.81 (m, 1H), 1.70 – 1.55 (m, 2H), 1.21 – 1.13 (m, 1H), 0.86 – 0.78 (m, 1H). EXAMPLE 280 (E)-4-(Dimethylamino)-1-((1S*,5R*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1-one LCMS 1: RT 0.77 min, m/z 411 [M+H]+, 99%; EXAMPLE 281 (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.5 min, m/z 444 [M+H]+, 98%; 1H NMR (400 MHz, CD3CN) δ 9.27 (br, 1H), 7.91 (d, J = 5.8 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.71 – 6.59 (m, 1H), 6.59 – 6.46 (m, 1H), 4.89 – 4.42 (m, 1H), 4.40 – 4.21 (m, 2H), 4.05 – 3.90 (m, 3H), 3.82 – 3.63 (m, 1H), 3.63 – 3.48 (m, 2H), 3.11 – 2.96 (m, 3H), 2.86 – 2.57 (m, 1H), 2.49 – 2.33 (m, 1H), 2.30 – 2.21 (m, 1H), 2.11 (overlap, 6H), 1.83 – 1.44 (m, 4H), 1.22 – 1.08 (m, 1), 1.00 – 0.83 (m, 3H). EXAMPLE 282 4-(((3R,6S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-6-methylpiperidin-3-yl)amino)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile LCMS 1: RT 1.8 min, m/z 451 [M+H]+, 98%; 1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 8.09 (s, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6.69 (s, 2H), 4.36 (m, 2H), 4.04 (m, 2H), 3.82 (s, 2H), 3.69 (d, J = 11.4 Hz, 2H), 2.80 (s, 6H), 2.22 – 1.51 (m, 6H), 1.51 – 1.10 (m, 4H), 1.10 – 0.95 (m, 2H), 0.95 – 0.77 (m, 2H). EXAMPLE 283 (E)-4-(Dimethylamino)-1-((1S*,4R*,6R*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one LCMS 1: RT 1.2 min, m/z 439 [M+H]+, 100%; 1H NMR (400 MHz, DMSO) δ 11.45 – 11.37 (m, 1H), 8.11 – 8.07 (m, 1H), 6.95 – 6.88 (m, 1H), 6.73 – 6.39 (m, 2H), 5.66 – 5.59 (m, 1H), 4.66 – 4.25 (m, 3H), 3.97 – 3.90 (m, 2H), 3.63 – 3.50 (m, 3H), 3.42 – 3.34 (m, 2H), 3.08 – 3.00 (m, 2H), 2.31 – 2.08 (m, 7H), 2.09 – 1.97 (m, 1H), 1.97 – 1.84 (m, 2H), 1.73 – 1.48 (m, 6H). EXAMPLE 284 (E)-4-(Dimethylamino)-1-((1R*,4S*,6S*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one LCMS 1: RT 1.2 min, m/z 439 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.45 – 11.37 (m, 1H), 8.11 – 8.07 (m, 1H), 6.95 – 6.88 (m, 1H), 6.73 – 6.39 (m, 2H), 5.66 – 5.59 (m, 1H), 4.66 – 4.25 (m, 3H), 3.97 – 3.90 (m, 2H), 3.63 – 3.50 (m, 3H), 3.42 – 3.34 (m, 2H), 3.08 – 3.00 (m, 2H), 2.31 – 2.08 (m, 7H), 2.09 – 1.97 (m, 1H), 1.97 – 1.84 (m, 2H), 1.73 – 1.48 (m, 6H). EXAMPLE 285 (E)-4-(Dimethylamino)-1-((1R*,4S*,6R*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one LCMS 4: RT 2.2 min, m/z 439 [M+H]+, 99%; 1H NMR (400 MHz, DMSO) δ 11.48 – 11.35 (m, 1H), 8.12 – 8.07 (m, 1H), 6.94 – 6.87 (m, 1H), 6.74 – 6.37 (m, 2H), 5.66 – 5.59 (m, 1H), 4.65 – 4.28 (m, 2H), 3.97 – 3.90 (m, 2H), 3.63 – 3.50 (m, 3H), 3.42 – 3.34 (m, 1H), 3.08 – 3.01 (m, 2H), 2.29 – 2.12 (m, 7H), 2.08 – 2.00 (m, 1H), 1.93 – 1.86 (m, 3H), 1.70 – 1.53 (m, 7H). EXAMPLE 286 (E)-4-(Dimethylamino)-1-((1S*,4R*,6S*)-6-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2-en-1-one LCMS 4: RT 2.2 min, m/z 439 [M+H]+, 99%; 1H NMR (500 MHz, DMSO) δ 11.42 (dd, J = 15.0, 2.5 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 6.92 (dd, J = 9.1, 2.3 Hz, 1H), 6.70 – 6.43 (m, 2H), 5.64 (t, J = 5.7 Hz, 1H), 4.66 – 4.63 (m, 1H), 4.41 (q, J = 3.1 Hz, 1H), 4.32 (dt, J = 10.1, 4.7 Hz, 1H), 3.95 (dd, J = 10.8, 4.9 Hz, 2H), 3.63 – 3.50 (m, 2H), 3.43 – 3.34 (m, 3H), 3.13 (s, 2H), 2.23 (s, 7H), 2.05 (dt, J = 18.6, 3.1 Hz, 1H), 1.91 (tt, J = 13.5, 9.5 Hz, 3H), 1.70 – 1.51 (m, 5H). EXAMPLE 287 4-(Dimethylamino)-1-(5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one LCMS 1: RT 0.6 min, m/z 439 [M+H]+, 98%; 1H NMR (400 MHz, CD3CN) δ 9.39 (s, 1H), 8.16 (s, 1H), 6.93 (s, 1H), 3.98 – 3.87 (m, 5H), 3.70 – 3.61 (m, 4H), 3.57 – 3.50 (m, 2H), 3.45 – 3.40 (m, 3H), 3.22 –3.16 (m, 1H), 3.07 – 3.00 (m, 2H), 2.27 (s, 6H), 2.03 – 1.98 (m, 2H), 1.63 – 1.55 (m, 2H). EXAMPLE 288 (E)-1-((3aR,6aS)-3a,6a-difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2- en-1-one LCMS 1: RT 1.2 min, m/z 461 [M+H]+, 89%; EXAMPLE 289 (E)-4-(Dimethylamino)-1-((2S,5R)-2-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 0.9 min, m/z 426 [M+H]+, 99%; 1H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 7.91 (s, 1H), 7.04 (s, 1H), 6.91 (d, J = 15.3 Hz, 1H), 6.67 (m, 3H), 4.45 (s, 1H), 4.12 – 3.95 (m, 2H), 3.78 (bs, 2H), 3.67 (td, J = 11.6, 4.6 Hz, 2H), 2.87 (m, 1H), 2.76 (s, 6H), 2.17 – 1.52 (m, 4H), 1.44 – 1.25 (m, 4H), 1.25 – 1.08 (m, 1H), 0.98 (m, 3H), 0.93 – 0.57 (m, 2H). EXAMPLE 290 (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 0.9 min, m/z 430 [M+H]+, 91%; 1H NMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.83 (s, 1H), 6.96 – 6.82 (m, 2H), 6.73 (dt, J = 14.8, 6.9 Hz, 1H), 6.59 – 6.34 (m, 2H), 3.99 – 3.76 (m, 5H), 3.68 (d, J = 6.8 Hz, 1H), 3.65 – 3.34 (m, 4H), 2.66 (s, 3H), 2.56 (s, 3H), 2.35 (s, 2H), 1.98 – 1.77 (m, 3H), 1.72 – 1.37 (m, 4H). EXAMPLE 291 (E)-4-(dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-((2R*,4R*)-2-methyltetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 0.9 min, m/z 444 [M+H]+, 94%; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.25 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.69 (s, 1H), 6.43 (m, 1H), 6.30 (d, J = 5.5 Hz, 1H), 5.17 (d, J = 8.2 Hz, 1H), 5.02 (d, J = 8.0 Hz, 1H), 4.89 (m, 1H), 3.86 (s, 3H), 3.80-2.95 (m, 5H), 2.93 – 2.70 (m, 3H), 2.16 (s, 3H), 1.97 (s, 3H), 1.89 (d, J = 9.3 Hz, 2H), 1.48 – 1.21 (m, 2H), 1.14 (d, J = 6.1 Hz, 3H). EXAMPLE 292 (E)-4-(dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-((2S*,4S*)-2-methyltetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.0 min, m/z 444 [M+H]+, 96%; 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.23 (s, 1H), 7.83 (s, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.69 (s, 1H), 6.54 (d, J = 12.1 Hz, 1H), 6.29 (s, 1H), 5.20 (s, 1H), 5.04 (d, J = 28.2 Hz, 1H), 4.88 (s, 1H), 4.23 (s, 1H), 4.06 – 3.73 (m, 6H), 3.90-2.95 (m, 5H), 2.16 (s, 3H), 2.03 (s, 3H), 1.82 (d, J = 13.8 Hz, 3H), 1.07 (d, J = 6.1 Hz, 3H). EXAMPLE 293 (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one LCMS 1: RT 1.1 min, m/z 448 [M+H]+, 99%; EXAMPLE 294 (R,E)-4-(Dimethylamino)-1-(4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)but-2-en-1-one LCMS 1: m/z 424 [M+H]+, 96%; EXAMPLE 295 (S,E)-1-(4,4-Difluoro-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)-4-(dimethylamino)-3-methylbut-2-en-1-one LCMS 1: RT 0.9 min, m/z 462 [M+H]+, 96%; EXAMPLE 296 (E)-1-((3aR,6aS)-3a,6a-Difluoro-5-(3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4- (dimethylamino)but-2-en-1-one LCMS 1: m/z 474 [M+H]+, 95%; Pharmacological activity 1. In vitro ITK kinase Assay: Time Dependent Inhibition (TDI) 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 MBP 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 (5 nM), ATP and MBP in Kinase Assay Buffer III without DTT (12.5 µM DTT is included in normal ADP-Glo assay). The ATP concentration in the reaction was 30 µM and the final concentration of DMSO was 1%. The enzyme was pre-incubated with the compounds for 0 minutes and 180 minutes to record any shift in potency of the compounds. Following pre- incubation, the enzymatic reaction took place for 40 minutes at room temperature. Then, the enzymatic reaction was stopped with the addition of 5 µl of ADP-Glo and incubation for 40 minutes. Finally, 10 µl of Kinase Detection Reagent was added and incubated the plate for 60 minutes before reading the luminescence on PheraStar FSX (BMG plate reader). 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 Example Enzymatic IC50 ITK (nM) Ritlecitinib A ATI-2138 A A A B A A A A A A A B B A B B C A C A A A A A A A A A A A A A A A B A A A A B C B A A A A C B B A A A A A B A A C A B A A A C A A B B A A A A A A A A A B C A A A A A A A A B A A A 169 A 170 A 171 A 173 A 174 A 175 B 176 A 177 B 180 A 181 A 182 A 183 A 184 A 186 B 187 B 188 A 193 A 194 A 196 B 197 A 245 A 257 A 265 A Table 1 It can be seen from Table 1 that the heterobicyclic derivatives of the present invention are inhibitors of ITK kinase. In vitro ITK kinase Assay: Determination of kinact/KI Kinetic Parameters of ITK inhibition This in-vitro assay was developed to better understand the SAR by assessing the association kinetics of the compounds to the target (KI) as well as the rate of inactivation of the target (kinact). This was done by using the PhosphoSens® kinase assay platform which provides a simple, one-step homogeneous, fluorescence-based assay for rapid and sensitive detection of target ITK kinase activity. The test compounds (ITK inhibitors) were spotted into an ARP using the Tecan D300e (start concentration 10 µM, 1:2 serial dilution to obtain 16-point CRCs). Then, the 1X reaction buffer was freshly prepared by diluting the 10X reaction buffer in ultrapure water. To the 1X reaction buffer, 1.25X ATP (FAC:1mM) and 1.25X substrate-AQT0101 (FAC: 20uM) was added.5X ITK enzyme (FAC: 5nM) is prepared in 1X enzyme dilution buffer.16µL/well of the reaction buffer containing ATP and substrate was carefully added with the ThermoFisher E1-ClipTip™ (16 channel, 2 to 125 µl), followed by addition of 4µL/well of enzyme-buffer mix. Next, the assay plates were shortly centrifuged at 1000 rpm for 1 minute and immediately placed into Pherastar for fluorescence measurement for 180 min at 30°C. Raw traces were analysed using the Mechanistic Analysis Package (MAP) of the Genedata software. In vitro JAK3 kinase Assay: Determination of kinact/KI Kinetic Parameters of JAK3 inhibition In an analogous way, the kinact/KI value for JAK3 inhibition was generated for the assessment of the selectivity inhibiting ITK over JAK3. The test compounds were spotted into an ARP using the Tecan D300e (start concentration 10µM, 1:2 serial dilution to obtain 16-point CRCs). Then, the 1X reaction buffer was freshly prepared by diluting the 10X reaction buffer in ultrapure water. To the 1X reaction buffer, 1.25X ATP (FAC:1mM) and 1.25X substrate-AQT0661 (FAC: 20uM) was added. 5X JAK3 enzyme (FAC: 5nM) is prepared in 1X enzyme dilution buffer. 16µL/well of the reaction buffer containing ATP and substrate was carefully added with the ThermoFisher E1-ClipTip™ (16 channel, 2 to 125 µl), followed by addition of 4µL/well of enzyme-buffer mix. Next, the assay plates were shortly centrifuged at 1000 rpm for 1 minute and immediately placed into Pherastar for fluorescence measurement for 180 min at 30°C. Raw traces were analysed using the Mechanistic Analysis Package (MAP) of the Genedata software. In the following Table 2, kinact/KI values for ITK and JAK3 are represented by letters according to the value: A: > 2000 (M-1s-1) B: 500 – 2000 (M-1s-1) C: 100 - <500 (M-1s-1) And selectivity ITK/JAK3 (kinact/KI) is represented by the following symbols: +++: >10 ++: 5-10 +: 2-<5 -: <2 Example ITK JAK3 Selectivity kinact/KI kinact/KI ITK/JAK3 (M-1s-1) (M-1s-1) ratio kinact/KI Ritlecitinib C A - ATI-2138 A A - 1 A C ++ 7 C D + 15 B D ++ 22 C D ++ 23 C D +++ 24 B D ++ 25 C D ++ 26 A B ++ 28 A B ++ 29 B D +++ 30 A B +++ 31 A C +++ 32 C D +++ 33 A D +++ 34 A C ++ 36 B D +++ 41 A B ++ 43 C D + 48 B D +++ 50 B D +++ 63 B D +++ A C +++ A C +++ A D +++ A C +++ A B + A A ++ A B + A A + A B +++ B d ++ A C ++ B C + A C +++ A D +++ A D +++ A C +++ A D +++ B D +++ C D ++ B D +++ A B ++ A C +++ A C ++ B C +++ C D +++ B D +++ A A + A C +++ A C +++ A B +++ A D +++ A A + B D +++ B C ++ A D +++ B C +++ A B + A C +++ A B +++ B B + A A + A A + A A ++ B D +++ A C +++ C D + B D +++ B C ++ C D +++ B D +++ B D +++ B D +++ A D +++ B C + C D ++ C D +++ B C +++ C D ++ B D +++ B D +++ C D ++ C D +++ A B ++ A B + B D +++ B D +++ B C ++ B B + C D + B D +++ C D + B D +++ B D +++ B D +++ C D ++ B D +++ A A + B C + B D ++ C D + C D + A C +++ B D +++ A D +++ A D +++ A D +++ 247 C D ++ 248 A C +++ 249 A C +++ 250 A D +++ 251 A D +++ 252 A C +++ 253 A B +++ 254 A D +++ 255 A C +++ 256 A C +++ 257 A C +++ 258 B D +++ 259 B D +++ 260 A D +++ 262 A A +++ 263 A D +++ 264 A D +++ 265 A D +++ 266 B D +++ 267 B D +++ 268 A D +++ 269 C D +++ 270 A D +++ 271 C D +++ 272 B D +++ 273 C D +++ 274 B D +++ 275 B D +++ 278 A C +++ 281 A D +++ Table 2 It can be seen from Table 2 that the heterobicyclic derivatives of the present invention are efficient inhibitors of ITK kinase and selective over JAK3. 4. ITK cellular activity assay: IL-2 inhibition in Jurkat cells The ITK Inhibitors’ potency inhibiting IL-2 cytokine was tested in Jurkat cells (Jurkat clone E6-1, ATCC-TIB-152) stimulated with PHA (Phytohemagglutinin PHA-M, Sigma-L8902) to activate the production of IL-2 in T-lymphocyte. Method: 1.00E6 Jurkat cells/well in 130 µl of assay media (RPMI-1% Glutamax-10% FBS) were seeded in 96 well plates and incubated for 2 h. Then 20 µl of dose response (range from 5 µM to 64 pM) of inhibitors (pre-diluted 1/20 in assay media) were added to cells and pre-incubated 60 min. Then 50 µl of PHA (at its EC80) were added. After over/night incubation, 100 µl of supernatants were tested by ELISA to detect the IL-2 levels (readout at 450 nm in a multimode plate reader). 5. ITK cellular activity assay: IL-2 inhibition in PBMC cells The ITK Inhibitors’ potency inhibiting IL-2 cytokine was tested in PBMC cells (isolated from healthy donors) stimulated with aCD3-aCD28 Dynabeads (Dynabeads Human T-activator CD3/CD28, Gibco-11132D) to activate the production of IL-2 in these cells. Method: 0.15x106 PBMC cells/well in 80 µl of assay media (RPMI/Glutamax, 20 mM Hepes, 10.000 U/mL penicillin/streptamycin, 10% FBS) were seeded in 96 well plates and incubated for 2 h at 37 ºC, 5% CO2. Then 10 µl of dose response (range from 5 µM to 64 pM) of inhibitors (pre-diluted 1/20 in assay media) were added to cells and pre-incubated 60 min at 37 ºC, 5% CO2. Then 10 µl of Dynabeads (at its EC80) were added. After over/night incubation at 37 ºC, 5% CO2, 100 µl of diluted supernatants were tested by ELISA (DuoSet ELISA Human IL-2, R&D Systems, DY202) to detect the IL-2 levels (readout at 450 nm in a multimode plate reader). 6. JAK3 cellular activity assay: IL4-induced pSTAT6 assay in human reporter Ramos cells IL4-induced pSTAT6 assay in Ramos cells transfected with a β-lactamase reporter gen system under the control of STAT6 promoter, Ramos STAT6-bla RA-1, (Life Technologies K1243) were seeded at a concentration of 0.75x106 cells/well in 384-well plate (40 µL) and incubated overnight at 37 ºC, 5% CO2 in complete Optimem Media containing 556 ng/mL CD40, 0.5% FBS, 10 mM non-essential aminoacids, 100 mM sodium pyruvate and 10.000 U/mL penicillin/streptamicin. Next day, inhibitors were initially dissolved in 100% DMSO and curves prepared using 1/5 serial dilutions (10 dilutions, final range from 5 µM to 64 pM).5 ^l of the inhibitor dilution curves, pre-diluted 1/50 in complete Optimem Media, were added to the cells and pre-incubated 60 min at 37 ºC, 5% CO2.. A solution of IL-4 was prepared at 10-fold its EC80 in Optimem media and 5 µL were added to cells for IL-4 stimulation and incubated during 4h at 37 ºC, 5% CO2. To stop the reaction 10 µL of the b-lactamase substrate mixture was added to the wells and the plate was left over/night in the dark. FRET reading was determined using Envision reader (Perkin Elmer) and IC50 values determined by non-linear regression using XL-fit software for calculations (204 four- parameter log model). In the following Tables 3 and 4, IC50 values for ITK and JAK3 are represented by letters according to the value: A: < 100 nM B: 100 – 1000 nM C: >1000 – 10000 nM D: > 10000 nM And selectivity JAK3 IC50 /ITK IC50 is represented by the following symbols: +++: >100 ++: 30-100 +: 10-<30 -: <10 Ratio JAK3 JAK3 cellular ITK cell ce (Ramos)IC50 (Jurkat) ll Example / ITK IC (Ramos) 50 cellular IC50 (nM) IC50 (nM) (Jurkat) A>100 B>30 C>10 Ritlecitinib A A - 1 A n.t. 2 A B + 4 B n.t. 5 B C + 7 A B ++ 8 A B ++ 9 A C ++ 10 A C + 14 A n.t. 15 A C +++ 22 B C + 23 B D ++ 24 A B +++ 25 A C ++ 26 A B ++ 28 A A ++ 29 A C +++ A B +++ A B + B D ++ A B +++ A B +++ A C +++ A B + A B ++ A B + A B + A C +++ A C +++ A C ++ A C +++ A C +++ A C +++ B C ++ B D ++ A C +++ B C + A C +++ A C ++ A C +++ A D +++ A B +++ A C +++ A D +++ A B +++ A C +++ A B ++ A C +++ A D +++ A C +++ C D + A D +++ A C +++ A B ++ A C +++ A C +++ A C +++ A C +++ A C ++ Table 3 Ratio JAK3 ITK cell JAK3 cellular (PB cell (Ramos) Example MC) IC (Ramos) IC50 / 50 (nM) IC50 ITK (nM) cellular IC50 (PBMC) Ritlecitinib B A - ATI-2138 A A - 1 A n.t. 7 A B + 14 B n.t. 24 A B ++ 26 A B ++ 28 A A ++ 29 B C + 30 A B ++ 31 A B ++ 33 A B + 36 A C +++ 41 A B + 48 A C +++ 49 A C +++ 50 B C + 60 B C + 63 A C ++ 72 A C + 84 A B ++ 86 A B ++ 88 A B ++ 89 A B +++ 90 A C +++ 91 A B +++ 92 A B ++ 93 A C +++ 96 A C +++ 97 A C +++ 98 A C +++ 99 A C +++ 100 A C +++ 101 A n.t. 102 A n.t. 104 A n.t. C n.t. A n.t. A n.t. A n.t. B n.t. C n.t. + B D +++ A C +++ A D +++ A B + B C + A A + A n.t. A C +++ A B ++ A A + A C +++ A A + A C ++ A B + A C ++ A B ++ A C ++ A n.t. A B +++ A B ++ A D +++ B C ++ A B + B C + B C + A C + B C + A C + A B ++ A B + B C + A B ++ A B + A B + B C + A B + B C + A C ++ B D ++ B D +++ 244 B C + 245 A C +++ 249 A n.t. 250 A B + 251 A C + 252 A B + 253 A B ++ 256 A n.t. 257 A C +++ 258 B D ++ 260 B C + 265 A C + 266 B D ++ 267 B D ++ 270 B D ++ 271 B C + 273 B C + 277 B C + 278 A B ++ 279 C D + 281 A C + 282 B C + 287 B C ++ 288 A C +++ 290 B C + Table 4 It can be seen from Tables 3 and 4 that the heterobicyclic derivatives of the present invention are selective versus JAK3 in cells. The heterobicyclic derivatives of the present invention also exhibit high selectivity against other kinases. 7. ITK/JAK3 cellular activity assay NanoBRET ITK-NanoLuciferase and JAK3-NanoLuciferase fusion vectors were purchased from Promega. Nanoluciferase target fusion constructs and transfection carrier DNA were combined at a mass ratio of 1:10 before addition of FuGENE HD to form complexes at a ratio of 1:3 DNA:FuGENE according to the manufacturers protocol.20 parts of HEK cells resuspended at a density of 2 x 105 cells/ml in OptiMEM + 1% FBS were combined with 1 part of the transfection complexes (v/v). Cells were seeded into white, cell culture treated plates (Greiner) at a density of 8 x104 cells/well and incubated for 20 hrs. Compounds were dissolved in 100% DMSO and prepared on an intermediate plate in a half log dilution series and normalised to 1% DMSO.10X final assay concentration of compound was transferred to the assay plate and pre-incubated with the cells at 37 °C for 3 hrs.2 uL/well of K-520X tracer (final assay concentration 0.25 uM) was added to the assay plate and incubated at 37 °C for 2 hrs. To measure BRET, 20 uL/well NanoBRET NanoGlo substrate and extracellular inhibitor solution was added. Dual filtered luminescence was measured on BMG Labtech Pherastar FSX with a 450 nm BP filter (donor) and 610 LP filter (acceptor). Some of the acronyms used above have the following meaning: n.t.: not tested 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.

Claims

CLAIMS 1. A heterobicyclic derivative, which heterobicyclic derivative is a compound of formula (I) or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, wherein • X1 is N or CR1, wherein R1 is selected from H, halogen, nitrile, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and -C1-2 alkyl-O-C1-2 alkyl; • (a) X2 is C and X3 is NH or (b) X2 is N and X3 is CH • G1 is a 5-7 membered O-containing heterocyclic ring, wherein said O-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R3 groups and/or (b) two R3a groups, wherein each R3 group is independently selected from C1-4 alkyl, oxo, hydroxy, nitrile, C1-4 alkoxy, halogen, C1-4 haloalkyl and -C1-2 alkyl-O-C1-2 alkyl, provided that two hydroxy groups are not attached to the same atom, and wherein the two R3a groups are attached to the same carbon atom of the O- containing heterocyclic ring, and the two R3a groups together form a 3-to 6- membered spirocyclic group optionally comprising an O atom; • Y is selected from -N(R2)-, -O- and -C(HR2a)-, wherein R2 is selected from H, C1-4 alkyl and C1-4 haloalkyl; and R2a is selected from H, halogen, C1-4 alkyl and C1-4 haloalkyl; • n is 0 or 1; • G2 is a 4-10 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, hydroxy, C1-4 hydroxyalkyl and C1-4 alkoxy, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3-to 6- membered spirocyclic group optionally comprising an O atom; and • G3 is selected from -C(=O)C2-4 alkenyl, -NR5C(=O)C2-4 alkenyl, -C(=O)C2-4 alkynyl, -NR5C(=O)C2-4 alkynyl and –(NR5)0-1CN, provided that G3 is neither - NR5C(=O)C2-4 alkenyl, -NR5C(=O)C2-4 alkynyl nor –(NR5)CN when G3 is attached to a N- atom in G2, wherein said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C1-2 haloalkyl, nitrile and N(R6)2, and said C2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C1-2 haloalkyl, nitrile and N(R6)2, wherein R5 is H or C1-4 alkyl, and each R6 is the same or different and is a C1-3 alkyl.
2. A heterobicyclic derivative according to claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt, or a solvate, or a tautomer, or a stereoisomer thereof.
3. A heterobicyclic derivative of any one of claims 1 to 2, wherein G1 is a 5 or 6 membered O-containing heterocyclic ring, wherein said heterocyclic ring is unsubstituted or substituted with one, two or three R3 groups.
4. A heterobicyclic derivative of any one of the preceding claims, wherein each R3 is independently selected from C1-2 alkyl, C1-2 alkoxy, halogen or C1-2 haloalkyl.
5. A heterobicyclic derivative of any one of the preceding claims, wherein each R3 is independently selected from methyl, methoxy and fluoro.
6. A heterobicyclic derivative of any one of the preceding claims, wherein G1 is saturated.
7. A heterobicyclic derivative of any one of the preceding claims, wherein G1 is tetrahydropyran or tetrahydrofuran.
8. A heterobicyclic derivative of any one of the preceding claims, wherein G1 is .
9. A heterobicyclic derivative of any one of the preceding claims, wherein X2 is C and X3 is NH.
10. A heterobicyclic derivative of any one of the preceding claims, wherein X1 is N.
11. A heterobicyclic derivative of any one of the preceding claims, wherein X1 is CR1, preferably wherein X1 is CH.
12. A heterobicyclic derivative of any one of the preceding claims, wherein G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N- containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one, two or three R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, hydroxy, C1-4 hydroxyalkyl and C1-4 alkoxy, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3-to 6- membered spirocyclic group optionally comprising an O atom.
13. A heterobicyclic derivative of any one of the preceding claims, wherein G2 is unsubstituted or substituted with one or two R4, wherein each R4 is independently selected from C1-2 alkyl, C1-2 alkoxy, halogen or C1-2 haloalkyl.
14. A heterobicyclic derivative of any one of the preceding claims, wherein each R4 is independently selected from methyl and fluoro.
15. A heterobicyclic derivative of any one of the preceding claims, wherein G2 is substituted with two R4a groups, wherein the two R4a groups are attached to the same carbon atom of the N-containing heterocyclic ring and the two R4a groups together form a 3-to 4-membered spirocyclic group.
16. A heterobicyclic derivative of any one of the preceding claims, wherein n is 1.
17. A heterobicyclic derivative of claim 16, wherein Y is -N(H)-.
18. A heterobicyclic derivative of claim 16, wherein Y is -O-.
19. A heterobicyclic derivative of claim 16, 17 or 18, wherein G2 is selected from: wherein: each of p, q, r, r’, s, t and t’ is independently 0, 1, 2 or 3; u is 1, 2 or 3; the point of attachment to Y is obtained by removing a hydrogen atom from one of the carbon atoms in G2; the N atom in G2 is bonded to G3; and G2 is unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are two groups bonded to the same carbon atom in G2 and the two groups together form a 3- to 4-membered spirocyclic group.
20. A heterobicyclic derivative of any one of claims 16 to 19, wherein G2 is selected from: wherein * represents the point of attachment to Y, the N atom in G2 is bonded to G3, and G2 is unsubstituted or substituted with one methyl group.
21. A heterobicyclic derivative of claim 20, wherein G2 is selected from wherein G2 is unsubstituted or substituted with one methyl group.
22. A heterobicyclic derivative of any one of claims 1 to 15, wherein n is 0.
23. A heterobicyclic derivative of claim 22, wherein: each of p, q, r, r’, s, s’, t, t’, v and v’ is independently 0, 1, 2 or 3; m is 2 or 3; and one N is attached to the atom adjacent to X1 and the other N is attached to G3; or w is 1 or 2, the dotted double bond is present or absent, the point of attachment to the atom adjacent to X1 is obtained by removing a hydrogen atom from a ring carbon atom, and the N is attached to G3, wherein G2 is unsubstituted or substituted with one or two substituents which are independently selected from methyl and fluoro, optionally wherein the two substituents are two groups bonded to the same carbon atom in G2 and the two groups together form a 3-4 membered spirocyclic group.
24. A heterobicyclic derivative of claim 22 or 23, wherein G2 is selected from:
wherein, * represents the point of attachment to the atom adjacent to X1, and ** represents the point of attachment to G3.
25. A heterobicyclic derivative of any one of claims 22 to 24, wherein G2 is selected from wherein, * represents the point of attachment to the atom adjacent to X1, and ** represents the point of attachment to G3.
26 A heterobicyclic derivative of any one of the preceding claims, wherein G3 is attached to a N-atom in G2 and G3 is -C(=O)C2-4 alkenyl or -C(=O)C2-4 alkynyl, wherein said C2-4 alkenyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C1-2 haloalkyl, nitrile or N(R6)2, and said C2-4 alkynyl is unsubstituted or substituted by one or two substituents which are the same or different and are selected from C1-2 haloalkyl, nitrile or N(R6)2, wherein each R6 is the same or different and is a C1-3 alkyl.
27. A heterobicyclic derivative of any one of the preceding claims, wherein G3 is selected from:
.
28. A heterobicyclic derivative of any one of the preceding claims, wherein G3 is .
29. A heterobicyclic derivative of claims 1 to 10, 12 to 21 or 26 to 28, wherein the heterobicyclic derivative is a compound of formula (II), or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, wherein: Y is -NH- or -O-; G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring and the two R4a groups together form a 3-to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2.
30. A heterobicyclic derivative of claims 1 to 9, 11 to 21 or 26 to 28, wherein the heterobicyclic derivative is a compound of formula (IIa), or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, wherein: R1 is H, halogen, nitrile or C1-4 alkyl; preferably H; Y is -NH- or -O-; G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring and the two R4a groups together form a 3-to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2.
31. A heterobicyclic derivative of any one of claims 1 to 10, 12 to 15 or 22 to 28 which heterobicyclic derivative is a compound of formula (III) or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, wherein: G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2.
32. A heterobicyclic derivative of any one of claims 1 to 10, 12 to 15 , 22 to 28 or 31 which heterobicyclic derivative is a compound of formula (IV) or a pharmaceutically acceptable salt, or a solvate, or an N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, wherein: G2 is a 5-8 membered N-containing monocyclic or bicyclic heterocyclic ring, wherein said N-containing heterocyclic ring contains at least two nitrogen atoms, and is (i) unsubstituted or (ii) substituted with (a) one or two R4 groups and/or (b) two R4a groups, wherein each R4 is independently selected from C1-2 alkyl and halogen, and wherein the two R4a groups are attached to the same carbon atom of the N- containing heterocyclic ring, and the two R4a groups together form a 3- to 4- membered spirocyclic group; and G3 is , wherein R7a is H or F and R7b is H, -CH3 or -CH2-N(CH3)2.
33. A heterobicyclic derivative according to any one of the preceding claims, which heterobicyclic derivative is an ITK inhibitor.
34. A heterobicyclic derivative according to any one of the preceding claims, which is one of: • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one • N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin- 3-yl)acrylamide • 1-((1R,5R)-6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,6-diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one • (R)-1-(2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(4-(3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1- yl)prop-2-en-1-one • (R)-1-(3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1- yl)prop-2-en-1-one • (S)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R,E)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one • (R,Z)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-yn-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-yn-1-one • (R)-2-methyl-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (R)-2-fluoro-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (R,E)-4-(dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (R,E)-4-(dimethylamino)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one • (R)-1-(3,3-difluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-fluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2R,5R)-2-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2S,5R)-2-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2S,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,4R)-2-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-3-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-3-methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,4S)-3-fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)prop-2-en-1-one • 1-(7-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1R,2R,5R)-2-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one • (R)-1-(3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin- 1-yl)prop-2-en-1-one • rac-1-((4aR,7aR)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one • 1-((4aS,7aS)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one • 1-((4aR,7aR)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one • 1-((1R,4R)-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1S,4S)-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(2-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one • rac-1-((3aR,7aS)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one • 1-((3aS,7aR)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one • 1-((3aR,7aS)-1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)prop-2-en-1-one • rac-1-((3aR,7aR)-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one • 1-((3aS,7aS)-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one • 1-((3aR,7aR)-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl)prop-2-en-1-one • 1-(8-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one • 1-(5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)prop-2-en-1-one • 1-((1S,5S)-6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,6-diazabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((1S,5R)-3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,6-diazabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one • 1-((1R,5S)-3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,6-diazabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one • 1-(7-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7- diazaspiro[3.5]nonan-1-yl)prop-2-en-1-one • 1-(6-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.5]nonan-1-yl)prop-2-en-1-one • 1-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one • 1-(2-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazaspiro[3.5]nonan-6-yl)prop-2-en-1-one • 1-(2-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazaspiro[3.4]octan-5-yl)prop-2-en-1-one • 1-((2S,6R)-2,6-dimethyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one • 1-(7-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one • (S)-1-(2-methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazin-1-yl)prop-2-en-1-one • 1-(2,2-dimethyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazin-1-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- dihydropyridin-1(2H)-yl)prop-2-en-1-one • 1-(4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin- 1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dihydro-1H-pyrrol-1-yl)prop-2-en-1-one • 1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-1-yl)prop-2-en-1-one • (S)-1-(3-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-1-yl)prop-2-en-1-one • N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin- 4-yl)acrylamide • (R)-N-(1-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)acrylamide • (R)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acrylamide • (S)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acrylamide • (S)-N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)acrylamide • 1-((1S*,4S*)-4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1R*,4R*)-4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-(4-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazin-1-yl)prop-2-en-1-one • rac-1-((1R,4R,5R)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-((1R*,4R*)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • rac-1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • N-(1-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-4-yl)cyanamide • 1-((1S*,4S*)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • (R)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)prop-2-en-1-one • 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-oxa- 2,8-diazaspiro[3.5]nonan-8-yl)prop-2-en-1-one • (R)-1-(3-((5-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • (R)-1-(3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 4-((1S,4S)-5-Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1R*,4R*,5R*)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-((1S*,4S*,5S*)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-(6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,6- diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2S,3S)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(2-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-oxa- 2,5-diazaspiro[3.5]nonan-5-yl)prop-2-en-1-one • 4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidine-1-carbonitrile • 1-((1S,4S)-5-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propan-1-one • (R)-4-((1-Acryloylpiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile • (R)-4-((1-Acryloylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((1S,4S)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin- 4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-yn-1-one • 1-((3R,5R)-3-Methoxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 5-azaspiro[2.5]octan-5-yl)prop-2-en-1-one • 1-((1S*,5R*)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one • 1-((1R*,5S*)-6-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,6-diazabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one • 1-((3aR,6aR)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)prop-2-en-1-one • (R)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R*)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-azaspiro[2.5]octan-5-yl)prop-2-en-1-one • (S*)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-azaspiro[2.5]octan-5-yl)prop-2-en-1-one • 1-((1R*,4R*,7R*)-7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((1S*,4S*,7S*)-7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(7-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-oxa- 7,9-diazabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one • 1-((3aS,6aS)-5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)prop-2-en-1-one • (R)-1-(3,3-Dimethyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-(Methyl(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-(Methyl(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azetidin-1-yl)prop-2-en-1-one, • (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • (R*)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • (S*)-1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • 1-((2S,4R)-2-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3R,4S)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 4-(((2R,3R)-1-Acryloyl-2-methylpyrrolidin-3-yl)oxy)-3-(tetrahydro-2H-pyran- 4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-4-((1-Acryloyl-4,4-dimethylpyrrolidin-3-yl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((2R,3R)-3-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)-2-methylpyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,4R)-2-Methyl-4-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,4R)-2-Methyl-4-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • (S*)-1-(4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)-2-azabicyclo[3.1.1]heptan-2-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((3-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4R)-4-Fluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one • 1-((2R,3R)-2-Methyl-3-((3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2R*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methyl-5-((5-((2S*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((3aS*,6aR*)-3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR*,6aS*)-3a-Methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-((3aR,6aS)-3a,6a-dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 1-(1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one • 1-((1S*,5R*)-1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one • 1-((1R*,5S*)-1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one • 1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (S*)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (R*)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-Fluoro-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (S*)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R*)-1-(3,3-Difluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-5-(trifluoromethyl)piperidin-1-yl)prop-2-en-1-one • (S)-1-(4,4-Difluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-(oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,5R)-2-Methyl-5-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3aR,6aS)-5-(3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one • 4-(((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)amino)-3-(tetrahydro-2H-pyran- 4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 4-((3aR,6aS)-5-Acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 4-(((3R,6S)-1-Acryloyl-6-methylpiperidin-3-yl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 4-(((3R,5S)-1-Acryloyl-5-methylpiperidin-3-yl)amino)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • 1-((3S,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-(5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-azabicyclo[2.1.1]hexan-2-yl)prop-2-en-1-one • 1-((1R,4R)-5-(5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-((3S,4S)-3-Methoxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(3-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazin-1-yl)prop-2-en-1-one • rac-1-((1R,4R,6R)-6-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • rac-1-((1R,4R,6S)-6-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one • 1-(4-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-azabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one • (R)-1-(3-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,4S)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 4-(4-Acryloylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridine-5-carbonitrile • 1-((3R,5R)-3-Hydroxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((R)-3-((5-((2R*,4R*)-2-Methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((R)-3-((5-((2S*,4S*)-2-Methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,4R)-4-Methyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3S,4S)-3-Hydroxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,5R)-2-Isopropyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((1S,5R,6R)-5-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1-one • 1-((3S,4R)-3-Methyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-((5-((S*)-3,3-Difluorotetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-((5-((R*)-3,3-Difluorotetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • rac-1-((3R,4R)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S*,4S*)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R*,4R*)-3-Fluoro-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-(9-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,9- diazabicyclo[3.3.1]nonan-3-yl)prop-2-en-1-one • (S)-1-(2-Methyl-4-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazin-1-yl)prop-2-yn-1-one • 1-((3R,4S)-3-Hydroxy-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-(8-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6,8- diazabicyclo[3.2.2]nonan-6-yl)prop-2-en-1-one • 1-((3S,4S)-4-Methoxy-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-((3R,5R)-3-Methyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-yl)oxy)piperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((S*)-oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Methyl-3-((5-((R*)-oxepan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3S,5R)-3-Methoxy-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • 1-(1-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 3-azabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one • 1-((2R,3R)-2-Isopropyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one • 1-((2S,5R)-5-((5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one • 1-((2R,3R)-2-Isopropyl-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • (R)-1-(7-((5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one • (R)-1-(3,3-Dimethyl-4-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one • 1-((3R,5S)-3-((5-((3R*,4R*)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • 1-((3R,5S)-3-((5-((3S*,4S*)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one • 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one • 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-yn-1-one • 1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one • 1-(5-(5-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-yn-1-one • (E)-1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-en- 1-one • (Z)-1-((3aR,6aS)-3a,6a-Difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-en- 1-one • (Z)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • 1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one • 2-Fluoro-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one • (E)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • 1-((3aR,6aS)-5-(3-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en- 1-one • 1-((3aR,6aS)-5-(3-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en- 1-one • (E)-4-(Dimethylamino)-1-((3S,4R)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (S*,E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (R*,E)-1-(3,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (S,E)-1-(4,4-Difluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)but-2- en-1-one • (E)-4-(Dimethylamino)-1-((3R,4S)-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)piperidin-1-yl)but-2- en-1-one • 4-(((3S,4S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-4-fluoropiperidin-3- yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5- carbonitrile • (S,E)-4-((1-(4-(Dimethylamino)but-2-enoyl)-4,4-difluoropiperidin-3-yl)amino)- 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile • (E)-4-(Diethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-1-((3S)-4,4-Difluoro-3-((5-(2-methyltetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2- en-1-one • (E)-1-((S)-4,4-Difluoro-3-((5-((2R*,4R*)-2-methyltetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but- 2-en-1-one • (E)-1-((S)-4,4-Difluoro-3-((5-((2S*,4S*)-2-methyltetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but- 2-en-1-one • (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one • rac-(E)-1-((2R,3R,5S)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2- en-1-one • (E)-1-((2S*,3S*,5R*)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2- en-1-one • (E)-1-((2R*,3R*,5S*)-2,3-Dimethyl-5-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2- en-1-one • 4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-1-((3S,4S)-4-Fluoro-3-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-yl)-4-(isopropyl(methyl)amino)but-2-en-1- one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (R,E)-1-(3,3-Dimethyl-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)pyrrolidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)piperidin-1-yl)but-2-en-1-one • (R,E)-4-((1-(4-(Dimethylamino)but-2-enoyl)-4,4-dimethylpyrrolidin-3- yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5- carbonitrile • (E)-4-(Dimethylamino)-1-((2R,3R)-2-methyl-3-((3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((2R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpyrrolidin-1-yl)but-2-en-1-one • 4-(((3R,5S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-5-methylpiperidin-3- yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5- carbonitrile • (E)-4-(Dimethylamino)-1-((2S,5R)-5-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)but-2-en-1-one • (R,E)-4-(Dimethylamino)-1-(7-((5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)but-2-en-1-one • (E)-4-(Diisopropylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,5R)-3-methyl-5-((5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-(tetrahydro-2H-pyran-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-5-methylpiperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((1R*,5S*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1- one • (E)-4-(Dimethylamino)-1-((1S*,5R*)-1-((5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)but-2-en-1- one • (E)-4-(Dimethylamino)-1-((3R,5S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)but-2-en-1-one • 4-(((3R,6S)-1-((E)-4-(Dimethylamino)but-2-enoyl)-6-methylpiperidin-3- yl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-5- carbonitrile • (E)-4-(Dimethylamino)-1-((1S*,4R*,6R*)-6-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2- en-1-one • (E)-4-(Dimethylamino)-1-((1R*,4S*,6S*)-6-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2- en-1-one • (E)-4-(Dimethylamino)-1-((1R*,4S*,6R*)-6-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2- en-1-one • (E)-4-(Dimethylamino)-1-((1S*,4R*,6S*)-6-((5-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)but-2- en-1-one • 4-(Dimethylamino)-1-(5-(5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)but-2-yn-1-one • (E)-1-((3aR,6aS)-3a,6a-difluoro-5-(5-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4- (dimethylamino)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((2S,5R)-2-methyl-5-((3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-((2R*,4R*)-2- methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(dimethylamino)-1-((3S,4S)-4-fluoro-3-((3-((2S*,4S*)-2- methyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidin-1-yl)but-2-en-1-one • (E)-4-(Dimethylamino)-1-((3S,4S)-4-fluoro-3-((5-fluoro-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)but-2-en-1-one • (R,E)-4-(Dimethylamino)-1-(4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)-2-azabicyclo[3.1.1]heptan-2-yl)but-2-en-1-one • (S,E)-1-(4,4-Difluoro-3-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)-3-methylbut-2-en-1- one, or • (E)-1-((3aR,6aS)-3a,6a-Difluoro-5-(3-(2-methyltetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4- (dimethylamino)but-2-en-1-one
35. A pharmaceutical composition comprising a heterobicyclic derivative according to any one of claims 1 to 34 and a pharmaceutically acceptable carrier or diluent.
36. A heterobicyclic derivative according to any one of claims 1 to 34, or the composition of claim 35, for use as a medicament.
37. A heterobicyclic derivative according to any one of claims 1 to 34, or the composition of claim 35, for use in a method of treating a condition or disease selected from atopic dermatitis, psoriasis, chronic hand eczema, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis.
38. Use of a heterobicyclic derivative according to any one of claims 1 to 34, or the composition of claim 35, in the manufacture of a medicament for treating a condition or disease selected from atopic dermatitis, psoriasis, chronic hand eczema, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis.
39. A method of treating a condition or disease selected from atopic dermatitis, psoriasis, chronic hand eczema, alopecia areata, hidradenitis suppurativa, vitiligo, T-cell lymphoma, asthma, inflammatory bowel disease and multiple sclerosis, the method comprising administering to said subject a therapeutically effective amount of a heterobicyclic derivative according to any one of claims 1 to 34, or the composition of claim 35.
PCT/EP2025/055361 2024-02-28 2025-02-27 Heterobicyclic derivatives as itk inhibitors Pending WO2025181247A1 (en)

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