PHARMACEUTICALLY ACTIVE HETEROCYCLIC ACRYLAMIDS AND COMPOSITIONS TO TREAT AND PREVENT JAC MEDIATED C

专利摘要:
pyrrole [2,3-d] pyrimidinyl, pyrrole [2,3-b] pyrazinyl and pyrrole [2,3-d] pyridinyl acrylamides. the present invention provides pyrrolo [2,3-d] pyrimidinyl and pyrrolo [2,3-d] pyridinyl acrylamides pharmaceutically active and the like. such compounds are useful for the inhibition of janus kinase (jak). this invention is also directed to compositions that comprise methods of preparing such compounds, and methods for treating and preventing conditions mediated by jak.
公开号:BR112016012262B1
申请号:R112016012262-3
申请日:2014-11-20
公开日:2021-04-13
发明作者:Matthew Frank Brown；Agustin Casimiro-Garcia；Ye CHE；Jotham Wadsworth Coe；Mark Edward Flanagan；Adam Matthew Gilbert；Matthew Merrill Hayward；Jonathan David Langille；Justin Ian Montgomery；Jean-Baptiste Telliez；Atli Thorarensen；Rayomand Jal Unwalla；John I. Trujillo
申请人:Pfizer Inc；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[001] The present invention provides pharmaceutically active heterocyclic acrylamides, among others, pyrrolo [2,3-d] pyrimidinyl, pyrrole [2,3-b] pyrazinyl and pyrrole [2,3-d] pyridinyl acrylamides and analogs of themselves. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention is also directed to compositions that comprise methods for the preparation of such compounds, and methods for treating and preventing JAK-mediated conditions. BACKGROUND OF THE INVENTION
[002] Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine / threonine kinases. Inappropriate kinase activity, arising from mutation, overexpression, or inappropriate regulation, deregulation or deregulation, as well as over or underproduction of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer , cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders, such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cell responses related to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases.
[003] In this way, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) plays a central role in cytokine signaling (Kisseleva, et al., Gene, 2002, 285, 1; Yamaoka, et al. Genome Biology, 2004, 5, 253)). In connection with their receptors, cytokines activate JAK which then phosphorylates the cytokine receptor, thereby creating anchoring sites for signaling molecules, notably members of the signal transducer and transcription activator (STAT) family that ultimately lead to expression of gene. Numerous cuticubes are known to activate the JAK family. These cytokines include the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23, IL-27 and IL-35), common gamma chain family (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21,), and IL-13, TLSP, IL-3 family (IL-3, IL-5, GM-CSF ), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).
[004] There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK3 in particular. JAK3 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2, and is expressed at various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1 / JAK2, JAK1 / JAK3, JAK1 / TYK2, JAK2 / TYK2 or JAK2 / JAK2. Animal studies have shown that JAK3 is implicated in the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK3 kinase activity may prove to be useful in the treatment of various immune disorders (Murray, PJJ Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285, 1-24 (2002); O'Shea, JJ, et al., Cell, 109, (suppl.) S121-S131 (2002)) while avoiding JAK2-dependent erythropoietin signaling ( EPO) and thrombopoietin (TPO) (Neubauer, H., et al., Cell, 93 (3), 397-409 (1998); Parganas, E., et al., Cell, 93 (3), 385-95 (1998)). SUMMARY OF THE INVENTION
[005] The present invention provides a compound that has the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R5, R6, R7, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic heteroaryl or bicyclic, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1- C6 straight chain alkyl or branched) heteroaryl, and (C1-C6 straight or branched chain) heterocyclic alkyl, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6 or R7, respectively together with any one of R4, R5, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4 or R5, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a bond or a linear C1-C6 alkyl chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; Y is O or N, where when Y is O, n is 0; one and only one of the dotted bonds to Z and Z 'constitutes a single bond, the other being absent, and either Z is C when the dotted bond to Z is a single bond, and Z' is N or CR16; or, Z is CR16 or N when the dotted bond to Z 'is a single bond, and Z' is C; where R16 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6-membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, or ( C1-C6 straight chain or branched alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl ; X and the dotted connections to it may be present or absent, whereby, (a) if X is present, Y is N, and X is O or - (CReRf) s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising rings of 5 and / or 6 members, (aryl) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, or ( heterocyclic) C1-C6 straight or branched chain alkyl, and said dotted bonds are present and are unique bonds, whereby when n is 0, and X is O, said O is linked to H, and said bond dotted between X and - (CH2) n-- is absent, and when X is - (CReRf) s--, and X is linked directly to Y; and (b) if X is absent, said dotted bonds are absent and n is 0, whereby when Y is N, any of (i) said N atom is replaced by H, (ii) Z is C, Z 'is C or N, the dotted link to Z is a single link, the dotted link to Z' being absent, or (iii) Z is C or N, Z 'is C, the dotted link to Z' is a single bond, the dotted bond to Z being absent, where said Y being an N atom can together with R2 and the intermediate atoms between them form a 6-membered ring optionally substituted by straight or branched C1-C6 alkyl or C3- C6 cycloalkyl; and, n, p, q, res are independently 0, 1 or 2.
[006] In other respects, the present invention also provides: pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the invention; methods to treat or prevent a selected disorder or condition of rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis, Alzheimer's disease, lupus, nephritis, systemic lupus erythematosus, psoriasis, eczema dermatitis, pruritus or other pruritic conditions, vitiligo, alopecia, autoimmune thyroid disorders, multiple sclerosis, major depression disorder, allergy, asthma, Sjogren's disease, Reiter's syndrome, polymyositis- dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune disease, Goodpasture disease, autoimmune thrombocytopenia, severe ophthalmia, sympathetic ophthalmia Serious, primary biliary cirrhosis, chronic aggressive hepatitis, glomerulopathy me mbranosa, organ transplant rejection, graft versus host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidneys, limb, liver, lung, muscle, myoblast, nerve , pancreas, skin, small intestine, or trachea, or xenotransplantation, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type 1 or youth-onset diabetes, and complications of diabetes, or thyroiditis, obstructive disorder chronic lung disease, acute respiratory disease, cachexia, cancer, including food / gastrointestinal cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and breast cancer, ovarian cancer, cancer prostate cancer, leukemia, adult T cell leukemia, large diffuse B cell lymphoma, activated B cell type, kidney cancer, lung cancer, muscle cancer, bone cancer, cancer bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, septic shock from Kaposi's sarcoma, cardiopulmonary dysfunction, acute myeloid leukemia, acute T-cell lymphoblastic leukemia, multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, or angiogenic disorders -associated including solid tumors, pancreatic cancer, brain tumors, gliomas including astrocytoma, oligodendroglioma, and glioblastoma, acute CNS trauma including traumatic brain damage, encephalitis, stroke, and spinal cord injury, epilepsy, convulsive crises, associated chronic neuroinflammation with neurodegeneration, including Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, cerebral ischemia, fronto-temporal lobe dementia, and with neuropsychiatric disorders, including schizophrenia, bipolar disorder, treatment-resistant depression, Post-Stress Disorder Traumatic, anxiety , and autoantibody-mediated encephalopathies, diseases, disorders or ophthalmic conditions, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis , corneal epithelial dystrophy, keratoleucoma, ocular pemphigus, Mooren's ulcer, scleritis, Grave ophthalmopathy, Vogt-Koyanagi- syndrome Harada, dry keratoconjunctivitis (dry eye), phythagula, iridocyclitis, sarcoidosis, endocrine ophthalmology, endocrine ophthalmology, endocrine ophthalmology, endocrine ophthalmology -genic, and ocular neovascularization, which comprises the step of administering to an individual an effective amount of a composition comprising a compound or a pharmaceutically acceptable salt thereof mentioned herein; methods for the treatment of conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritic conditions, allergic reactions including allergic dermatitis in mammal, allergic horse diseases including hypersensitivity to bite, summer eczema, mild itching in horses, sighs, inflammatory airway disease, recurrent airway obstruction, airway hypersensitivity, and chronic obstruction lung disease by administering to a mammal in need, a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt of the same; and, methods for the preparation of compounds of the present invention. The present invention will also be understood from the following description given by way of example only. The present invention is directed to a class of pyrrolo [2,3-d] pyrimidinyl and pyrrole [2,3-d] pyridinyl acrylamides and the like. In particular, the present invention is directed to compounds including pyrrolo [2,3-d] pyrimidinyl and pyrrolo [2,3-d] pyridinyl acrylamides which are useful as inhibitors of JAK, and particularly JAK3. Although the present invention is not thereby limited, an appreciation of various aspects of the invention will be obtained by means of the following description and examples.
[007] The term "alkyl", alone or in combination, means a saturated acyclic hydrocarbon group of the formula CnH2n + 1 which can be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl and hexyl. Unless otherwise specified, an alkyl group comprises 1 to 6 carbon atoms. The content of alkyl carbon atom and various other hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the portion, that is, the prefix Ci-Cj indicates a portion of the integer "i" for the whole number "j" of carbon atoms, inclusive. Thus, for example, C1-C6 alkyl refers to the alkyl of one to six carbon atoms, inclusive.
[008] The term "hydroxy," as used here, means an OH radical. The term "heterocyclic" refers to a saturated or partially saturated (i.e., non-aromatic) heterocycle that can be attached via a ring nitrogen atom (when the heterocycle is attached to a carbon atom) or an atom ring carbon (in all cases). Likewise, when substituted, the substituent can be located on a ring nitrogen atom (if the substituent is joined via a carbon atom) or a ring carbon atom (in all cases). Specific examples include oxiranyl, aziridinyl, oxetanil, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanil, oxepanyl, oxazepanil and diazepinyl.
[009] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon that can be attached via a ring carbon atom. Likewise, when substituted, the substituent can be located on a ring carbon atom. Specific examples include phenyl, toluyl, xylyl, trimethylphenyl, and naphthyl. Examples of aryl substituents include alkyl, hydroxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO2Me, benzyl, and substituted benzyl.
[010] The term "heteroaryl" refers to an aromatic heterocycle that can be attached via a ring carbon atom (in all cases) or a ring nitrogen atom with an appropriate valence (when the heterocycle is attached to a carbon atom). Also, when substituted, the substituent can be located on a ring carbon atom (in all cases) or a ring nitrogen atom with an appropriate valence (if the substituent is attached via a carbon atom). Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyriminyl. The term "cycloalkyl" means a saturated, monocyclic hydrocarbon group of the formula CnH2n-1. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, a cycloalkyl group comprises 3 to 8 carbon atoms.
[011] The terms "halo" and "halogen" refer to fluoride (F), chloride (Cl), bromide (Br) or iodide (I).
[012] The term "mammal" refers to humans, cattle or companion animals.
[013] The term "pet animal" or "pet animals" refers to animals kept as a pet or domestic animal. Examples of companion animals include dogs, cats, and rodents, including hamsters, guinea pigs, gerbils and the like, ferrets and birds.
[014] The term "livestock" refers to livestock or reared in an agricultural setting to prepare products, such as food or fiber, or for their work. In some embodiments, livestock is suitable for consumption by mammals, for example, humans. Examples of livestock animals include cattle, goats, horses, pigs, sheep, including lambs, and rabbits, as well as birds, such as chickens, ducks and turkeys.
[015] The term "treat" or "treatment" means relief from symptoms associated with a disease, disorder or condition, or interruption of new progression or worsening of these symptoms. Depending on the patient's disease or condition, the term "treatment" as used here may include one or more of curative, palliative and prophylactic treatment. Treatment may also include administering a pharmaceutical formulation of the present invention in combination with other therapies.
[016] The term "therapeutically effective" indicates an agent's ability to prevent, or improve the severity of the disorder, while avoiding adverse side effects typically associated with alternative therapies. The phrase "therapeutically effective" should be understood to be equivalent to the phrase "effective for treatment, prevention, or improvement", and both are intended to qualify the amount of each agent for use in combination therapy that will achieve the goal of improving severity cancer, cardiovascular disease, or pain and inflammation and the frequency of incidence during the treatment of each agent alone, while avoiding adverse side effects typically associated with alternative therapies.
[017] "Pharmaceutically acceptable" means suitable for use in mammals, pets or livestock.
[018] If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent, therefore, can be identical to, or different from, the other substituent (s). DETAILED DESCRIPTION OF THE INVENTION
[019] The present invention relates to new compounds that are selective JAK3 modulators useful for the treatment of diseases and conditions associated with JAK3 dysregulation. The present invention also provides pharmaceutical compositions that comprise such JAK3 modulators, as well as methods of treating and preventing such diseases and conditions. Consequently, the present invention provides a compound that has the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R5, R6, R7, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic heteroaryl or bicyclic, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl ) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6 or R7, respectively together with any one of R4, R5, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4 or R5, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a bond or a linear C1-C6 alkyl chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; Y is O or N, where when Y is O, n is 0; one and only one of the dotted bonds to Z and Z 'constitutes a single bond, the other being absent, and either Z is C when the dotted bond to Z is a single bond, and Z' is N or CR16; or, Z is CR16 or N when the dotted bond to Z 'is a single bond, and Z' is C; where R16 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6-membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, or heterocyclic (C1-C6 straight or branched chain alkyl), where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl; X and the dotted connections to it may be present or absent, whereby, (a) if X is present, Y is N, and X is O or - (CReRf) s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising rings of 5 and / or 6 members, (aryl) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, or ( heterocyclic) C1-C6 straight or branched chain alkyl, and said dotted bonds are present and are unique bonds, whereby when n is 0, and X is O, said O is linked to H, and said bond dotted between X and - (CH2) n-- is absent, and when X is - (CRθRf) s—, and X is directly linked to Y; and (b) if X is absent, said dotted bonds are absent and n is 0, whereby when Y is N, any of (i) said N atom is replaced by H, (ii) Z is C, Z 'is C or N, the dotted link to Z is a single link, the dotted link to Z' being absent, or (iii) Z is C or N, Z 'is C, the dotted link to Z' is a single bond, the dotted bond to Z being absent, where said Y being an N atom can together with R2 and the intermediary atoms between them form a 6-membered ring optionally substituted by straight chain C1-C6 alkyl or branched or C3-C6 cycloalkyl; and, n, p, q, res are independently 0, 1 or 2.
[020] In one embodiment, the invention provides a compound that has the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 chain alkyl linear or branched) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, wherein said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; Y is O or N, where when Y is O, n is 0; one and only one of the dotted bonds to Z and Z 'constitutes a single bond, the other being absent, and either Z is C when the dotted bond to Z is a single bond, and Z' is N or CR16; or, Z is CR16 or N when the dotted bond to Z 'is a single bond, and Z' is C; where R16 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6-membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, or ( C1-C6 straight chain or branched alkyl) heterocyclic, wherein said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl; X and the dotted connections to it may be present or absent, whereby, (a) if X is present, Y is N, and X is O or - (CReRf) s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising rings of 5 and / or 6 members, (aryl) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, or (heterocyclic) C1-C6 straight or branched chain alkyl, and said dotted bonds are present and are unique bonds, whereby when n is 0, and X is O, said O is linked to H, and said dotted bond between X e - (CH2) n-- is absent, and when X is - (CReRf) s--, and X is directly linked to Y; and (b) if X is absent, said dotted bonds are absent and n is 0, whereby when Y is N, any of (i) said N atom is replaced by H, (ii) Z is C, Z 'is C or N, the dotted link to Z is a single link, the dotted link to Z' being absent, or (iii) Z is C or N, Z 'is C, the dotted link to Z' is a single bond, the dotted bond to Z being absent, where said Y being an N atom can together with R2 and the intermediary atoms between them form a 6-membered ring optionally substituted by straight or branched C1-C6 alkyl or C3-C6 cycloalkyl; and, n, p, q, res are independently 0, 1 or 2.
[021] In another embodiment, the invention provides a compound that has the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1- C6 straight or branched chain alkyl) heteroaryl , and (C1-C6 straight or branched chain alkyl) heterocyclic, wherein said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; Z is CR16 or N, where R16 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight chain alkyl or branched) heteroaryl, or (C1-C6 straight chain or branched) heterocyclic alkyl, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3 , and C3-C6 cycloalkyl; X and the dotted bonds to it may be present or absent, whereby, (a) if X is present, X is O or - (CReRf) s--, where Re and Rf are independently hydrogen, deuterium, halo , hydroxy, C1-C4 alkoxy, amino, CF3, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl ) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, or (heterocyclic) C1-C6 straight or branched chain alkyl , and said dotted bonds are present and are unique bonds, whereby when n is 0, and X is O, said O is linked to H, and said dotted bond between X and - (CH2) n— is absent; and (b) if X is absent, said dotted bonds are absent and n is 0, whereby either of (i) the adjacent N atom is replaced by H, or (ii) said N atom can together with R2 and the intermediate atoms between them form a 6-membered ring optionally substituted by straight or branched C1-C6 alkyl or C3-C6 cycloalkyl; and, n, p, q, res are independently 0, 1 or 2.
[022] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 chain alkyl linear or branched) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3 -C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; Z is CR16 or N, where R16 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight chain alkyl or branched) heteroaryl, or (C1-C6 straight chain or branched) heterocyclic alkyl, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3 , and C3-C6 cycloalkyl; R11 is hydrogen or deuterium; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; and, p, q, er are independently 0, 1 or 2.
[023] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, aryl, alkylaryl, (aryl) C1-C6 straight chain alkyl or branched, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) straight chain or C1-C6 alkyl branched, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3 -C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; Z is CR16 or N, where R16 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight chain alkyl or branched) heteroaryl, or (C1-C6 straight chain or branched) heterocyclic alkyl, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3 , and C3-C6 cycloalkyl; R11 is hydrogen or deuterium; and, R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1- C6 straight or branched chain alkyl.
[024] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, aryl, alkylaryl, (aryl) C1-C6 straight chain alkyl or branched, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) straight chain or C1-C6 alkyl branched, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3 -C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; and, R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1- C6 straight or branched chain alkyl.
[025] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, aryl, alkylaryl, (aryl) C1-C6 straight chain alkyl or branched, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) straight chain or C1-C6 alkyl branched, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3 -C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; and, R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1- C6 straight or branched chain alkyl.
[026] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, aryl, alkylaryl, (aryl) C1-C6 straight chain alkyl or branched, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) straight chain or C1-C6 alkyl branched, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, wherein said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl, where said alkyl is also optionally substituted by one or more substituents selected from the group which consists of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3 -C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; and, R11 is hydrogen or deuterium; Y is O or N, where when Y is O, n is 0; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; X and the dotted connections to it may be present or absent, whereby, (a) if X is present, Y is N, and X is O or - (CReRf) s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising rings of 5 and / or 6 members, (aryl) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, or (heterocyclic) C1-C6 straight or branched chain alkyl, and said dotted bonds are present and are unique bonds, whereby when n is 0, and X is O, said O is linked to H, and said bond dotted between X and - (CH2) n-- is absent, and when X is - (CRθRf) s—, and X is linked directly to Y; and (b) if X is absent, said dotted bonds are absent and n is 0, whereby when Y is N, either (i) said N atom is replaced by H, or (ii) said atom of N can together with R2 and the intermediate atoms between them form a 6-membered ring optionally substituted by straight or branched C1-C6 alkyl or C3-C6 cycloalkyl; and, n, p, q, res are independently 0, 1 or 2.
[027] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight chain alkyl or branched, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl) heterocyclic, C1-C6 perfluoroalkyl of straight or branched chain, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1-C6 straight or branched chain alkyl) aminocarbonylamino, (C1-C6 straight or branched chain alkyl) aminocarbonyl, -SOR12, -SO2R12, -NR 13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; R0, R1, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises rings 5 and / or 6 membered, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 chain alkoxy linear or branched, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a bond or a linear C1C6 alkyl chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; R11 is hydrogen or deuterium; and, R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1- C6 straight or branched chain alkyl.
[028] In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heteroaryl) (C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, (C1-C6 straight or branched chain alkyl - da) heterocyclic, C1-C6 straight or branched chain perfluoroalkyl, C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1- C6 straight chain or branched alkyl) aminocarbonylamino, (C1-C6 straight chain alkyl ear or branched) aminocarbonyl, -SOR12, -SO2R12, -NR13SO2R12, -SO2NR13R14, and - NR13SO2NR14R15; where said alkyl, aryl and heteroaryl are independently optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 alkyl straight or branched chain) aminocarbonyl, and C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 straight or branched chain alkyl, C1-C6 perfluoro-straight or branched chain alkyl, halogen, and cyano; A is - (CRaRb) q- (CRcRd) r ~, where Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight chain C1-C6 perfluoroalkyl or branched, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and / or 6 membered rings, alkylaryl, C1-C6 straight or branched chain alkyl (heteroaryl) C1-C6 straight or branched chain alkyl , halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl , (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo , hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; Ra, Rb, Rc and Rd are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, aryl, alkylaryl, (aryl) C1-C6 straight chain alkyl or branched, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 straight or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic) straight chain or C1-C6 alkyl branched, (C1-C6 straight or branched chain alkyl) aryl, (C1-C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, wherein said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl, where said alkyl is also optionally substituted by one or more substituents selected from the group which consists of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; R0, R1, R4, R6, R8, R9 and R10 are independently selected from hydrogen, C1-C6 straight or branched chain alkyl, C1C6 straight or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, which comprises 5 and / or 6 membered rings, (aryl) C1-C6 straight or branched chain alkyl, (heteroaryl) C1-C6 straight or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 alkoxy straight or branched chain, amino, carboxy, aminocarbonyl, (heterocyclic) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) aryl, (C1C6 straight or branched chain alkyl) heteroaryl, and (C1-C6 straight or branched chain alkyl) heterocyclic, where said alkyl is also optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3 -C6 cycloalkyl; where, alternatively, R0 or R1, and / or R6, respectively together with any one of R4, Ra, Rb, Rc or Rd, can independently form a linear C1-C6 alkyl bond or chain; and / or, alternatively, R4, respectively together with any one of Ra, Rb, Rc or Rd, can independently form a linear alkyl bond or C1-C6 chain; and / or, alternatively, R8 and R9 can together form a 3- to 6-membered ring optionally containing one or two O or N atoms; and, R11 is hydrogen or deuterium; Y is O or N, where when Y is O, n is 0; R12, R13, R14 and R15 are independently selected from hydrogen, straight or branched C1-C6 alkyl, straight or branched C1-C6 perfluoro-alkylalkyl, C6-C10 aryl, alkylaryl, and (aryl) C1-C6 alkyl straight or branched chain; X and the dotted connections to it may be present or absent, whereby, (a) if X is present, Y is N, and X is O or - (CReRf) s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising rings of 5 and / or 6 members, (aryl) C1-C6 straight or branched chain alkyl, (C1-C6 straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, or (heterocyclic) C1-C6 straight or branched chain alkyl, and said dotted bonds are present and are unique bonds, whereby when n is 0, and X is O, said O is linked to H, and said dotted bond between X e - (CH2) n-- is absent, and when X is - (CReRf) s--, and X is directly linked to Y; and (b) if X is absent, said dotted bonds are absent and n is 0, whereby when Y is N, either (i) said N atom is replaced by H, or (ii) said atom of N can together with R2 and the intermediate atoms between them form a 6-membered ring optionally substituted by straight or branched C1-C6 alkyl or C3-C6 cycloalkyl; and, n, p, q, res are independently 0, 1 or 2.
[029] Specifically, the invention provides compounds selected from the group consisting of: 2- (1-acryloylpiperidin-4-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; N-isopropyl-2- (3- (N-methylacrylamide) azetidin-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; 2 - (((3R, 4R) -1-acryloyl-3-hydroxypiperidin-4-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2- (1-acryloylpyrrolidin-3-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2 - ((1-acryloylpyrrolidin-2-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; 2 - ((1R, 3R) -3-acrylamidocyclobutylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; and, (S) -2 - ((1-acryloylpyrrolidin-3-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; or, a pharmaceutically acceptable salt thereof.
[030] The invention also provides additional compounds selected from the group consisting of: (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; (R) -1- (3- (5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1- (5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - ((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3S, 4R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-ethylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) tetrahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H, 7H, 7aH) -yl) prop-2-en-1-one; (R) -1- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((1R, 2R, 5R) -2- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -8-azabicyclo [3.2.1] octan-8-yl) prop-2-en -1-one; 1 - (((2R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((2S, 5R) -5- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en -1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; (R) -4- (1-acryloylpiperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile; and, (3R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -1- acryloylpiperidine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.
[031] In particular, the invention provides 2- (1-acryloylpiperidin-4-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; or a pharmaceutically acceptable salt thereof; N-isopropyl-2- (3- (N-methylacrylamide) azetidin-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; or, a pharmaceutically acceptable salt thereof; 2 - ((3R, 4R) -1- acryloyl-3-hydroxypiperidin-4-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; or, a pharmaceutically acceptable salt thereof; (S) -2- (1-acryloylpyrrolidin-3-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; or, a pharmaceutically acceptable salt thereof; (S) -2 - ((1-acryloylpyrrolidin-2-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; or a pharmaceutically acceptable salt thereof; 1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) tetrahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H, 7H, 7aH) -yl) prop-2-en-1-one; or, a pharmaceutically acceptable salt thereof; 1 - (((1R, 2R, 5R) -2- (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) prop- 2-en-1-one, or a pharmaceutically acceptable salt thereof; 1 - (((3R, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1-one, or a pharmaceutically acceptable salt thereof; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; or, a pharmaceutically acceptable salt thereof; (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; or, a pharmaceutically acceptable salt thereof.
[032] The present invention also provides a pharmaceutical or veterinary composition comprising a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[033] The present invention also provides a method for treating or preventing a selected disorder or condition of rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, celiac diseases, proctitis, eosinophilic gastroenteritis, or mastocytosis, Alzheimer's disease, lupus, nephritis, systemic lupus erythematosus, psoriasis, eczema dermatitis, pruritus or other pruritic conditions, vitiligo, alopecia, autoimmune thyroid disorders, multiple sclerosis, major depression, major depression allergy, asthma, Sjogren's disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune encephalitis Goodpasture disease, autoimmune thrombo-cytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis chronic aggressive hepatitis, membranous glomerulopathy, organ transplant rejection, graft versus host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidneys, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xenotransplantation, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type 1 or onset diabetes, and complications of diabetes, or thyroiditis, chronic obstructive pulmonary disorder, acute respiratory disease, cachexia, cancer, including cancer of the alimentary / gastrointestinal tract, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, cancer and breast cancer, ovarian cancer, prostate cancer, leukemia, adult T-cell leukemia, diffuse large B-cell lymphoma, activated B-cell type, kidney cancer, cancer lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, septic shock from Kaposi's sarcoma, cardiopulmonary dysfunction, acute myeloid leukemia, acute T-cell lymphoblastic leukemia, multiple myeloma, myeloproliferative disorders , proliferative diabetic retinopathy, or angiogenic-associated disorders including solid tumors, pancreatic cancer, brain tumors, gliomas including astrocytoma, oligodendroglioma, and glioblastoma, acute CNS trauma including traumatic brain damage, encephalitis, stroke, and spinal cord injury spinal cord, epilepsy, seizures, chronic neuroinflammation associated with neurodegeneration, including Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, cerebral ischemia, fronto-temporal lobe dementia, and with neuropsychiatric disorders, including schizophrenia, bipolar disorder , treatment-resistant depression to, Post Traumatic Stress Disorder, anxiety, and encephalopathies mediated by autoantibodies, diseases, disorders or ophthalmic conditions, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and uveitis induced by lenses, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleucoma, ocular pemphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, dry keratitis, dry eye, flickering, iris , endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization, which comprises the step of administering to an individual an effective amount of a composition comprising a compound mentioned above.
[034] In specific embodiments, the invention provides the treatment or prevention method mentioned above, in which the compound is selected from the group consisting of: 2- (1-acryloylpiperidin-4-ylamino) -N-isopropyl-5H-pyrrole [2,3-b] pyrazine-7-carboxamide; N-isopropyl-2- (3- (N-methylacrylamide) azetidin-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; 2 - (((3R, 4R) -1-acryloyl-3-hydroxypiperidin-4-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2- (1-acryloylpyrrolidin-3-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2 - ((1-acryloylpyrrolidin-2-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; 2 - ((1R, 3R) -3-acrylamidocyclobutylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2 - ((1-acryloylpyrrolidin-3-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; (R) -1- (3- (5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1- (5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - ((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3S, 4R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-ethylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) tetrahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H, 7H, 7aH) -yl) prop-2-en-1-one; (R) -1- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((1R, 2R, 5R) -2- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -8-azabicyclo [3.2.1] octan-8-yl) prop-2-en -1-one; 1 - (((2R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((2S, 5R) -5- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en -1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; (R) -4- (1-acryloylpiperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile; and, (3R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -1- acryloylpiperidine-3-carbonitrile; or, a pharmaceutically acceptable salt thereof.
[035] The present invention also provides a method for treating or preventing inflammatory bowel disease by administering to a mammal in need, a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof.
[036] In specific embodiments, the invention provides the method of treating or preventing inflammatory bowel disease, wherein the compound is selected from the group consisting of: 2- (1-acryloylpiperidin-4-ylamino) -N-isopropyl-5H -pyrrole [2,3-b] pyrazine-7-carboxamide; N-isopropyl-2- (3- (N-methylacrylamide) azetidin-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; 2 - (((3R, 4R) -1-acryloyl-3-hydroxypiperidin-4-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2- (1-acryloylpyrrolidin-3-ylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2 - ((1-acryloylpyrrolidin-2-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; 2 - ((1R, 3R) -3-acrylamidocyclobutylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (S) -2 - ((1-acryloylpyrrolidin-3-yl) methylamino) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide; (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; (R) -4- (1-acryloylpiperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile; (R) -1- (3- (5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1- (5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - ((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3S, 4R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-ethylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) tetrahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H, 7H, 7aH) -yl) prop-2-en-1-one; (R) -1- (3- (3-chloro-1H-pyrrolo [2,3-b] pyridin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((1R, 2R, 5R) -2- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -8-azabicyclo [3.2.1] octan-8-yl) prop-2-en -1-one; 1 - (((2R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((2S, 5R) -5- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en -1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; (R) -4- (1-acryloylpiperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile; and, (3R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -1- acryloylpiperidine-3-carbonitrile; or, a pharmaceutically acceptable salt thereof.
[037] More generally, the present invention provides a method of treating a disorder or condition related to dysregulation of JAK, and particularly JAK3, in an individual, which comprises administering to the individual a therapeutically effective amount of the compound described above, or a salt pharmaceutically acceptable product.
[038] In certain embodiments, the therapeutically effective amount used according to the method is 0.01 mg / kg body weight / day to 100 mg / kg body weight / day. In certain other embodiments, the therapeutically effective amount used according to the method is the therapeutically effective amount of 0.1 mg / kg body weight / day to 10 mg / kg body weight / day. In practice of the method, the compound is preferably selected from those specified above.
[039] In certain embodiments, the therapeutically effective amount used according to the method is 0.01 mg / kg body weight / day to 100 mg / kg body weight / day. In certain other embodiments, the therapeutically effective amount used according to the method is the therapeutically effective amount is 0.1 mg / kg body weight / day to 10 mg / kg body weight / day. According to the method, the mammal treated with the compound of the invention is selected from companion animals, dogs, and livestock animals. In certain embodiments, the compound of the invention, or a pharmaceutically acceptable salt thereof, can be administered according to the method orally, parenterally, or topically.
[040] Compounds that have the same molecular formula but differ in the nature or binding sequence of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". It will be appreciated by those skilled in the art that the compound of the invention may exist as cis- and trans-aquir diastereomers.
[041] Included in the scope of the described compounds are all isomers (for example, cis-, trans-, or diastereomers) of the compounds described here alone, as well as any mixtures. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are included in the compounds described. Stereoisomeric mixtures, for example, mixtures of diastereomers, can be separated into their corresponding isomers in a manner known for their proper separation methods. Diastereomeric mixtures, for example, can be separated into their individual diastereomers by fractional crystallization methods, chromatography, solvent distribution, and similar procedures. This separation can occur either at the level of one of the starting compounds or in a compound of the invention itself. Enantiomers can be separated by forming diastereomeric salts, for example, by forming salt with a pure enantiomer chiral acid, or by chromatography, for example, by HPLC, using chromatographic substrates with chiral ligands.
[042] In therapeutic use to treat disorders in a mammal, a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Topical administrations include the treatment of skin or organs easily accessible by local application, for example, eyes or ears. They also include transdermal delivery to generate a systemic effect. Rectal administration includes suppositories. Preferred administration routines are oral and parenteral.
[043] Pharmaceutically acceptable salts of the compounds of the invention include the addition of acid and base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, cyclamate, edisylate, esilate, formate, smoke, gluceptate, gluconate, glucuronate, hexafluorophosphate , hibenzate, hydrochloride / chloride, hydrobromide / bromide, iodate / iodide, isethionate, lactate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotine, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / phosphate of hydrogen / phosphate of dihydrogen, pyroglutamate, sucrate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate.
[044] Suitable base salts are formed from bases that are non-toxic salts. Examples include the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc.
[045] Hemisals of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
[046] Pharmaceutically acceptable salts of compounds of the invention, can be prepared, respectively, by one or more of three methods: (i) reacting the compound with the desired acid or base; (ii) removing an acid-labile protecting group or base from a suitable precursor of the compound of the invention, or by ring opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) converting one salt of the compound of the invention, to another by reaction with an appropriate acid or base, or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from completely ionized to almost non-ionized.
[047] Pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, drug preparation, levigation, emulsification, encapsulation, capture, lyophilization or spray drying processes. .
[048] Pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable vehicles comprising excipients and auxiliaries, which facilitate the processing of the active compound in preparations, which can be used pharmaceutically. . The appropriate formulation is dependent on the chosen administration routine. Pharmaceutically acceptable excipients and vehicles are generally known to those skilled in the art and are, therefore, included in the present invention. Such excipients and vehicles are described, for example, in "Remington’s Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991). The formulations of the invention can be designed to be short acting, quick releasing, long acting, and prolonged releasing. In this way, pharmaceutical formulations can also be formulated for controlled release or slow release.
[049] Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., control or treatment of disorders or diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, relieve or ameliorate symptoms / signs of illness or prolong the survival of the individual being treated.
[050] The amount of active compound, which is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof, can be varied or adjusted widely depending on the mode of administration, the potency of the particular compound and the desired concentration. The determination of a therapeutically effective amount is well included in the ability of those skilled in the art. Generally, the amount of active component will vary between 0.01% to 99% by weight of the composition.
[051] Generally, a therapeutically effective dosage amount of the active component will be in the range of about 0.01 to about 100 mg / kg of body weight / day, preferably about 0.1 to about 10 mg / kg of body weight / day, more preferably about 0.3 to 3 mg / kg body weight / day, even more preferably about 0.3 to 1.5 mg / kg body weight / day. it should be understood that dosages may vary depending on the requirements of each individual and the severity of the disorders or diseases being treated.
[052] The desired dose can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The subdose itself can also be divided, for example, into several discrete, freely spaced administrations; such as multiple inhalations of an insufflator or by applying a plurality of drops to the eye.
[053] In addition, it should be understood that the initial dosage administered can be increased beyond the upper level mentioned above, in order to quickly obtain the desired plasma concentration. On the other hand, the initial dosage may be less than ideal and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times a day.
[054] There are substantial needs for safe and effective agents to control JAK-related disorders, such as atopic dermatitis, in both humans and animals. The market for treating atopic dermatitis in animals is currently dominated by corticosteroids, which cause distressing and undesirable side effects in animals, specifically in pets, such as dogs. APOQUELTM is a recently approved pan-JAK inhibitor for atopic dermatitis in canines. Antihistamines are also used, but are not very effective. A canine formulation of cyclosporine (ATOPICATM) is currently being marketed for atopic dermatitis, however it is expensive and has a slow onset of effectiveness. In addition, there are issues of GI tolerance with ATOPICATM. Compounds of the present invention are JAK inhibitors with selective efficacy against JAK3. These compounds are expected to provide an alternative to steroid use and provide resolution of chronic itching and inflammation that would either persist in atopic dermatitis or slowly regress after removing the allergen or causative agent, such as fleas in allergic flea dermatitis.
[055] The compounds of the present invention can be administered in a pharmaceutically acceptable form, either alone or in combination with one or more additional agents that modulate a mammalian immune system or with anti-inflammatory agents. These agents may include, but are not limited to, cyclosporin A (eg, Sandimmune ™ or Neoral ™, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (eg, Cell-cept ™, azathioprine (eg Imuran ™), daclizumab (for example, Zenapax ™), OKT3 (for example, Orthocolone ™), AtGam ™, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (for example, prednisolone or dexamethasone), IFN - beta, teriflunomide, Laquinimod, glatiramer acetate, dimethyl fumerate, rituximab, fingolimod, natalizumab, alentuzumab, mitoxantrone. mercaptopurine (Puricinol), antibiotics (antimycobacterial drugs, for example, Me- tronidazole, ciprofloxacin), Ustekinumab and vedolizumab These agents can be administered as part of the same or separate dosage forms, by means of the same or different administration routines, and on the same or different administration scales, according to standard pharmaceutical practice known to someone skilled in the art.
[056] Accordingly, the invention provides methods of treating or preventing a disease, condition or disorder associated with JAK in an individual, such as a human or non-human mammal, which comprises administering an effective amount of one or more compounds described herein to the individual . Suitable individuals that can be treated include domestic or wild animals, companion animals, such as dogs, cats, horses and the like; livestock animals including, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example, monkeys, such as rhesus monkeys and cynomolgus (also known as crab or long-tailed eaters), marmosets, monkeys, chimpanzees, monkeys and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.
[057] Another modality provides a method of selectively inhibiting a JAK3 enzyme, which includes contacting the JAK enzyme with either a non-therapeutic amount or a therapeutically effective amount of one or more of the compounds currently taught. Such methods can occur in vivo or in vitro. In vitro contact may involve an evaluation assay to determine the effectiveness of one or more compounds against a selected enzyme in varying amounts or concentrations. In vivo contact with a therapeutically effective amount of one or more compounds may involve the treatment of a disease, disorder or condition described or prophylaxis of organ transplant rejection in the animal in which the contact occurs. The effect of one or more compounds on the JAK enzyme and / or host animal can also be determined or measured. Methods for determining JAK activity include those described in the examples, as well as those described in WO99 / 65908, WO 99/65909, WO01 / 42246, WO02 / 00661, WO02 / 096909, WO2004 / 046112 and WO2007 / 012953. Chemical Synthesis
[058] The following schemes and written descriptions provide general details with respect to the preparation of the compounds of the invention. It will be apparent to those skilled in the art that sensitive functional groups (PG) may need to be protected and unprotected during the synthesis of a compound of the invention. Protection and deprotection can be achieved by conventional methods, as described, for example, in Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, John Wiley & Sons Inc. (1999), and references cited here.
[059] There are several methods for the preparation of such compounds, which are well known to those skilled in the art, and have been described in texts, such as Advanced Organic Chemistry by J. March, John Wiley & Sons (1985). It is observed that certain compounds of the invention can be obtained by functional group transformations at a late stage of the synthesis. Such functional group transformations can include one step or multiple steps, for example, reduction of an ester in an alcohol, reoxidation in an aldehyde, addition of an organomagnesium reagent to form a secondary alcohol, reoxidation in a ketone and, finally, addition an organomagnesium reagent to produce a tertiary alcohol. The intermediates and compounds were named using ChemDraw11 framework (CambridgeSoft ™) to name converter or ACD Labs Name Software v12. The inclusion of a rac- (or racemic) modifier indicates that the material is racemic. When rac- (or racemic) is included with indications R, S, it is intended to convey the relative stereochemistry, however in the absence of rac- (or racemic) notation the absolute stereochemistry of the compounds is known. In some cases the rac- (or racemic) notation conveys the stereochemistry of a fragment of the compound, while the designation R, S conveys the absolute stereochemistry of another portion. For cases where racemates are separated into their constituent enantiomers, absolute stereochemistry is arbitrarily designated, unless otherwise mentioned.
[060] When performing the synthesis of the compounds of the invention, someone skilled in the art will recognize the need to sample and test reaction mixtures prior to preparation in order to monitor the progress of reactions and decide whether the reaction should be continued or if it is ready to be worked on to obtain the desired product. Common methods for testing reaction mixtures include thin layer chromatography (TLC), liquid chromatography / mass spectroscopy (LCMS), and nuclear magnetic resonance (NMR).
[061] Someone skilled in the art will also recognize that the compounds of the invention can be prepared as mixtures of diastereomers or geometric isomers (for example, cis and trans substitution on a cycloalkane ring). These isomers can be separated by standard chromatographic techniques, such as normal phase chromatography on silica gel, preparative high pressure liquid chromatography, reverse phase or supercritical fluid chromatography. One skilled in the art will also recognize that some compounds of the invention are chiral and thus can be prepared as racemic or scalemic mixtures of enantiomers. Several methods are available and are well known to those skilled in the art for the separation of enantiomers. A preferred method for the routine separation of enantiomers is supercritical fluid chromatography employing a chiral stationary phase. EXPERIMENTAL SECTION
[062] Except where otherwise noted, reactions were conducted under a nitrogen atmosphere. Chromatography on silica gel was performed using 250 to 400 mesh silica gem using pressurized nitrogen (~ 0.70 to 1.05 kg / cm2 (10 to 15 psi)) to propel the solvent through the column ("flash chromatography") . Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum. Example 1: (R) -1- (3 - ((3-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) amino) piperidin-1-yl) prop-2-en-1- ona. Example 2: (R) -4 - ((1-acryloylpiperidin-3-yl) amino) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile. Example 3: (R) -1- (3 - ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1- ona.
Step 1. Halide monomers (300 μmol) were dissolved anhydrous DMF (10 ml / mmol, 3 ml) under an argon atmosphere. NaH (60% suspension in mineral oil, 2 equiv, 600 μmol, ~ 30 mg) was added at 0 oC for each reaction flask. Each reaction flask was shaken at 0 oC for 30 minutes. SEM chloride (2 equiv, 600 μmol, 106 μL) was added dropwise to the reaction mixture and stirring was continued at 25 oC for 16 hours. Completion of the reaction was monitored by LCMS / TLC and the solvents were removed using a thermo-explorer (1 hour, 5 torr, and 45 oC). The residue was purified by column chromatography using 5 to 10% ethyl acetate-hexane as the eluent. For each production of monomer it was around 75 to 80%. Step 2. The amine standard (0.2 M solution) in anhydrous toluene was prepared (solution A). 0.3 M solution of SEM protected halide monomers in anhydrous toluene was prepared (solution B). One ml of solution A (1 equiv, 200 μmol) was added followed by 1 ml of solution B (1.5 equiv, 300 μmol) to each reaction flask under argon purge condition. anhydrous t-BuONa (3 equiv, 600 μmol, ~ 60 mg) was added to each reaction flask. Pd2 (dba) 3 (0.03 equiv, 6 μmol, ~ 6 mg) was dispensed under argon flow followed by BINAP (0.06 equiv, 12 μmol, ~ 7.5 mg). Each reaction flask was shaken at 90 oC for 16 hours. The reaction was checked by LCMS. The reaction mixture was filtered and the solvent was evaporated in a thermo-explorer (1 hour, 5 torr, and 45oC) Step 2. (Group 2 monomers) The amine standard (0.2 M solution) in t-BuOH was prepared ( solution A). 0.3 M solution of SEM protected halide monomers in t-BuOH was prepared (solution B). One ml of solution A (1 equiv, 200 μmol) was added followed by 1 ml of solution B (1.5 equiv, 300 μmol) for each reaction flask. 103 μL (3 equiv, 600 μmol) of DIPEA was dispensed for each vial. Reaction flasks were shaken for 16 hours at 80 oC. The reaction was checked by LC-MS. Solvent was evaporated in a thermo-explorer (1 hour, 5 torr, and 45oC) Step 3 and 4 (Boc deprotection and Sem deprotection) Each residue from Step 2 was treated with 2 ml of TFA at 25 oC for 4 hours. LCMS monitoring was done to check complete conversion to an intermediate hydroxyl methyl derivative. After completion of the reaction, solvents were evaporated using a thermo-explorer (1 hour, 5 torr, and 45oC) and azeotroped with toluene to remove traces of TFA (1 hour, 5 torr, and 45oC). Each residue was dissolved in 2 ml of MeOH and ~ 70 μL of ethylenediamine were added to each reaction flask and again stirred for 16 hours at 25 oC. Reactions were checked by LC-MS. After completion of the reaction, the solvent was evaporated and the residue was dissolved in 5 ml ethyl acetate. The organic layer was washed with water (2 ml) and brine (2 ml). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Step 5 (Rxn with acryloyl chloride) All calculations were made on a 100 μmol scale in the final step. Each residue from Step 4 was dissolved in anhydrous THF (1 ml) under an argon atmosphere. 200 μmol (2 equiv, 28 μL) of TEA was added for each reaction mixture. Reaction mixtures were cooled to 0 oC and a 0.5 equiv solution of acryloyl chloride in THF (4 μL in 500 μL THF) was added slowly maintaining a cooling condition during the addition. After stirring for 10 minutes at 0 oC, the solvent was evaporated and the residue was dissolved in 1 ml DMSO. 10 μL of the DMSO solution was diluted in 200 μL with DMSO for QC analysis and the remaining quantity was submitted for purification by preparative HPLC. Purification in Xterra® RP18 (19 x 250 mm, 10 μ, H2O (10mM NH4OAc): CH3CN).
Example 4: 1 - ((3S, 4S) -3 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-fluoropiperidin-1-yl) prop-2-en-1 -one. Step 1. Benzyl (3S, 4S) -4-fluoro-3 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine (140 mg, 0.354 mmol) and cesium fluoride (430 mg, 2.83 mmol) in DMSO (2.0 mL ) benzyl (3S, 4S) - benzyl 3-amino-4-fluoropiperidine-1-carboxylate (prepared as described in WO2010016005) (100 mg, 0.346 mmol) was added. The reaction mixture was heated to 120 ° C for 9 hours. LCMS showed that 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine was consumed completely. The reaction mixture was diluted as a 1: 1 mixture of DCM / water (200 ml). The organic layer was extracted and the aqueous layer was extracted again with DCM (2 x 50 ml). The organic extracts were combined, washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide the crude product which was loaded dry with Celite® onto a Silicycle 25g HP column and purified by normal phase column chromatography (0 to 75% EtOAc / heptanes over 15 column volumes) to provide (3S, 4S) -4-fluoro-3 - (((7-trityl-7H-pyrrole [2,3- d] benzyl pyrimidin-4-yl) amino) piperidine-1-carboxylate (149.6 mg, 69%) as a colorless solid. 1H NMR (400MHz, DMSO-d6) 7.74 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.39-7.18 (m, 15 H), 7, 09-7.05 (m, 5H), 6.84 (d, J = 3.8 Hz, 1H), 6.68 (d, J = 3.8 Hz, 1H), 5.05 (s, 2H ), 4.84-4.64 (m, 2H), 4.35 - 4.24 (m, 1H), 4.15 - 4.05 (m, 1H), 3.95 - 3.85 (m , 1H), 2.25 - 2.13 (m, 1H), 1.70 - 1.58 (m, 1H). Step 2. N - (((3S, 4S) -4-Fluoropiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a dry hydrogenation flask, 10% Pd / C (65 mg) was added under a nitrogen atmosphere. Then, a solution of benzyl (3S, 4S) -4-fluoro-3 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate ( 150 mg, 0.245 mmol) in anhydrous ethanol (5.0 mL) was added and the resulting mixture was hydrogenated under 3.51 kg / cm2 (50 psi) of H2 at room temperature for 3 hours. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered through a thin pad of Celite® and the filter cake was washed with ethanol. The combined filtrate was evaporated, azeotroped with toluene (5 x) at 75 ° C to provide compound N - ((3S, 4S) -4-fluoropiperidin-3-yl) -7-trityl-7H-pyrrole [2,3 -d] pyrimidin-4-amine (104 mg, 89%) as a colorless solid, which was used directly in the next Step without further purification. Step 3. 1 - (((3S, 4S) -4-Fluoro-3 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one. To a solution of N - (((3S, 4S) - 4-fluoropiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (102 mg, 0.214 mmol) in d -Anhydrous CHCl3 (5.0 mL) is added to the Hunig base (0.2 mL, 1.0 mmol). The reaction mixture was cooled to 2 ° C and then treated, dropwise, with a solution of acrylic chloride (0.017 ml, 0.214 mmol) in anhydrous d-CHCl3 (1.0 ml). The reaction mixture was allowed to warm to room temperature and after 30 minutes, LCMS showed that compound N - ((3S, 4S) -4-fluoropiperidin-3-yl) - 7-trityl-7H-pyrrole [2,3- d] pyrimidin-4-amine was completely consumed. The reaction mixture was cooled to 2 ° C and quenched with 10% aqueous sodium bicarbonate (5 ml). The organic layer was extracted and the aqueous layer was extracted again with chloroform (2 x 2 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the crude product that was loaded dry with Celite® on a Silicycle 12 g HP column and purified by normal phase column chromatography (50 80% EtOAc / heptanes over 10 column volumes) to provide 1 - ((3S, 4S) -4-fluoro-3 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) piperidin-1-yl) prop-2-en-1-one (79.0 mg, 69%) as a colorless solid. LCMS (M + H) 532.64. Step 4. Preparation of 1 - ((3S, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-fluoropiperidin-1-yl) prop-2-en -1-one. A solution of 1- ((3S, 4S) -4-fluoro-3 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one (79.0 mg, 0.150 mmol) in trifluoroacetic acid (1.15 ml) was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and loaded dry with Celite® on a Silicycle® 12 g HP column and purified by normal phase column chromatography (0 to 20% MeOH / DCM over 10 column volumes) to provide 1- ((3S, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-fluoropiperidin-1-yl) prop-2-en-1-one ( 37.6 mg, 87%) as a colorless solid. LCMS (M + H) 290.48. HPLC 1.330 min. 1H NMR (400 MHz, MeOH-d4) δ 8.20 (s, 1H), 7.23-7.10 (m, 1H), 6.90-6.62 (m, 2H), 6.21 ( t, J = 20 Hz, 1 H), 5.82-5.66 (m, 1H), 4.93 - 4.71 (m, 1H), 4.62 - 4.03 (m, 3H), 3.44 - 3.04 (m, 2H), 2.36 -2.24 (m, 1H), 1.89-1.74 (m, 1H). Example 5: 1 - ((2S, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1 -one. Step 1. tert-Butyl (6-methylpyridin-3-yl) carbamate. To a solution of 6-methylpyridin-3-amine (25 g, 231. mmol)) in EtOH (100 mL) at 0 ° C was added (Boc) 2O (55.5 g, 298 mmol) dropwise slowly. After the addition, the solution was stirred at room temperature overnight. TLC (petroleum ether / EtOAc, 2: 1) showed that 6-methylpyridin-3-amine was completely consumed. The reaction mixture was filtered and the filter cake was washed with EtOH (30 mlx3). The combined filtrate was concentrated in vacuo to provide a yellow residue, which was purified by chromatography (petroleum ether / EtOAc, 4: 1 to 1: 1) to provide tert-butyl (6-methylpyridin-3-yl) carbamate ( 32.5 g, 67.4%) as a white solid. 1H NMR (400MHz, CDCl3) 8.30 (d, J = 2.0 Hz, 1H), 7.86 (br s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6 , 57 (br s, 1H), 2.49 (s, 3H), 1.51 (s, 9H) Step 2. tert-butyl rac-cis / trans- (6-methylpiperidin-3-yl) carbamate. To a dry hydrogenation flask, PtO2 (2.5 g) was added under Ar atmosphere. Then, a solution of tert-butyl (6-methylpyridin-3-yl) carbamate (33 g, 158.5 mmol) in HOAc (300 ml) was added and the resulting mixture was hydrogenated under 3.86 kg / cm2 (55 psi) of H2 at 50 oC for 30 hours. TLC (petroleum ether / EtOAc, 2: 1) showed that the starting material was completely consumed. The reaction mixture was filtered and the filter cake was washed with MeOH (50 ml x 2). The combined filtrate was evaporated to provide tert-butyl (6-methylpiperidin-3-yl) carbamate (34 g, 100%) as a yellow oil (~ 2: 1 cis / trans), which was used directly in the next step without another purification. LC / MS (M + H) 215.2. Step 3. benzyl rac-cis / trans-5 - ((tert-butoxycarbonyl) amino) -2-methylpiperidine-1-carboxylate. To a stirred solution of tert-butyl (6-methylpiperidin-3-yl) carbamate (27.0 g, 126 mmol) and NaHCO3 (74.2 g, 883 mmol) in THF (350 mL) / H2O (350 mL ) CbzCl (32.17 g, 189 mmol) was added dropwise at room temperature. After the addition, the resulting mixture was stirred at room temperature for 2 hours. TLC (CH2Cl2 / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was extracted with EtO-Ac (300 mlx2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide the crude product. The crude product was again purified by chromatography (PE / EA, 30: 1-10: 1) to provide rac-cis / trans 5 - ((tert-butoxycarbonyl) amino) -2-methylpiperidine-1-carboxylate (44 , 0 g, 100%) as a colorless oil. (1H NMR showed ~ 1mol of BnOH.) 1H NMR (400MHz, CDCl3) δ 7.35 - 7.19 (m, 9 H), 5.14 - 4.99 (m, 2H), 4.82 (d , J = 6.0 Hz, 1H), 4.67 - 4.59 (m, 2H), 4.48 - 4.28 (m, 2H), 4.17 (d, J = 9.8 Hz, 1H), 3.97 (d, J = 13.8 Hz, 1H), 3.73 (br s, 1H), 3.39 (br s, 1H), 3.02 (d, J = 14.1 Hz, 1H), 2.49 (t, J = 12.0 Hz, 1H), 1.89 - 1.59 (m, 3H), 1.48 (dd, J = 1.5, 13.8 Hz , 1H), 1.39 - 1.32 (m, 8H), 1.11 - 1.01 (m, 3H). Step 4. benzyl rac- (2S, 5R) -5 - ((tert-butoxycarbonyl) amino) -2-methylpiperidine-1-carboxylate and rac- (2S, 5S) -5 - ((tert-butoxycarbonyl) amino) -2-benzyl methylpiperidine-1-carboxylate. Rac-cis / trans 5 - ((tert-butoxycarbonyl) amino) -2-methyl benzylpiperidine-1-carboxylate (44 g) was separated by chiral SFC to provide rac-cis- (2S, 5R) -5- ( benzyl (tert-butoxycarbonyl) amino) -2-methylpiperidine-1-carboxylate (Peak 2, 24.5 g, 55.68%) and rac-trans - (2S, 5S) -5 - ((tert-butoxycarbonyl) amino) - Benzyl 2-methylpiperidine-1-carboxylate (Peak 1, 12.3 g, 27.95%). Peak 2, cis material was used to remove Boc. SFC Prep column: ChiralCel OD 300mmx50mm, 10 μm; Mobile phase: A: Supercritical CO2, B: IPA (0.1% NH3H2O), A: B = 85: 15 to 180ml / min; Column temperature: 38 oC; Nozzle pressure: 100 Bar; Nozzle temperature: 60 oC; Evaporator temperature: 20 oC; Adjuster Temperature: 25 oC; Wavelength: 220nm Peak 1 (trans): 1H NMR (400MHz, CDCl3) δ 7.44 - 7.28 (m, 5H), 5.23 - 5.06 (m, 2H), 4.55 - 4 , 35 (m, 2H), 4.25 (d, J = 10.0 Hz, 1H), 3.58 - 3.25 (m, 1H), 2.58 (t, J = 12.0 Hz, 1H), 1.87 (d, J = 11.0 Hz, 1H), 1.82 - 1.69 (m, 2H), 1.56 (d, J = 13.8 Hz, 1H), 1, 50 - 1.36 (m, 9H), 1.21 (d, J = 6.3 Hz, 3H). Peak 2 (cis): 1H NMR (400MHz, CDCl3) δ 7.42 - 7.29 (m, 5H), 5.20 - 5.08 (m, 2H), 4.89 (br s, 1H), 4.47 (br s, 1H), 4.05 (d, J = 14.1 Hz, 1H), 3.81 (br s, 1H), 3.11 (d, J = 13.8 Hz, 1H ), 1.93 - 1.68 (m, 4H), 1.43 (s, 9H), 1.20 - 1.13 (m, 3H). Step 5. Racemic benzyl (2S, 5R) -5-amino-2-methylpiperidine-1-carboxylate. To a solution of benzyl rac-cis - (2S, 5R) -5 - ((tert-butoxycarbonyl) amino) -2-methylpiperidine-1-carboxylate (peak 2, 40.0 g, 115.6 mmol) in CH2Cl2 (60 mL) at 0 oC was added (4M HCl (g) / dioxane (200 mL) dropwise. After the addition, the solution was stirred at room temperature for 4 hours. TLC (petroleum ether / EtOAc, 2: 1) showed that the starting material was completely consumed.The reaction mixture was concentrated to provide racemic benzyl (2S, 5R) -5-amino-2-methylpiperidine-1-carboxylate (31.0 g, 94, 8%) as a white solid (HCl salt). 1H NMR (400MHz, DMSO-d6) δ 8.37 (br s, 3H), 7.24 - 7.49 (m, 5H), 5.09 ( s, 2H), 4.32 (m, 1H), 4.16 (d, J = 8.28Hz, 1H), 3.00 (br s, 2H), 1.83 (m, 2H), 1, 59 (m, 2H), 1.11 (d, J = 7.03Hz, 3H). Step 6. (2S, 5R) -5 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin -4-yl) amino) -2-methylpiperidine-racemic benzyl 1-carboxylate A mixture of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (21.8 g, 0.116 mol), DIPEA (67.7 g, 0.525 mol) and (2S, 5R) -5-amino-2-m racemic benzyl ethylpiperidine-1-carboxylate (30 g, 0.105 mol) in n-BuOH (300 ml) was heated to 140 ° C overnight. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and evaporated to dryness; the residue was partitioned with EtOAc (500 ml) and water (500 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was triturated with MTBE to provide (2S, 5R) -5 - ((2-chloro-7H-pyrrole [2,3-d] pyrimidin-4-yl) amino) - racemic benzyl 2-methylpiperidine-1-carboxylate (36 g, 86%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.70 (br s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.46 - 7.25 (m, 5H), 7 , 10 (br s, 1H), 6.56 (br s, 1H), 5.18 - 5.00 (m, 2H), 4.38 (d, J = 6.8 Hz, 1H), 4, 16 (br s, 1H), 4.03 (q, J = 7.3 Hz, 2H), 2.76 (t, J = 11.8 Hz, 1H), 1.87 - 1.68 (m, 2H), 1.63 (d, J = 7.3 Hz, 1H), 1.19 - 1.12 (m, 3H). Step 7. rac-N - ((3R, 6S) -6-Methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a dry hydrogenation flask, 10% dry Pd / C (7 g) was added under an atmosphere of Ar. Subsequently, a solution of (2S, 5R) -5 - ((2-chloro-7H-pyrrole [2, Racemic benzyla pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate (36 g, 0.09 mol) in MeOH (1500 ml) and THF (250 ml) was added and the resulting mixture was stirred in a Parr apparatus (3.16 kg / cm2 (45 psi) of H2 at 25 oC for 48 hours). LC-MS indicated that Cbz was removed completely, but ~ 30% chloride remained. The reaction mixture was filtered and the filtrate was subjected to reaction conditions again with 5 g of 10% dry Pd / C under 3.51 kg / cm2 (50 psi) of H2 at 45 oC for 12 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered through a pad of Celite® and the cake was washed with MeOH three times. The combined filtrates were concentrated to provide rac-N - ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (23 g, 94.6% ) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.11 (d, J = 12.5 Hz, 1H), 7.30 (dd, J = 6.5, 18, 6 Hz, 1H), 7.10 (br s, 1H), 6.90 - 6.73 (m, 1H), 6.59 - 6.52 (m, 1H), 6.10 (dd, J = 1.5, 17.1 Hz, 1H), 5.68 (d, J = 10.5 Hz, 1H), 4.86 - 4.51 (m, 1H), 4.41 - 3.97 (m , 2H), 3.02 - 2.55 (m, 1H), 1.89 - 1.59 (m, 3H), 1.28 - 1.10 (m, 3H). Step 8. rac-1 - (((2S, 5R) -5 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en -1-one. To a stirred solution of rac-N- ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine HCl salt (5.00 g, 18 , 5 mmol) in THF (250 mL) and saturated aqueous NaHCO3 solution (250 mL) was added acryloyl chloride (2.02 g, 22.2 mmol) dropwise at 0 oC carefully. After the addition, the resulting mixture was stirred at 0 ° C for 4 hours. TLC (DCM / MeOH / NH4OH, 10: 1: 1) showed that rac-N - ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4- amine was consumed completely. The reaction mixture was diluted with H2O (125 ml) and extracted with EtOAc (125 ml x 3); the combined organic layer was washed with brine, and dried over Na2SO4. The most volatile components were removed in vacuo. The crude product was purified by column chromatography on silica gel (DCM / MeOH, 10: 1) to provide the crude product. The product was triturated with EtOAc (150 mL) and filtered to provide rac-1 - ((2S, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- methylpiperidin-1-yl) prop-2-en-1-one (2.0 g, 38% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 7.30 (dd, J = 6.8, 18, 8 Hz, 1H), 7.10 (br s, 1H), 6.89-6.71 (m, 1H), 6.56 (d, J = 1.8 Hz, 1H), 6.10 (dd , J = 2.1, 16.7 Hz, 1H), 5.72-5.61 (m, 1H), 4.81 (br s, 0.5H), 4.56 (d, J = 10, 3 Hz, 0.5H), 4.37 (br s, 0.5H), 4.20 - 3.95 (m, 1.5H), 2.96 (t, J = 11.9Hz, 0.5H ), 2.60 (t, J = 12.0 Hz, 0.5H), 1.92 - 1.59 (m, 4H), 1.30 - 1.07 (m, 3H). Step 9. Preparation of (+) - 1 - ((2R, 5S) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop -2-en-1-one (peak 1) and (-) 1 - ((2S, 5R) - 5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- methylpiperidin-1-yl) prop-2-en-1-one (peak 2). The racemic compound: rac-1 - ((2S, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2- en-1-one (from Step 8) was purified by chiral SFC to provide pure enantiomers. Peak 1 (4.63 g, +) and peak 2 (4.42 g, -) SFC conditions: Column: ChiralPak IC (300 mm * 50 mm, 10 μm); Mobile Phase: 40% ethanol (0.05% NH3 in H2O) in CO2; Flow Rate: 200 mL / min; Wavelength: 220nm. Absolute stereochemistry was designed based on X-ray crystallographic analysis. Peak 1: (+) 1 - ((2R, 5S) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2- en-1-one 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 7.30 (dd, J = 6 , 8, 18.8Hz, 1H), 7.10 (br s, 1H), 6.89 - 6.71 (m, 1H), 6.56 (d, J = 1.8 Hz, 1H), 6 , 10 (dd, J = 2.1, 16.7 Hz, 1H), 5.72-5.61 (m, 1H), 4.81 (br s, 0.5H), 4.56 (d, J = 10.3 Hz, 0.5H), 4.37 (br s, 0.5H), 4.20 - 3.95 (m, 1.5H), 2.96 (t, J = 11.9 , Hz, 0.5H), 2.60 (t, J = 12.0 Hz, 0.5H), 1.92 - 1.59 (m, 4H), 1.30 - 1.07 (m, 3H ). LC / MS (M + H) 286.2. OR = [a] D20 = +0.34 (c = 0.6, MeOH). Peak 2: (-) 1 - ((2S, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2- en-1-one 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 7.30 (dd, J = 6 , 8, 18.8 Hz, 1H), 7.10 (br s, 1H), 6.89 - 6.71 (m, 1H), 6.56 (d, J = 1.8 Hz, 1H), 6.10 (dd, J = 2.1, 16.7 Hz, 1H), 5.72-5.61 (m, 1H), 4.81 (br s, 0.5H), 4.56 (d , J = 10.3 Hz, 0.5H), 4.37 (br s, 0.5H), 4.20 - 3.95 (m, 1.5H), 2.96 (t, J = 11, 9, Hz, 0.5H), 2.60 (t, J = 12.0 Hz, 0.5H), 1.92 - 1.59 (m, 4H), 1.30 - 1.07 (m, 3H). LC / MS (M + H) 286.2. OR [a] D20 = -0.36 (c = 0.6, MeOH). Example 6: (3R, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1- acryloylpiperidine-3-carbonitrile. Step 1. Preparation of N - ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin -4-amine. To a mixture of 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine (16.3 g, 41.18 mmol) and compound (3R, 5R) -1-benzyl-5 - (( tert-butyldimethylsilyl) oxy) piperidin-3-amine (prepared as described in Eur. J. Org. Chem. 2012, 10, 2023. (12 g, 37.44 mmol) in n-BuOH (250 mL) at room temperature DIPEA (14.5 g, 112.32 mmol) was added. The reaction mixture was heated to 110 oC for 3 days. TLC (DCM / MeOH, 10: 1) showed that more of the amine was consumed. was cooled to room temperature and evaporated to dryness using an oil pump at 45 oC, the residue was partitioned with EtOAc (800 ml) and water (500 ml) The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by chromatography (0% to 30% EtO-Ac / PE) to provide N - ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3 -yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (15 g, 65%) as a yellow solid LC / MS (M + H) 679.4. 1H NMR ( 400 MHz, CDCl3) δ -0.03 (d, J = 2.01 Hz, 6 H) 0.82 (s, 9 H) 1.50 (d, J = 12.55 Hz, 1 H) 2.31 (d, J = 11.54 Hz, 2 H) 2.74 (d, J = 12.55 Hz, 1 H) 2.96 (br s, 1 H) 3.40 - 3.73 (m, 2 H) 3, 99 (br s, 1 H) 4.50 (br s, 1 H) 5.58 (br s, 1 H) 6.32 (d, J = 4.02 Hz, 1 H) 6.90 (d, J = 3.51 Hz, 1 H) 7.13 - 7.38 (m, 20 H) 8.00 (s, 1 H). Step 2. (3R, 5R) -3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1- tert-butyl carboxylate. To a dry hydrogenation flask, 10% dry Pd / C (1.5 g) was added. Then a solution of N - ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin -4-amine (14.8 g, 21.76 mmol) and (Boc) 2O (5.22 g, 23.94 mmol) in MeOH (300 mL) was added and the resulting mixture was hydrogenated under 3.51 Kg / Cm2 (50 psi) of H2 at 40 oC for 12 hours. TLC (PE / EtOAc 4: 1) showed that the reaction was complete. The reaction solution was filtered through a pad of Celite® and the cake was washed with MeOH three times. The combined filtrate was concentrated to provide (3R, 5R) -3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) tert-butyl piperidine-1-carboxylate (14.8 g, ~ 100%) as a yellow solid, which was used directly in the next Step without further purification. 1H NMR (400 MHz, CDCl3) δ 0.06 (br s, 6 H) 0.72 - 0.94 (m, 9 H) 1.16 - 1.43 (m, 4 H) 1.49 (br s, 9 H) 1.57 - 2.40 (m, 3 H) 2.93 - 3.13 (m, 1 H) 3.37 - 4.01 (m, 3 H) 4.45 (br s , 1 H) 4.72 - 5.38 (m, 1 H) 6.30 (br s, 1 H) 6.90 (br s, 1 H) 7.08 - 7.36 (m, 16 H) 8.01 (s, 1 H). Step 3. tert-Butyl (3R, 5R) -3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of (3R, 5R) -3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1 tert-butyl carboxylate (15 g, 21.74 mmol) in anhydrous THF (300 mL) n-Bu4NF (11.38 g, 43.47 mmol) was added. The reaction mixture was then heated to 40 ° C overnight. TLC (PE / EtOAc 4: 1) indicated that the reaction was complete. The reaction solution was diluted with water (300 ml) and then extracted with EtOAc (2x200 ml). The combined organic layers were washed with water, brine and dried over Na2SO4, which after concentration gave (3R, 5R) -3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin- 4 il) tert-butyl amino) piperidine-1-carboxylate (14.6 g, ~ 100%), which was used directly in the next step without further purification. 1H NMR (400MHz, CDCl3) δ 8.01 (s, 1H), 7.37 - 7.08 (m, 17H), 6.91 (d, J = 3.5 Hz, 1H), 6.30 ( br s, 1H), 4.48 (d, J = 3.5 Hz, 1H), 4.05 (br s, 1H), 3.83 - 3.51 (m, 4H), 3.23 (br s, 1H), 1.58 - 1.29 (m, 10H). Step 4. tert-Butyl (R) -3-oxo-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of tert-butyl (3R, 5R) -3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (5.0 g, 8.68 mmol) in DCM (100 mL) Dess-Martin periodinane (4.0 g, 9.55 mmol) was added. The mixture was stirred at room temperature for 18 hours. TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was concentrated to provide the crude product (7.8g) as a yellow solid, which was purified by preparative HPLC to provide (R) -3-oxo-5 - ((7-trityl-7H-pyrrole [2 , 3-d] pyrimidin-4-yl) amino) tert-butyl piperidine-1-carboxylate (3.7 g, 74%) as a white solid. LC / MS (M + H) = 574.3. 1H NMR (400 MHz, DMSO-d6) d ppm 1.24 (s, 9 H) 2.20 - 2.45 (m, 2 H) 3.04 - 3.36 (m, 2 H) 3.92 - 4.27 (m, 3 H) 6.88 - 7.46 (m, 16 H) 8.29 - 8.57 (m, 2 H) 10.46 - 10.71 (m, 1 H). Step 5. tert-Butyl (5-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) tert-butyl piperidine-1-carboxylate (mixture of isomers ). To a mixture of tert-butyl (R) -3-oxo-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (1, 0 g, 1.74 mmol) and TOS-MIC (693.7 mg, 3.83 mmol) in DME (30 ml) at 0 oC was added t-BuOK (624.4 mg, 5.58 mmol) and EtOH (176.3 mg, 3.83 mmol) in portions. The resulting mixture was stirred at 0 ° C for 0.5 hour. The mixture was allowed to warm to room temperature and stirred for 2 hours. TLC (DCM / MeOH, 10: 1) showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to dryness and purified by preparative TLC (petroleum ether / EtOAC, 2: 1) to provide (5R) -5 - ((7-trityl-7H-pyrrole [2, 3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (mixture of isomers, 200 mg, 20%) as a yellow solid. LC / MS (M + H) 585.3. Step 6. Preparation of (5R) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (mixture of isomers). To a solution of tert-butyl (5R) -3-cyano-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (235 mg , 0.41 mmol) in DCM (1.5 ml) at 0 ° C, TFA (229.0 mg, 2.0 mmol) was added. The reaction mixture was then stirred at room temperature for 12 hours. TLC (petroleum ether / EtOAC, 1: 1) showed that the reaction was complete. The reaction mixture was concentrated in vacuo to provide (5R) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (mixture of iso- (235 mg, 100%) as a yellow solid. LC / MS (M + H) 485.0. Step 7. Preparation of (5R) -1-acryloyl-5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (mixture of isomers). To a stirred solution of (5R) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (100 mg, 0.206 mmol) in THF ( 3 mL): Aqueous NaHCO3 solution (2.5 mL) at 0 oC was added acryloyl chloride (22.4 mg, 0.247 mmol) dropwise. After the addition, the resulting mixture was stirred at 0 ° C for 2 hours. TLC (DCM / MeOH, 20: 1) showed that the reaction was complete. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (30 ml * 2), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was again purified by Preparative TLC (petroleum ether / EtOAC, 1: 1) to provide (5R) -1-acryloyl-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine -3-carbonitrile and trans isomer (80 mg, 72%) as a yellow solid. LC / MS (M + H) 539.1. Step 8. Preparation of (3S, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile and (3R, 5R) -5- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile. To a round bottom flask containing (5R) -1-acryloyl-5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile and compound 5 a 1 (80 mg, 0.272 mmol) TFA (1 ml) was added. The mixture was stirred at room temperature for 12 hours. TLC (petroleum ether / EtOAC, 1: 1) showed that 20% of the starting material remained. The reaction was heated to 30 oC for another 5 hours. LCMS indicated completion. The reaction mixture was concentrated to provide the crude product, which was again purified by preparative TLC (petroleum ether / EtOAC, 1: 1) to provide a mixture of (3S, 5R) -5 - ((7H-pyrrole) [2,3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile and (3R, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile (12 mg, 10% over three steps) as a white solid. Chiral HPLC showed that it was a trans / cis mixture, which was purified again by chiral SFC. After chiral SFC, 1.4 mg of peak 1 and 3.3 mg of peak 2 was obtained. Peak 1: (3S, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile and Peak 2: (3R, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile. Separation Conditions SFC: Column: ChiralPak AD (250mmx30mm, 20 μm); Mobile Phase: 50% EtOH + NHβ / H2θ 80mL / min; Column: Chiralpak AD-H 250 * 4.6mm ID, 5 μm; Mobile Phase: ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow Rate: 2.35mL / min; Wavelength: 220nm; Peak 1: 1H NMR (400MHz, CD3OD) δ 8.16 (br s, 1H), 7.10 (d, J = 3.5 Hz, 1H), 6.85 (dd, J = 10.4, 16 , 7 Hz, 1H), 6.57 (d, J = 3.5 Hz, 1H), 6.27 (dd, J = 1.8, 16.8 Hz, 1H), 5.80 (d, J = 9.5 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.63 (s, 1H), 4.43 (d, J = 11.8 Hz, 1H), 4.28 - 4.19 (m, 1H), 3.14 - 2.97 (m, 2H), 2.55 (d, J = 12.5 Hz, 1H), 2.00 (d, J = 14.6 Hz, 1H). Peak 2: 1H NMR (400MHz, CD3OD) δ 8.20 (br s, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.90 - 6.54 (m, 2H), 6.32 - 6.07 (m, 1H), 5.90 - 5.57 (m, 1H), 4.71 - 4.41 (m, 2H), 4.40 - 4.01 (m, 2H ), 3.71 - 3.40 (m, 2H), 2.39 (br s, 1H), 2.17 (d, J = 9.0 Hz, 1H). Example 7: 1 - (((2R, 5R) -5 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidin-1-yl) prop-2- en-1-one. Step 1. Methyl 5-aminopicolinate. To a stirred solution of 5-aminopicolinic acid (170g, 1.23 mol) in MeOH (1700 ml) was added SOCl2 (178.6 ml, 2.47 mol) at 0 ° C. The reaction mixture was then refluxed for 72 hours. The mixture was then cooled to 0 ° C and additional SOCl2 was added (40 ml, 0.55 mol). The mixture was then refluxed for 24 hours. The excess SOCl2 was removed under reduced pressure and the crude material was neutralized with aqueous NaHCO3. The mixture was filtered and the filter cake dried at 40 to 50 ° C overnight. The solid was collected to provide methyl 5-aminopicolinate (350g). The filtrate was again extracted with DCM (3x2 L). The organic extract was washed with brine, dried (Na2SO4) and concentrated to dryness to provide crude compound (200g). All solids were collected to provide methyl 5-aminopicolinate (550g of 680g of compound 1, 73%) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.12 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 2, 8, 8.5 Hz, 1H), 4.24 (br s, 2H), 3.93 (s, 3H). Step 2. 5 - Methyl ((tert-butoxycarbonyl) amino) picolinate. 5-Methyl aminopicolinate (110g, 0.723mol) was dissolved in DCM (2000 ml) at 20 ° C under N2. To the reaction mixture, Boc-anhydride (173.6 g, 0.80 mol) and DMAP (8.8 g, 0.0723 mol) were added. The reaction mixture was stirred at 20 ° C for 20 hours. TLC (PE / EA, 2: 1) showed that the starting material was completely consumed. The reaction mixture was filtered and washed with DCM (4x3000ml). H2O (2000 ml) was added and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to provide the crude product. The crude compound was washed with petroleum ether (4000mL) and stirred for 1.0 hour. Vacuum filtration and evaporation provided 5 - ((tert-butoxycarbonyl) amino) methyl picolinate (750g of 550 g of methyl 5-aminopicolinate, 82.3%) as a white solid for the next step without further purification. LC / MS (M + H) = 253.1. Step 3. tert-Butyl (6- (hydroxymethyl) pyridin-3-yl) carbamate. LAH powder (36 g, 0.96 mol) was suspended in dry THF (1000 ml) under N2 atmosphere and cooled to 0 ° C. To the mixture, compound 3 (150g, 0.60 mol) in dry THF (1000 ml) was added slowly at 0 ° C. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. TLC (PE / EA, 1: 1) showed that the reaction was complete, and the reaction was quenched with the dropwise addition of THF-Water (9: 1, 400 mL) followed by 90 ml of 15% aqueous NaOH and 50 ml of water at 0 ° C, stirred at room temperature, filtered through a pad of Celite®, and then washed with THF (4 x 1000 ml). The filtrate was concentrated under reduced pressure to provide the crude which was purified by column chromatography on silica gel eluting with PE / EA (2: 1 ~ 1: 2). The desired fraction was concentrated to provide tert-butyl (6- (hydroxymethyl) pyridin-3-yl) carbamate (450g, 67%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 9.58 - 9.40 (m, 1H), 8.59 - 8.45 (m, 1H), 7.95 - 7.78 (m, 1H), 7 , 42 - 7.22 (m, 1H), 5.42 - 5.21 (m, 1H), 4.58 - 4.40 (m, 2H), 1.48 (s, 9H). Step 4. tert-Butyl (6- (hydroxymethyl) piperidin-3-yl) carbamate. To a solution of tert-butyl (6- (hydroxymethyl) pyridin-3-yl) carbamate (30g, 0.134mol) in EtOH (300ml) and HOAc (20ml) was added PtO2 (3.0g, 0.0223mol) under N2. The mixture was hydrogenated at 65 ° C / 3.86 Kg / Cm2 (55 psi) H2 for 72 hours. The mixture was filtered through a pad of Celite® and the filter cake was washed with EtOH (3x2000ml). The filtrate was concentrated under reduced pressure to remove EtOH and HOAc. Saturated aqueous NaHCO3 was added to adjust the pH to 6 ~ 7 and the aqueous layer was extracted with EtOAc (3x2000ml). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to provide the crude product, which was triturated with PE / EA (1: 1) for 2 hours and filtered to provide (6- (hydroxymethyl) pyridin-3 -yl) tert-butyl carbamate recovered (90g, 50%) as a white solid. The aqueous layer was evaporated to remove more of the water to provide a mixture of tert-butyl (6- (hydroxymethyl) piperidin-3-yl) carbamate (90g, 50%) in aqueous NaHCO3, which was used directly for the next step without further purification. LC / MS (M + H) = 231.2. Step 5. Benzyla ((tert-butoxycarbonyl) amino) -2- (hydroxymethyl) piperidine-1-carboxylate. To a stirred solution of tert-butyl (6- (hydroxymethyl) piperidin-3-yl) carbamate (45g, 0.20mol) in THF (600 ml) and H2O (300 ml) was added NaHCO3 (33.6 g, 0.40 mol). To this mixture was added Cbz-Cl (41g, 0.24 mol) dropwise at 0 ° C and the resulting mixture was allowed to return to room temperature and stirred for 12 hours. TLC (5% MeOH in DCM) was checked to show that the starting material was completely consumed. Volatiles were removed under reduced pressure, water (500ml) was added, and the aqueous mixture was extracted with EtOAc (2x600 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to provide the crude product, which was purified by column chromatography (silica gel eluted with DCM / EA (4: 1 ~ 2: 1) to provide 5 - Benzyl ((tert-butoxycarbonyl) amino) -2- (hydroxymethyl) piperidine-1-carboxylate (90 g, 63%) as a gum. 1H NMR (400MHz, DMSO-d6) δ 7.37 (s, 5H ), 7.05 - 6.76 (m, 1H), 5.20 - 4.99 (m, 2H), 4.89 - 4.67 (m, 1H), 4.24 - 3.92 (m , 2H), 3.62 - 3.40 (m, 2H), 3.34-2.88 (m, 1H), 2.18 - 1.62 (m, 2H), 1.55 - 1.13 (m, 12H) Step 6. (2R, 5R) -5 - ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl ) benzyl piperidine-1-carboxylate To a round bottom flask was added 2,4-dichloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (6.03 g, 17.6 mmol), DIPEA (6.8 mL, 2.2 eq), 5 - ((tert-butoxycarbonyl) amino) -2- (hydroxymethyl) benzyla piperidine-1-carboxylate (5.6 g, 1.0 eq) and n- butanol (50 mL). The reaction mixture was heated to 50 oC during the ite. The reaction mixture was poured into ethyl acetate / water and the layers separated. The aqueous layer was extracted (2 x EtOAc). The organic extracts were collected, washed with brine, dried (Na2SO4) and the solvent removed to provide an oil, which after chromatography (silica, ethyl acetate / heptanes) provided two main peaks with equivalent mass. Peak 1 = 2.5 g (trans material); Peak 2 = 3.3 g (cis material): Peak 1 (trans): (2S, 5R) -2- (hydroxymethyl) -5 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin- Benzyl 4-yl) amino) piperidine-1-carboxylate. LC / MS (M + H) 570.1 1H NMR (400 MHz, MeOH-d4) δ ppm 1.63 - 1.81 (m, 2 H) 1.99 - 2.18 (m, 2 H) 2 , 43 (s, 3 H) 3.19 (d, J = 12.49 Hz, 1 H) 3.65 - 3.82 (m, 2 H) 4.16 - 4.48 (m, 4 H) 6.85 (d, J = 3.90 Hz, 1 H) 6.90 - 7.20 (m, 5 H) 7.29 - 7.44 (m, 2 H) 7.50 (d, J = 3.90 Hz, 1 H) 8.06 (d, J = 8.20 Hz, 2 H) Peak 2 (cis): (2R, 5R) -5 - ((2-chloro-7-tosyl-7H- benzyl pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidine-1-carboxylate. LC / MS (M + H) 570.1. 1H NMR (400 MHz, MeOH-d4) δ 1.63 - 2.02 (m, 4 H) 2.42 (s, 3 H) 2.71 - 2.84 (m, 1 H) 3.61 - 3.81 (m, 3 H) 4.30 - 4.41 (m, 2 H) 5.08 - 5.23 (m, 2 H) 6.74 (d, J = 3.90 Hz, 1 H ) 7.26 - 7.44 (m, 7 H) 7.49 (br s, 1 H) 8.03 (d, J = 8.20 Hz, 2 H) Step 7. (2R, 5R) -5 - Benzyl ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidine-1-carboxylate and (2S, 5S) - 5 - Benzyl ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidine-1-carboxylate. cis- (2R, 5R) -5 - ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidine-1-carboxylate racemic benzyl (3.31 g) was separated by chiral-Chiral SFC (Lux Cellulose-3 250 mm x 21.2 mm, 5 μm, CO2 / MeOH, 80 mL / min) to provide two peaks, absolute stereochemistry arbitrarily designated: peak 1 (1.5 g) (2R, 5R) -5 - ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) benzyl piperidine-1-carboxylate. OR a [D] 20 = -0.10 (c = 0.5, MeOH). Peak 2 (1.5 g) (2S, 5S) -5 - (((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) benzyl piperidine-1-carboxylate. OR a [D] 20 = + 0.12 (c = 0.5, MeOH). Step 8. (((2R, 5R) -5 - ((2-Chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol. To a Parr hydrogenation flask was added (2R, 5R) -5 - (((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- ( hydroxymethyl) benzyl piperidine-1-carboxylate (in 100 mL of EtOH) and Pd (OH) 2 (1.2 g). The reaction was stirred in a Parr shaker at 1.40 Kg / Cm2 (20 psi) H2 for 4 hours at room temperature. The reaction mixture was then filtered through a pad of Celite® and the solvent removed in vacuo to provide ((2R, 5R) -5 - ((2-chloro-7-tosyl-7H-pyrrole [2,3- d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol (1.73 g, 91%). LC / MS (M + H) = 436.1. 1H NMR (400 MHz, MeOH-d4) δ 1.33 - 1.65 (m, 2 H) 1.84 (dd, J = 13.07, 2.93 Hz, 1 H) 2.13 (d, J = 12.10 Hz, 1 H) 2.46 (m, 3 H) 2.52 (t, J = 11.32 Hz, 1 H) 2.66 - 2.80 (m, 1 H) 3, 39 - 3.64 (m, 3 H) 4.21 - 4.26 (m, 1 H) 6.76 (d, J = 3.90 Hz, 1 H) 7.33 - 7.44 (m, 2 H) 7.49 (d, J = 3.90 Hz, 1 H) 8.02 (d, J = 8.20 Hz, 2 H). Step 9. (((2R, 5R) -5 - ((2-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol. To a round bottom flask containing (2R, 5R) -5 - ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol (1.1 g, 2.52 mmol) MeOH (10 mL) and K2CO3 (767 mg, 2.2 eq) were added. The reaction was stirred at room temperature overnight and then poured into water. The aqueous mixture was extracted with n-BuOH. The organic extracts were dried (Na2SO4) and the solvent removed to provide the crude product, which was purified by chromatography (silica, DCM / MeOH (10: 1, MeOH: NH4OH) to provide the desired product (610 mg, 86%) LC / MS (M + H) 282.1. 1H NMR (400 MHz, MeOH-d4) δ 1.19 - 1.67 (m, 2 H) 1.84 (dd, J = 13.07, 2 , 93 Hz, 1 H) 2.18 (d, J = 12.88 Hz, 1 H) 2.67 (dd, J = 7.22, 4.10 Hz, 1 H) 3.40 - 3.61 (m, 3 H) 3.94 - 4.09 (m, 1 H) 4.26 (t, J = 11.32 Hz, 1 H) 6.58 (d, J = 3.51 Hz, 1 H ) 6.95 - 7.06 (m, 1 H) Step 10. ((2R, 5R) -5 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2 - il) methanol To a round-bottom flask containing (2R, 5R) -5 - (((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol (202 mg, 0.72 mmol) in ethanol (20 ml) was added 10% Pd / C (100 mg) and ammonium formate (233 mg, 5 eq). The reaction mixture was heated to reflux overnight and then filtered through a pad of Celite®. The solvent was removed in vacuo to provide ((2R, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol (110 mg, 62% ). LC / MS (M + H) 248.1. 1H NMR (400 MHz, MeOH-d4) δ 1.80 - 2.24 (m, 4 H) 3.35-3.39 (m, 2 H) 3.66 - 3.89 (m, 3 H) 4.49 (t, J = 4.10 Hz, 1 H) 6.70 (d, J = 3.51 Hz, 1 H) 7.15 (d, J = 3.51 Hz, 1 H) 8, 11 - 8.28 (m, 1 H). Step 11. 1 - (((2R, 5R) -5 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidin-1-yl) prop-2- en-1-one. To a solution of ((2R, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-2-yl) methanol (172 mg, 0.69 mmol) in DCM / CHCl3 / CF3CH2OH (3: 1: 0.5 ml) TEA (0.19 ml, 2.0 eq) was added. The reaction mixture was cooled to 0 oC. After 30 minutes, acryloyl chloride (in DCM, 1 ml) was added dropwise. After 2 hours, the reaction mixture was poured into water / DCM and the layers separated. The organic layer was collected, dried (Na2SO4) and the solvent removed to provide the crude product (224 mg). A portion of the crude product (50 mg) was purified by RP-HPLC to provide 1 - ((2R, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2 - (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one (4.4 mg). LC / MS (M + H) 302.2. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.72 - 2.22 (m, 4 H) 2.81 - 2.99 (m, 1 H) 3.65 - 3.85 (m, 2 H ) 3.88 - 4.17 (m, 2 H) 4.25 - 4.45 (m, 1 H) 5.80 (d, J = 12.10 Hz, 1 H) 6.26 (d, J = 16.78 Hz, 1 H) 6.80 - 6.99 (m, 2 H) 7.39 (br s, 1 H) 8.21 - 8.40 (m, 1 H). Example 8: 1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) - il) prop-2-en-1-one. Step 1. tert-Butyl 1H-pyrrolo [2,3-c] piperidine-1-carboxylate. To a solution of 1H-pyrrolo [2,3-c] pyridine (250 g, 2.12 mol) in CH3CN (2L) was added K2CO3 (584 g, 4.23 mol) and DMAP (12.9 g, 0 , 11 mol). After 10 minutes, (Boc) 2O (508.7 g, 2.33 mol) was added over a period of 40 minutes. After the addition, the resulting mixture was stirred at room temperature for 3 hours. TLC (petroleum ether: ethyl acetate, 1: 1) indicated that the starting material was completely consumed. The mixture was filtered, and the filtrate was evaporated to dryness, and then partitioned between EtOAc (4 L) and water (2 L). The organic layer was washed with brine (1 L), dried over Na2SO4 and concentrated to provide tert-butyl 1H-pyrrolo [2,3-c] piperidine-1-carboxylate (830 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.3 (bs, 1 H) 8.32 (d, 1 H), 7.65 (bs, 1 H), 7.41-7.39 (m, 1 H ), 6.50 (d, 1 H), 1.62 (s, 9 H). Step 2. tert-Butyl tert-butyl (3S, 7aR) -octahidro-1H-pyrrolo [2,3-c] piperidine-1-carboxylate. To a dry hydrogenation flask, PtO2 (13 g) was added under Ar atmosphere. A solution of tert-butyl 1H-pyrrolo [2,3-c] piperidine-1-carboxylate (135 g, 0.62 mol) in EtOH (3 L) was added and the resulting mixture was hydrogenated at 3.51 Kg / Cm2 (50 psi) H2 at 80 oC for 48 hours. TLC (petroleum ether / EtOAc, 1: 1) showed that the starting material was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated to provide tert-butyl (3aS, 7aR) -octahidro-1H-pyrrolo [2,3-c] piperidine-1-carboxylate (810 g, 96.4%) like a colorless oil. 1H NMR (400 MHz, MeOH-d4) δ 1.27 - 1.43 (m, 9 H) 1.49 - 1.95 (m, 4 H) 2.18 - 2.48 (m, 2 H) 2.53 - 2.77 (m, 2 H) 3.09 (d, J = 5.02 Hz, 1 H) 3.19 - 3.42 (m, 2 H) 3.62 (br s, 1 H). Step 3. (3aR, 7aR) -hexahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) - benzyl carboxylate. To a stirred solution of tert-butyl (3aS, 7aR) -octahidro-1H-pyrrolo [2,3-c] piperidine-1-carboxylate (200 g, 0.885 mol) and DIPEA (251 g, 1.95 mol) in DCM (2L) at 0 ° C Cbz-Cl (181 g, 1.06 mol) was added dropwise over a period of 45 minutes. After the addition, the resulting mixture was stirred at room temperature for 16 hours. TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was evaporated to dryness, and then partitioned between EtOAc (8 L) and water (3 L); the organic layer was washed with water (3 L) and brine (3 L), dried over anhydrous Na2SO4 and concentrated to provide (3aS, 7aR) -octahidro-1H-pyrrolo [2,3-c] piperidine-1-carboxylate tert-butyl (1147 g, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.15 - 1.48 (m, 9 H) 1.51 - 1.65 (m, 1 H) 1.68 - 1.90 (m, 2 H) 2, 32 (br s, 1 H) 2.72 (t, J = 11.04 Hz, 1 H) 2.97 (br s, 1 H) 3.13 - 3.56 (m, 3 H) 3.73 (s, 2 H) 3.85 - 4.28 (m, 1 H) 4.91 - 5.14 (m, 2 H) 7.12 - 7.38 (m, 5 H). Steps 4, 5 and 6. (3aR, 7aR) -Henzahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) -carboxylate and (3aS, 7aS) -hexahydro-1H-pyrrole [2, 3- c] benzyl piperidine-6 (2H) -carboxylate. To a solution stirred at 0 oC of tert-butyl (3aS, 7aR) -octahidro-1H-pyrrolo [2,3-c] piperidine-1-carboxylate (280 g, 0.68 mol) in DCM (600 mL) 4M HCl in dioxane (2.5 L) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 15 hours. TLC (petroleum ether / EtOAc, 2: 1) showed that the starting material was completely consumed. The reaction mixture was evaporated to dryness, and then partitioned between MTBE (6L) and H2O water (4 L), the aqueous phase was then basified to pH 9 ~ 10 and extracted with DCM (3 L * 4). The combined organic layers were concentrated to provide benzyl rac- (3aR, 7aR) -hexahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) -carboxylate (687 g, 85%), which was separated by SFC to provide (3aS, 7aS) -hexahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) - benzyl carboxylate (280 g, 42.2%) and (3aR, 7aR) -hexahydro-1H - benzyl pyrrolo [2,3-c] piperidine-6 (2H) -carboxylate (270, 39.3%) as a yellow oil. (Peak 1 was benzyla (3aR, 7aR) -hexahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) -carboxylate, RT = 9.81; peak 2 was (3aS, 7aS) - hexahydro- 1H-benzyl pyrrolo [2,3-c] piperidine-6 (2H) -carboxylate, RT = 10.63). 1H NMR (400 MHz, CDCl3) δ 1.28 - 1.63 (m, 3 H) 1.68 - 1.90 (m, 2 H) 1.97 - 2.09 (m, 1 H) 2, 71 - 3.19 (m, 4 H) 3.26 - 3.43 (m, 1 H) 3.55 - 3.77 (m, 2 H) 5.02 (br s, 2 H) 7.10 - 7.35 (m, 5 H). Separation conditions: Instrument: SFC 350; Column: AS 250mmx50mm, 10 μm; Mobile Phase: A: Supercritical CO2, B: EtOH (0.05% DEA), A: B = 65: 35 to 240ml / min; Column temperature: 38 oC; Nozzle pressure: 100 Bar; Nozzle temperature: 60 oC; Evaporator temperature: 20 oC; Adjuster Temperature: 25 oC; Wavelength: 220nm. Step 7. (3aS, 7aS) -1- (2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) benzyl carboxylate. A mixture of (3aS, 7aS) -hexahydro-1H-pyrrolo [2,3-c] benzyla piperidine-6 (2H) -carboxylate, peak 2 (135 g, 0.52 mol), DIPEA (268 g, 2 , 1 mol) and 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (88.7 g, 0.47 mol) in n-BuOH (1L) was heated to 80 oC for 3 hours, TLC (petroleum ether / ether, 2: 1) showed that 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine was consumed completely. The reaction mixture was cooled to room temperature and evaporated to dryness using an oil pump at 45 oC. The residue was partitioned between DCM (2L) and water (1.5 L); the organic layer was washed with water (1 L) and brine (1 L), dried over Na2SO4 and concentrated to provide (3aS, 7aS) -1- (2-chloro-7H-pyrrolo [2,3-d] pyrimidine- Benzyl 4-yl) hexahydro-1H-pyrrolo [2,3-c] piperidine-6 (2H) -carboxylate (310 g, 80%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.58 - 2.35 (m, 5 H) 2.90 - 3.28 (m, 2 H) 3.58 - 4.07 (m, 3 H) 4.35 (br s, 2 H) 5.16 (br s, 2 H) 6.46 - 6.85 (m, 1 H) 7.12 - 7.57 (m, 6 H) 11.87 ( br s, 1 H). Step 8. 4 - ((3aR, 7aS) -Octahidro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine. To a dry Parr hydrogenation flask, Pd / C (12 g) was added under an atmosphere of air. Then a solution of (3aS, 7aS) -1- (2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] piperidine-6 ( 2H) benzyl carboxylate (62 g, 0.15 mol) in EtOH (1.2 L) was added and the resulting mixture was hydrogenated under 3.51 Kg / Cm2 (50 psi) of H2 at 65 oC for 48 hours , TLC (Petroleum ether / EtOAc, 1: 1) showed that the starting material was completely consumed; the reaction mixture was filtered and the filter cake was washed with hot MeOH and water (v / v 1: 1, 500 mLx2); the combined filtrate was evaporated to provide 4 - ((3aR, 7aS) -octahidro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine (190 g, 90%) as a white solid. Step 9. 1 - ((3aS, 7aS) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) - il) prop-2-en-1-one. To a solution of 4- ((3aR, 7aS) -octahidro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3- d] pyrimidine (150 g, 0.54 mol) in aqueous NaHCO3 (150 g, 1.79 mol) in H2O (1.5 L) at 0 oC a solution of acryloyl chloride (53.3 g, 0.59 mol) in MeCN ( 150 mL) carefully. After the addition, the resulting mixture was stirred at room temperature for 2 hours. TLC (DCM / MeOH, 5: 1) showed that 4- ((3aR, 7aS) -octahidro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine was consumed completely. The reaction mixture was extracted with DCM (500 mL * 4) and the combined organic layers were concentrated to provide the crude product, which was purified by column chromatography to provide 1 - ((3aS, 7aS) -1- (7H- pyrrolo [2,3- d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one (130 g, 81% ) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.58 (s, 1H) 8.09-8.07 (d, J = 9.2Hz, 1H) 7.115 (s, 1H), 6.82-6 , 78 (m, 1H), 6.51 (m, 1H), 6.05-6.01 (m, 1H), 5.69-5.85 (m, 1H), 4.69-4.68 (m, 0.5H), 4.27 (s, 1H), 3.90-3.74 (m, 3H), 3.13-3.24 (m, 2H), 2.74-2.71 (m, 0.5H), 2.19-1.74 (m, 4.5 H). Example 9: 1 - (((2S, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-ethylpiperidin-1-yl) prop-2-en-1 -one. Racemic 5 - ((tert-butoxycarbonyl) amino) -2-ethylpiperidine-1-carboxylate was prepared using a process similar to the methyl intermediate. The racemic intermediate contained cis isomers as the main component as was the case for the methyl intermediate. The racemic mixture was separated into four optically pure isomers by means of chiral SFC, and the two cis isomers were obtained as peak 3 and 4. Preparative SFC separation conditions: Column: Chiralcel OJ-H 30 * 250mm; Mobile Phase: 95/5 CO2 / methanol; Flow Rate: 120mL / min; Wavelength: 210nm; analytical condition SFC: Column: Chiralcel OJ-H 4.6 * 25mm; Mobile Phase: 5-60% CO2 / methanol; Flow Rate: 3mL / min; Wavelength: 210nm. Preparation of final analogs using enantiomerically pure benzyl 5 - ((tert-butoxycarbonyl) amino) -2-ethylpiperidine-1-carboxylate followed by protocols similar to other analogs (see Example 5). Thus 1 - ((2S, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-ethylpiperidin-1-yl) prop-2-en-1-one was prepared from peak 3 of the chiral separation of racemic 5 - ((tert-butoxycarbonyl) amino) -2-ethylpiperidine-1-carboxylate. 1H NMR (400MHz, DMSO-d6) δ 11.51 (br s, 1H), 8.11 (d, J = 13.6 Hz, 1H), 7.26 (dd, J = 6.6, 21, 4 Hz, 1H), 7.08 (br s, 1H), 6.9 - 6.7 (m, 1H), 6.53 (s, 1H), 6.10 (d, J = 16.8 Hz , 1H), 5.7 - 5.6 (m, 1H), 4.57 (br s, 1H), 4.07 (m, 2H), 2.90 (t, J = 12.1 Hz, 1H ), 1.92 - 1.5 (m, 6H), 0.81 (m, 3H). LCMS (acid, 3 minute cycle): RT 0.76 min. LC / MS (M + H) = 300.25. Example 10: 1 - (((3R, 5R) -3 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-fluoropiperidin-1-yl) prop-2-en-1 -one Step 1. N - (((3R, 5R) -1-Benzyl-5-fluoropiperidin-3-yl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine. A mixture of (3R, 5R) -1-benzyl-5-fluoropiperidin-3-amine (prepared as described in Eur. J. Org. Chem. 2012, 10, 2023 and Org. Lett. 2011, 13, 4442) ( 500 mg, 2.4 mmol), DIPEA (1.55 g, 12 mmol) and 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (495 mg, 2.64 mmol) in n-BuOH (35 ml) was heated to 130 to 140 oC overnight. LC-MS showed that the reaction was complete. TLC (PE / EtOAc, 1: 1) showed that the starting material was completely consumed and the desired product was formed. The reaction mixture was cooled to room temperature and evaporated to dryness under vacuum at 45 oC. The residue was treated with water (20 ml) and extracted with EtOAc (30 ml * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by chromatography to provide N - ((3R, 5R) -1-benzyl-5-fluoropiperidin-3- il) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (760 mg, 88.0%) as an oil. LC / MS (M + H) 360.2. Step 2. N - (((3R, 5R) -5-Fluoropiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a dry Parr hydrogenation flask, 10% dry Pd / C (160 mg) was added under Ar atmosphere followed by a solution of N - ((3R, 5R) -1-benzyl-5-fluoropiperidin-3-yl ) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (940 mg, 2.61 mmol) in MeOH (30 ml) and THF (6 ml). The resulting mixture was hydrogenated under 3.51 Kg / Cm2 (50 psi) of H2 at 35 oC for 72 hours. LC-MS showed that more of the starting material was consumed completely and the desired product was formed. The reaction solution was filtered through a pad of Celite®, and the filter cake was washed with MeOH three times. The combined filtrate was concentrated to provide N - (((3R, 5R) -5-fluoropiperidin-3-yl) - 7H-pyrrolo [2,3-d] pyrimidin-4-amine (600 mg, 97.5%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.61 (br s, 1H), 9.50 (br s, 1H), 8.22 - 8.11 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.23 - 7.03 (m, 1H), 6.61 (d, J = 1.8 Hz, 1H), 5.32 - 5.13 (m, 1H) , 4.80 - 4.64 (m, 1H), 3.32 - 3.24 (m, 1H), 3.22 - 3.12 (m, 1H), 2.84 (t, J = 11, 5 Hz, 1H), 2.32 (br s, 1H), 2.05 - 1.85 (m, 1H), 1.37 - 0.82 (m, 1H). Step 3. 1 - (((3R, 5R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-fluoropiperidin-1-yl) prop-2-en-1 -one. To a stirred solution of N- ((3R, 5R) -5-fluoropiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (200 mg, 0.85 mmol) in THF ( 12 ml) and aqueous NaHCO3 solution (12 ml) at 0 oC was added acryl-Cl (85 mg, 0.93 mmol) dropwise. The resulting mixture was stirred at 0 ° C for 2 hours. TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (30 ml * 2); the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was again purified by silica gel column chromatography (MeOH: DCM, 0-8%) to provide 1 - ((3R, 5R) -3- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-fluoropiperidin-1-yl) prop-2-en-1-one (130 mg, 53.0 %) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.55 (br s, 1H), 8.13 (d, J = 18.8 Hz, 1H), 7.41 - 7.27 (m, 1H), 7 , 10 (br s, 1H), 6.80 (dd, J = 10.5, 16.8 Hz, 1H), 6.55 (br s, 1H), 6.13 (dd, J = 2.3 , 16.6 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.17 - 4.91 (m, 1H), 4.71 - 4.18 (m, 3H) , 3.40 (d, J = 15.1 Hz, 0.5H), 3.19 - 2.98 (m, 1H), 2.61 (t, J = 11.5 Hz, 0.5H), 2.29 (d, J = 6.0 Hz, 1H), 2.05 - 1.74 (m, 1H). Example 11: 1 - (((3R, 4S) -3 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1 -one Step 1. rac- (3R, 4S) -3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) - tert- 4-methylpiperidine-1-carboxylate butyl. To a solution of tert-butyl rac- (3R, 4S) -3-amino-4-methylpiperidine-1-carboxylate (prepared as described in WO2011029046) (500 mg, 2,333 mmol) and 2,4-dichloro-7H- pyrrolo [2,3-d] pyrimidine (483 mg, 2.566 mmol, 1.1 eq.) in n-BuOH (15 mL) DIPEA (903 mg, 6.999 mmol, 3.0 eq.) was added at room temperature, and heated to 140 oC overnight. After LCMS indicated that the reaction was complete, the reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in EtOAc (50 ml) and diluted with water (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (50 ml * 1), and the combined organic layers were washed with brine, dried with sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (EtOAc / PE = 8% ~ 50%) to provide rac- (3R, 4S) -3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4 - yl) tert-butyl amino) -4-methylpiperidine-1-carboxylate (rac-trans, 563 mg, 66%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 11.92 (br s, 1H), 7.14 (br s, 1H), 6.46 (br s, 1H), 4.40 (d, J = 9.3 Hz , 1H), 4,083.65 (m, 2H), 2.98 - 2.63 (m, 2H), 1.90 - 1.60 (m, 3H), 1.52-1.38 (m, 1H ), 1.48 (s, 9H), 1.11 - 1.05 (m, 3H). Step 2. Tert-butyl rac- (3R, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidine-1-carboxylate. To a dry Parr hydrogenation flask, dry Pd / C (100 mg) was added under N2 atmosphere. A solution of tert-butyl rac- (3R, 4S) -3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidine-1-carboxylate ( 560 mg, 1.531 mmol) in MeOH / THF (30 mL / 10 mL) was added, and the resulting mixture was heated to 40 ° C under 3.51 kg / Cm2 (50 psi) of H2 for two days. After LCMS showed that the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with MeOH. The combined filtrate was evaporated to provide tert-butyl rac- (3R, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidine-1-carboxylate ( 520 mg, 93%) as a yellow solid. LC / MS (M + H) = 332.2. Step 3. Rac-N - ((3R, 4S) -4-Methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a solution of tert-butyl rac- (3R, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidine-1-carboxylate (520 mg, 1.531 mmol) in DCM (15 mL) at 0 oC 4.0 M HCl / dioxane (15 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. After LCMS showed that the reaction was complete, the reaction mixture was concentrated to provide rac-N - ((3R, 4S) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin- 4-amine (410 mg, 100%) as a solid. LC / MS (M + H) = 232.2. Step 4. rac-1 - (((3R, 4S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en -1-one. To a solution of rac-N - ((3R, 4S) - 4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (410 mg, 1.530 mmol) in THF (20 ml) and saturated NaHCO3 (15 ml) at 0 oC was added acryloyl chloride (152 mg, 1.683 mmol, 1.1 eq.). The reaction mixture was stirred at 0 ° C for 2 hours. After TLC (EtO-Ac / MeOH, 10: 1) showed that the reaction was complete, the reaction mixture was diluted with water (50 ml), and extracted with EtOAc (50 ml * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (MeOH / EtOAc, 2% ~ 10%) and lyophilized to provide rac-1 - ((3R, 4S) -3 - ((7H-pyrrole [2,3-d ] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1-one (150 mg, 34%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.08 (d, J = 15.1 Hz, 1H), 7.32 - 7.20 (m, 1H), 7 , 08 (br s, 1H), 6.81 (dt, J = 10.5, 17.3 Hz, 1H), 6.59 (br s, 1H), 6.12 (d, J = 14.8 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 4.65 - 4.39 (m, 1H), 4.27 - 4.04 (m, 1H), 3.94 - 3.71 (m, 1H), 3.08 - 2.96 (m, 0.5H), 2.89 - 2.77 (m, 0.5H), 2.71 - 2.60 (m, 0.5H), 2.46 - 2.28 (m, 0.5H), 1.82 (d, J = 12.3 Hz, 2H), 1.29 - 1.12 (m, 1H), 0 , 94 (dd, J = 6.0, 12.3 Hz, 3H). LCMS (M + H) = 286.1. Step 5. 1 - (((3R, 4S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1 -one (peak 1) and 1 - ((3S, 4R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2 -en-1-one (peak 2). rac-1 - (((3R, 4S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1- one (120 mg) was separated by chiral SFC (Chiral Pak-AD (250 x 30 mm, 5um), 30% EtOH (0.05% NH3 in H2O) in CO2) to provide the pair of enantiomers, (peak 1, 47.8 mg) and (peak 2, 48.2 mg) as white solids, absolute stereochemistry arbitrarily designated. Peak Data 1: 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.08 (d, J = 15.1 Hz, 1H), 7.32 - 7.20 (m , 1H), 7.08 (br s, 1H), 6.81 (dt, J = 10.5, 17.3 Hz, 1H), 6.59 (br s, 1H), 6.12 (d, J = 14.8 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 4.65 - 4.39 (m, 1H), 4.27 - 4.04 (m, 1H ), 3.94 - 3.71 (m, 1H), 3.08 - 2.96 (m, 0.5H), 2.89 - 2.77 (m, 0.5H), 2.71 - 2 , 60 (m, 0.5H), 2.46 - 2.28 (m, 0.5H), 1.82 (d, J = 12.3 Hz, 2H), 1.29 - 1.12 (m , 1H), 0.94 (dd, J = 6.0, 12.3 Hz, 3H). LCMS (M + H) = 285.9. Peak Data 2: 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.08 (d, J = 15.1 Hz, 1H), 7.32 - 7.20 (m , 1H), 7.08 (br s, 1H), 6.81 (dt, J = 10.5, 17.3 Hz, 1H), 6.59 (br s, 1H), 6.12 (d, J = 14.8 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 4.65 - 4.39 (m, 1H), 4.27 - 4.04 (m, 1H ), 3.94 - 3.71 (m, 1H), 3.08 - 2.96 (m, 0.5H), 2.89 - 2.77 (m, 0.5H), 2.71 - 2 , 60 (m, 0.5H), 2.46 - 2.28 (m, 0.5H), 1.82 (d, J = 12.3 Hz, 2H), 1.29 - 1.12 (m , 1H), 0.94 (dd, J = 6.0, 12.3 Hz, 3H). LCMS (M + H) = 285.9. Example 12: (R) -1- (3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one Step 1. (R) -tert-butyl 3 - ((7-Tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a stirred solution of 4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (8.73 g, 28.4 mmol) in n-butanol (100 mL) was added DIPEA (6.0 mL, 1.2 eq) and (R) -3-amino piperidine-1-carboxylic acid tert-butyl ester (6.82 g, 1.2 eq). The reaction mixture was heated to 70 ° C overnight. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography (100-200 silica mesh, 0-3% MeOH in DCM) to obtain 3 - ((7-tosyl-7H-pyrrole [2, (R) - tert-butyl 3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (5.6 g, 42%). LC / MS (M + H) = 472.2. 1H NMR (400 MHz, CDCl3) δ ppm 1.09 - 1.30 (m, 4 H) 1.33 (br s, 9 H) 1.49 - 1.94 (m, 2 H) 2.34 ( s, 3 H) 3.37 (br s, 2 H) 3.67 (d, J = 12.88 Hz, 1 H) 4.09 - 4.21 (m, 1 H) 6.39 (d, J = 4.10 Hz, 1 H) 7.10 - 7.29 (m, 2 H) 7.42 (d, J = 4.10 Hz, 1 H) 7.92 - 8.07 (m, 2 H) 8.39 (s, 1 H). Step 2. (R) -tert-butyl ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a stirred solution of (R) -tert-butyl 3 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (29.4 g, 62 mmol) in MeOH (96 mL), THF (96 mL) and water (96mL) LiOH ^ O (2.99 g, 125 mmol, 2 eq) was added. The mixture was heated to 60 ° C for 1 hour. After the reaction mixture was cooled to room temperature, the organic solvent was evaporated in vacuo. The aqueous mixture was prepared slightly acidic and then extracted with ethyl acetate (4 x 150 ml). The organic fractions were combined and washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (100-200 silica mesh, 02% MeOH in DCM) to provide 8.5 g (70%) of 3 - ((7H-pyrrolo [2,3-d] pyrimidin -4-yl) amino) (R) -tert-butyl amino) piperidine-1-carboxylate as an off-white solid. LC / MS (M + H) 318.2. 1H NMR (400 MHz, CDCl3) δ 1.45 (br s, 9 H) 1.58 - 1.87 (m, 3 H) 2.04 (dd, J = 8.39, 4.10 Hz, 1 H) 3.35 - 3.56 (m, 2 H) 3.75 - 3.91 (m, 2 H) 4.22 - 4.38 (m, 1 H) 5.18 (br s, 1 H ) 6.33 - 6.47 (m, 1 H) 7.11 (d, J = 2.34 Hz, 1 H) 8.39 (s, 1 H) 10.19 (br s, 1 H). Step 3. (R) -N- (Piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a stirred solution of (R) -tert-butyl 3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (40 mL) was added HCl to 4 M in dioxane (60 mL) dropwise. The reaction was stirred for ~ 1 hour and then diluted with diethyl ether to form a solid, which was filtered and collected. The solid was dried under high vacuum to provide (R) -N- (piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine HCl salt (4.6 g, 92% ). LC / MS (M + H) = 218.2. 1H NMR (400 MHz, D2O) δ 1.70 - 2.31 (m, 4 H) 2.94 - 3.18 (m, 2 H) 3.32 - 3.45 (m, 1 H) 3, 64 (dd, J = 12.68, 4.10 Hz, 1 H) 4.31 - 4.47 (m, 1 H) 6.78 (d, J = 3.51 Hz, 1 H) 7.35 (d, J = 3.90 Hz, 1 H) 8.24 - 8.35 (m, 1 H). Step 4. (R) -1- (3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one. To a round-bottom flask containing (R) -N- (piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine HCl salt (1.0 g, 3.44 mmol ) DCM (30 ml), EtOH (3 ml) and TEA (2.11 ml, 4.4 eq) were added. After 30 min, acrylolyl chloride in 20 ml of DCM was added dropwise and the reaction stirred at room temperature for 2 hours. The mixture was poured into water and the layers separated. The organic layer was dried (Na2SO4) and the solvent removed to provide the crude product (~ 900 mg). The material was purified by chromatography (silica, DCM / MEOH) to provide (R) -1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1- il) prop-2-en-1-one (310 mg, 33%). LC / MS (M + H) = 272.1. 1H NMR (400 MHz, DMSO-d6) δ 1.40 - 2.12 (m, 3 H) 2.61 - 2.76 (m, 1 H) 2.89 - 3.18 (m, 2 H) 3.92 - 4.22 (m, 2 H) 4.55 (d, J = 12.10 Hz, 1 H) 5.47 - 5.75 (m, 1 H) 5.97 - 6.20 ( m, 1 H) 6.60 (br s, 1 H) 6.65 - 6.90 (m, 1 H) 7.00 - 7.13 (m, 1 H) 7.25 (d, J = 6 , 63 Hz, 1 H) 8.12 (d, J = 14.44 Hz, 1 H) 11.50 (br s, 1 H). Example 13: 1 - ((2S, 5R) -5 - ((5- (2-Methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl ) prop-2-en-1-one Step 1. (+) - (2S, 5R) 5-Amino-2-methylpiperidine-1-carboxylate and (5-amino-2-methylpiperidine-1-carboxylate) -) - (2R, 5S) - benzyl. Racemic (2S, 5R) -benzyl 5-amino-2-methylpiperidine-1-carboxylate (Example 5, Step 5, 10 g) was purified by chiral SFC (cellulose-2; CO2 / MeOH - 0.2% NH3 / EtOH) to provide (2R, 5S) -benzyl pk 1: 5- amino-2-methylpiperidine-1-carboxylate, [a] d20 = - 7.09 (c = 1.1, MeOH). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (br s, 3H), 7.24 - 7.49 (m, 5H), 5.09 (s, 2H), 4.32 (m, 1H ), 4.16 (d, J = 8.28Hz, 1H), 3.00 (br s, 2H), 1.83 (m, 2H), 1.59 (m, 2H), 1.11 (d , J = 7.03 Hz, 3H). pk2: (2S, 5R) -benzyl 5-amino-2-methylpiperidine-1-carboxylate, [a] d20 = +7.09 (c = 1.1, MeOH). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (br s, 3H), 7.24 - 7.49 (m, 5H), 5.09 (s, 2H), 4.32 (m, 1H ), 4.16 (d, J = 8.28Hz, 1H), 3.00 (br s, 2H), 1.83 (m, 2H), 1.59 (m, 2H), 1.11 (d , J = 7.03 Hz, 3H). Step 2. 5 ((2S, 5R ((2S, 5R ((5S (5S (5S (5S (5S (5R ) -benzyl. A mixture of (+) - (+) - (+) - (2S, 4-chloro-5- (2-methoxyethyl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine, 5-amino-2-methylpiperidine-1-carboxylate 5R) -benzyl and Hunig's base in n-BuOH was combined and heated to 90 ° C overnight. The mixture was removed from heating and concentrated. The residue was purified by CombiFlash® (24 g gold column, 0 to 50% EA in Hept) to provide 264 mg of 5 - ((5- (2-methoxyethyl) -7-tosyl-7H-pyrrole [2 , 3-d] pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate (2S, 5R) -benzyl. LC / MS (M + H) 578.5. Step 3. 5- (2-Methoxyethyl) -N - ((3R, 6S) -6-methylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a Parr reactor flask were added 5 - ((5- (2-methoxyethyl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) - 2-methylpiperidine-1-carboxylate (2S, 5R) -benzyl (in 10 mL of EtOH) and Pd (OH) 2 (126 mg). The reaction was stirred at 1.75 kg / cm2 (25 psi) of H2 overnight at room temperature. The mixture was filtered through Celite® and the solvent removed to provide 190 mg of 5- (2-methoxyethyl) -N - ((3R, 6S) -6-methylpiperidin-3-yl) -7-tosyl-7H-pyrrole [2,3-d] pyrimidin-4-amine as a white foam. LC / MS (M + H): 444.4. Step 4. 1 - ((2S, 5R) -5 - ((5- (2-Methoxyethyl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin -1-yl) prop-2-en-1-one. To a chloroform solution of 5- (2-methoxyethyl) -N - ((3R, 6S) -6-methylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine (5 mL)) was added to Hunig's base. The solution was cooled to 0 oC and acryloyl chloride was added. After 30 min, the reaction was determined to be complete by LC / MS, and NaHCO3 was added. The reaction was stirred for 30 minutes. The organic layer was separated and concentrated. The residue was purified by CombiFlash® (20 to 100 EA in heptane) to provide 210 mg of 1 - ((2S, 5R) -5 - ((5- (2-methoxyethyl) -7-tosyl-7H-pyrrole [2 , 3- d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one. LC / MS (M + H): 498.4. Step 5. 1 - ((2S, 5R) -5 - ((5- (2-Methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl ) prop-2-en-1-one. 1 - (((2S, 5R) -5 - ((5- (2- Methoxyethyl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin- 1- il) prop-2-en-1-one (200 mg) was dissolved in 3 ml of THF. A solution of TBAF (1 M in THF, 0.804 ml, 2 eq) was added. The reaction mixture was heated to 60 oC and stirred overnight. The reaction was cooled to room temperature and diluted with 10 ml of EtOAc. The solution was washed with NH4Cl (10%), brine and dried (Na2SO4). The mixture was filtered and concentrated. The residue was purified by CombiFlash® (12 g gold column, 0 to 10% MeOH in DCM) to provide 100 mg of 1 - ((2S, 5R) -5 - ((5- (2-methoxyethyl) - 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one. LC / MS (M + H) = 344.3. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.18 (br s, 1H), 7.08 (s, 1H), 6.82-6.77 (m. 1H ), 6.10-6.07 (m, 1H) 5.68-5.66 (m, 1H) 3.61-3.57 (m, 2H), 3.30 (s, 3H), 3, 05-3.00 (m, 2H), 2.49-2.48 (m, 3H), 1.87-1.56 (m, 5H), 1.22-1.18 (m, 3H). Example 14: 1 - (((3R, 5S) -3- (7H-Pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one ( chiral and rac-cis) Step 1: tert-Butyl (5-Methylpyridin-3-yl) carbamate. A solution of 5-methylpyridin-3-amine (20 g, 185 mmol) and (Boc) 2O (44.4 g, 203.5 mmol) in THF (360 mL) was stirred at room temperature for 5 h. TLC (PE / EtOAc, 1: 1) showed that the reaction was complete. The reaction mixture was concentrated, and triturated with MTBE to provide tert-butyl (5-methylpyridin-3-yl) carbamate (26.4 g, 69%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2.3 Hz, 1H), 8.15 - 8.10 (m, 1H), 7.88 (br s, 1H), 6, 66 (br s, 1H), 2.33 (s, 3H), 1.53 (s, 9H), Step 2. Rac-cis / trans-tert-butyl carbamate (5-Methylpiperidin-3-yl). To a dry hydrogenation flask, PtO2 (3.0 g) was added under an atmosphere of N2. A solution of compound 2 (26.4 g, 127 mmol) in CH3COOH (300 mL) was added, and the resulting mixture was heated to 50 ° C under 3.86 kg / cm2 (55 psi) of H2 for 5 days. 1H NMR showed that most of the starting material was consumed. The reaction mixture was filtered and the filter cake was washed with MeOH. The combined filtrate was evaporated under high vacuum to provide rac-cis / trans-tert-butyl (5-methylpiperidin-3-yl) carbamate (27.3 g, 100%) as a yellow oil. LC / MS (M + H) 214.2 Step 3. 3 - Rac-cis / trans-benzyl ((tert-Butoxycarbonyl) amino) -5-methylpiperidine-1-carboxylate. To a solution of rac-cis / trans-tert-butyl (5-methylpiperidin-3-yl) carbamate (27.3 g, 127 mmol) in THF (200 mL) and H2O (100 mL) was added NaHCO3 (40 , 53 g, 482 mmol, 3.8 eq.) At room temperature, and stirred at room temperature for 1 h. CbzCl (26 g, 152 mmol, 1.2 eq.) Was added dropwise, and stirred at room temperature for 8 h. TLC (PE / EtOAc, 2: 1) showed the reaction to be complete. The reaction mixture was extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE / EtOAc, 8: 1 ~ 4: 1) to provide rac-cis / trans-benzyl 3 - ((tert-butoxycarbonyl) amino) -5-methylpiperidine-1-carboxylate ( 20 g, 45%, containing some benzyl alcohol) as a white solid. LC / MS (M + H) 348.2. Step 4. Rac-cis / trans-benzyl 3-Amino-5-methylpiperidine-1-carboxylate. To a solution of rac-cis / trans-benzyl 3 - ((tert-butoxycarbonyl) amino) -5-methylpiperidine-1-carboxylate (20 g, 57.4 mmol) in DCM (40 mL) was added HCl (g ) / dioxane (50 mL, 4M) dropwise at room temperature, and stirred at room temperature for 6 hrs. LCMS showed the reaction to be complete. The reaction mixture was concentrated, filtered, and then triturated with MTBE to provide rac-cis / trans-benzyl 3-amino-5-methylpiperidine-1-carboxylate (5.8 g, 43%, 0.817 mol HCl) like a gray solid. 1H NMR (400 MHz, MeOD) δ 7.43 - 7.27 (m, 5H), 5.14 (s, 2H), 4.50 - 4.39 (m, 1H), 4.12 (d, J = 10.3 Hz, 1H), 4.04 - 3.90 (m, 1H), 3.74 - 3.43 (m, 1H), 3.23 - 3.10 (m, 1H), 2 , 82 - 2.59 (m, 1H), 2.40 (s, 1H), 2.26 - 2.05 (m, 1H), 1.92 (d, J = 11.3 Hz, 1H), 1.78 - 1.58 (m, 1H), 1.30 (s, 1H), 1.25 - 1.05 (m, 2H), 1.01 - 0.93 (m, 3H). LCMS (M + H) = 248.9. Step 5. Rac-cis- (3R, 5S) -benzyl (((2-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1-carboxylate (3R, 5S) -benzyl and Rac - trans - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1-carboxylate (3R, 5R) -benzyl. To a mixture of rac-cis / trans-benzyl 3 - ((tert-butoxycarbonyl) amino) -5-methylpiperidine-1-carboxylate (prepared similarly as described in WO201102904)) (4 g, 14.046 mmol) and 2.4 -dichloro-7H-pyrrolo [2,3-d] pyrimidine (2.9 g, 15.451 mmol, 1.1 eq.) in n-BuOH (70 mL) at room temperature DIPEA (7.248 g, 56.184 mmol, 4.0 eq.). The reaction mixture was heated to 140 oC for 30 h. After LCMS showed the reaction to be complete, the reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in EtOAc (150 ml), and diluted with water (150 ml) and the organic layer was separated. The aqueous layer was extracted with EtOAc (150 ml * 2), and the combined organic layers were washed with brine, dried with sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (PE / EtOAc, 6: 1 to 2: 1) to provide 3 - (((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) - Rac-cis- (3R, 5S) -benzyl 5-methylpiperidine-1-carboxylate (rac-cis, spot 2 on the high polarity TLC plate, 1.934 g, 34%) and 3 - ((2-chloro- 7H- pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1-carboxylate of rac-trans- (3R, 5R) -benzyl (rac-trans, spot 1 on the TLC plate low polarity, 559 mg, 10%) as a yellow solid.Pk2: 3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1- rac-cis- (3R, 5S) -benzyl (rac-cis) carboxylate: 1H NMR (400MHz, DMSO-d6) δ 11.70 (br s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.45 - 7.24 (m, 5H), 7.09 (br s, 1H), 6.58 (br s, 1H), 5.21 - 5.01 (m, 2H) , 4.33 (br s, 1H), 4.07 - 3.96 (m, 2H), 3.17 (d, J = 5.3 Hz, 1H), 2.61 - 2.53 (m, 1H), 2.33 (br s, 1H), 2.06 - 1.94 (m, 1H), 1.67 (br s, 1H), 1.29 - 1.13 (m, 1H), 0 , 91 (d, J = 6.5 Hz, 3H). Pk1: rac-trans- (3R, 5R) -3 (((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1-carboxylate (rac -trans): 1H NMR (400MHz, DMSO-d6) δ 11.69 (br s, 1H), 7.63 - 6.59 (m, 8H), 5.05 (d, J = 16.8 Hz, 1H), 4.87 (br s, 1H), 4.35 - 3.95 (m, 2H), 3.86 - 3.51 (m, 2H), 3.11 - 2.64 (m, 1H ), 2.19 (br s, 1H), 1.90 - 1.72 (m, 2H), 1.56 (br s, 1H), 0.91 (d, J = 6.5 Hz, 3H) , Step 6. rac-cis-N - ((3R, 5S) -5-Methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine
[063] To a dry Parr hydrogenation flask, dry Pd / C (500 mg) was added under N2 atmosphere. Then, a solution of rac-cis- 3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1-carboxylate (3R, 5S) benzyl (rac-cis, 1.934 g, 4.835 mmol) in CH3OH / THF (60 mL / 20 mL) was added. The resulting mixture was heated to 40 ° C under 3.51 kg / cm2 (50 psi) of H2 for 3 days. After LCMS showed the reaction to be complete and the Cl atom was removed, the reaction mixture was filtered, and the filter cake was washed with MeOH. The combined filtrate was evaporated to provide rac-cis-N- ((3R, 5S) -5-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (rac-cis, 1 , 4 g, 100%) as a pink solid. LC / MS (M + H) = 231.2. Step 7. rac-cis-1 - ((3R, 5S) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2 -en-1-one. To a solution of rac-cis-N- ((3R, 5S) -5-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (400 mg, 1.494 mmol) in THF (20 ml) saturated aqueous NaHCO3 (15 ml) was added at 0 ° C, then acryloyl chloride (149 mg, 1.643 mmol, 1.1 eq.) Was added slowly. The reaction was stirred at 0 ° C for 2 hours. After TLC (EtOAc / MeOH, 10: 1) shows the reaction to be complete, the reaction mixture was diluted with water (80 ml), and extracted with EtOAc (80 ml * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc / MeOH, 10: 1) to provide rac-cis-1 - ((3R, 5S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4 - yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (300 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (br s, 1H), 8.10 (d, J = 14.3 Hz, 1H), 7.39 - 7.22 (m, 1H), 7.07 (br s, 1H), 6.94 - 6.78 (m, 1H), 6.56 (br s, 1H), 6.12 (dd, J = 8.9, 16.2 Hz, 1H), 5.69 (t, J = 10.4 Hz, 1H), 4.71 (d, J = 10.0 Hz, 1H), 4.47 - 4.29 (m, 1H), 4, 03 (d, J = 11.0 Hz, 2H), 2.73 (t, J = 11.5 Hz, 1H), 2.58 (t, J = 12.3 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.19 (t, J = 11.5 Hz, 1H), 2.05 (d, J = 11.8 Hz, 1H), 1.36 - 1.17 (m , 1H), 0.97 - 0.89 (m, 3H). LCMS (M + H) 285.9. Step 8. 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1 -one and 1 - ((3S, 5R) -3 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1 -one. rac-cis-1- ((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en- 1-one was separated by chiral SFC (AD, 250 mm x 30 mm, 20 μm, 35% MeOH / NH4OH, 80 ml / min) to provide 1 - ((3R, 5S) -3- ((7H-pyrrole [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (pk1) and 1 - ((3S, 5R) -3 - (( 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (pk 2). Peak 1: 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.10 (d, J = 14.3 Hz, 1H), 7.42 - 7.23 (m, 1H), 7.08 (br s, 1H), 6.86 (td, J = 11.4, 16.4 Hz, 1H), 6.57 (br s, 1H), 6.18 - 6.06 (m, 1H), 5.70 (t, J = 10.2 Hz, 1H), 4.71 (d, J = 9.8 Hz, 1H), 4.48 - 4.30 (m, 1H) , 4.03 (d, J = 11.8 Hz, 1H), 2.79 - 2.54 (m, 1H), 2.42 - 2.14 (m, 1H), 2.06 (d, J = 12.5 Hz, 1H), 1.63 (br s, 1H), 1.39 - 1.17 (m, 1H), 0.99 - 0.87 (m, 3H). LCMS (M + H) = 285.9. Peak 2: 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.10 (d, J = 14.6 Hz, 1H), 7.38 - 7.23 (m, 1H), 7.08 (br s, 1H), 6.94 - 6.79 (m, 1H), 6.56 (br s, 1H), 6.12 (dd, J = 7.8, 16, 8 Hz, 1H), 5.75 - 5.64 (m, 1H), 4.71 (d, J = 11.8 Hz, 1H), 4.49 - 4.30 (m, 1H), 4, 03 (d, J = 11.5 Hz, 1H), 2.81 - 2.54 (m, 1H), 2.42 - 2.15 (m, 1H), 2.06 (d, J = 12, 3 Hz, 1H), 1.62 (br s, 1H), 1.38 - 1.18 (m, 1H), 0.99 - 0.88 (m, 3H). LCMS (M + H) 285.9. Example 15: 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-fluoropiperidin-1-yl) prop-2-en-1 -one. Step 1. (2S, 4R) -methyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate. To a stirred solution of (2S, 4R) - methyl 4-hydroxypyrrolidine-2-carboxylate (35 g, 193 mmol, 1 eq.) In DCM (300 ml) was added Et3N (78 g, 772 mmol, 4 eq. ) and BnBr (39.5 g, 231 mmol, 1.2 eq.) in cycles at 0 oC. The reaction mixture was stirred at room temperature for 12 hours. After TLC (DCM / MeOH, 10: 1) shows the complete reaction, the reaction mixture was diluted with saturated sodium carbonate (200 ml). The organic layer was washed with brine (200 ml), dried over Na2SO4 and concentrated to dryness, the crude product was purified by chromatography (MeOH / EtOAc, 0% to 10%) to provide 1-benzyl-4-hydroxypyrrolidine-2 (2S, 4R) -methylcarboxylate (30 g, 66%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.16 - 2.39 (m, 1 H) 2.42 - 2.65 (m, 2 H) 3.18 - 3.37 (m, 2 H) 3 .60 (d, J = 13.05 Hz, 1 H) 3.71 (s, 3 H) 4.03 (d, J = 13.05 Hz, 1 H) 4.97 - 5.23 (m, 1 H) 7.22 - 7.39 (m, 5 H). Step 2. (2S, 4S) -methyl 1-benzyl-4-fluoropyrrolidine-2-carboxylate. To a stirred solution of (2S, 4R) -methyl (2S, 4R) -methyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate (6 g, 25.37 mmol, 1 eq.) In anhydrous DCM (100 mL) was added DAST (10, 2 g, 63.4 mmol, 2.5 eq.) At -78 oC under N2. The reaction mixture was stirred at -78 ° C for 0.5 hours and then warmed to room temperature for 2 hours. After TLC (petroleum ether / ethyl acetate, 1: 1) shows that the starting material has been consumed, the reaction mixture was quenched with saturated sodium carbonate (200 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 again. The combined organic layers were washed with brine (200 ml), dried over Na2SO4 and concentrated to dryness, the crude product was purified by sp1 (EtOAc / petroleum ether, 10% to 80%) to provide 1-benzyl- (2S, 4S) -methyl 4-fluoropyrrolidine-2-carboxylate (2 g, 34%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 2.20 - 2.37 (m, 1 H) 2.43 - 2.67 (m, 2 H) 3.22 - 3.35 (m, 2 H) 3, 60 (d, J = 13.30 Hz, 1 H) 3.67 - 3.75 (m, 3 H) 4.03 (d, J = 13.05 Hz, 1 H) 4.99 - 5.22 (m, 1 H) 7.22 - 7.38 (m, 5 H). Step 3. ((2S, 4S) -1-Benzyl-4-fluoropyrrolidin-2-yl) methanol. To a stirred solution of LiAlH4 (1.28 g, 33.7 mmol, 1 eq.) In anhydrous THF (50 mL) was added dropwise a solution of 1-benzyl-4-fluoropyrrolidine-2-carboxylate (2S , 4S) -methyl (8 g, 33.7 mmol, 1 eq.) In anhydrous THF (50 mL) at 0 oC. The reaction mixture was stirred at room temperature for 10 hours. After TLC (petroleum ether / ethyl acetate, 4: 1) shows that the starting material was consumed, the reaction mixture was cooled to 0 oC and sequentially cooled with water (1.3 ml), 15% of NaOH solution (1.3 ml) and water (3.9 ml). MgSO4 (5 g) was added and the mixture was warmed to room temperature and stirred for 0.5 hours. The mixture was filtered and concentrated in vacuo to provide the crude product, which was purified by sp1 (EtOAc / petroleum ether, 40% to 100%) to provide (2S, 4S) -1-benzyl-4-fluoropyrrolidin-2- il) methanol (6 g, 70%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 2.09 - 2.51 (m, 3 H) 2.62 (d, J = 9.03 Hz, 1 H) 2.80 (t, J = 6.53 Hz , 1 H) 3.13 - 3.35 (m, 2 H) 3.49 (t, J = 9.79 Hz, 1 H) 3.77 (dd, J = 11.04, 3.01 Hz, 1 H) 4.05 (d, J = 13.05 Hz, 1 H) 4.94 - 5.16 (m, 1 H) 7.22 - 7.39 (m, 5 H). Step 4. (3R, 5S) -3-Azido-1-benzyl-5-fluoropiperidine and (2S, 4S) -2- (azidomethyl) -1-benzyl-4-fluoropyrrolidine. To a stirred solution of (2S, 4S) -1-benzyl-4-fluoropyrrolidin-2-yl) methanol (4 g, 19 mmol, 1 eq.) In anhydrous DCM (200 mL) was added n-Bu4NN3 (5, 96 g, 21 mmol, 1.1 eq.) And XtalFluor® (4.8 g, 21 mmol, 1.1 eq.) At -78 oC under N2 protection. The reaction mixture was stirred at -78 ° C for 6 hours. After TLC (petroleum ether / ethyl acetate, 4: 1) shows that the starting material was consumed, the reaction mixture was quenched with 15% NaOH solution (30 ml), and concentrated to dryness. The residue was purified by chromatography (EtOAc / petroleum ether, 0% to 20%) to provide a mixture of (3R, 5S) -3-azido-1-benzyl-5-fluoropiperidine and (2S, 4S) -2- (azidomethyl) -1-benzyl-4-fluoropyrrolidine (2.2 g, 50%) as a yellow oil. The mixture was separated by means of SFC (ChiralPak AD, 300 x 50 mm, 10 μm, 15% MeOH / NH4OH, 180 ml / min) to provide (3R, 5S) -3-azido-1-benzyl-5- fluoropiperidine (1.2 g) and (2S, 4S) -2- (azidomethyl) -1-benzyl-4-fluoropyrrolidine (1 g) as yellow oil. (3R, 5S) -3-azido-1-benzyl-5-fluoropiperidine: 1H NMR (400MHz, CDCl3) δ 1.48 - 1.67 (m, 1 H) 2.04 - 2.22 (m, 2 H) 2.34 (br s, 4 H) 2.58 - 2.90 (m, 2 H) 2.97 - 3.10 (m, 1 H) 3.50 - 3.65 (m, 2 H ) 4.55 - 4.82 (m, 1 H) 7.19 - 7.41 (m, 5 H). Step 5. (3R, 5S) -1-Benzyl-5-fluoropiperidin-3-amine. To a solution of (3R, 5S) -3-azido-1-benzyl-5-fluoropiperidine (1.4 g, 5.9 mmol, 1 eq.) In THF (50 mL) was added PPh3 (2.35 g , 90 mmol, 1.5 eq.) In portions at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Then, water (0.7 ml) was added dropwise to the mixture and heated to 60 oC for 10 hours. After TLC (petroleum ether / ethyl acetate, 4: 1) shows that the starting material was consumed, the reaction mixture was concentrated to dryness, and purified by sp1 (MeOH / CH2Cl2 0% to 10%) to provide (3R, 5S) -1-benzyl-5-fluoropiperidin-3-amine (1.1 g, 80%) as a colorless oil. LC / MS (M + H) = 209.2. 1H NMR (400MHz, CDCl3) δ 1.37 - 1.53 (m, 1 H) 1.99 (t, J = 9.41 Hz, 1 H) 2.12 - 2.36 (m, 2 H) 2.70 (d, J = 10.29 Hz, 1 H) 2.82 - 3.01 (m, 2 H) 3.53 - 3.62 (m, 2 H) 4.55 - 4.77 ( m, 1 H) 7.22 - 7.37 (m, 5 H). Step 6. N - (((3R, 5S) -1-Benzyl-5-fluoropiperidin-3-yl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine. A mixture of (3R, 5S) -1-benzyl-5-fluoropiperidin-3-amine (300 mg, 1.44 mmol), DIPEA (929 mg, 7.2 mmol) and 2,4-dichloro-7H-pyrrole [2,3-d] pyrimidine (297 mg, 1.59 mmol) in n-BuOH (10 mL) was heated to 130-140 ° C overnight. After LC-MS showed the reaction to be complete, the reaction mixture was cooled to room temperature and evaporated to dryness under vacuum at 45 oC. The residue was diluted with EtOAc (30 ml) and washed with water (20 ml). The aqueous layer was extracted with EtOAc (30 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by chromatography (EtOAc / petroleum ether, 10% to 80%) to provide N - ((3R, 5S) -1-benzyl-5-fluoropiperidin-3-yl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (300 mg, 65%) as a yellow solid. LC / MS (M + H) = 359.2. Step 7. N - (((3R, 5S) -5-Fluoropiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a bottle of dry Parr hydrogenation, 10% dry Pd / C (50 mg) was added under Ar atmosphere. A solution of N - ((3R, 5S) - 1-benzyl-5-fluoropiperidin-3-yl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (300 mg, 0.84 mmol) in MeOH (20 mL) was added and the resulting mixture was hydrogenated under 3.51 kg / cm2 (50 psi) of H2 at 35 oC for 72 hours. The reaction mixture was filtered through a pad of Celite®, and the filter cake was washed with MeOH three times. The combined filtrate was concentrated to provide N - ((3R, 5S) -5-fluoropiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (200 mg, 100%) as a solid White. 1H NMR (400 MHz, DMSO-d6) δ 0.74 - 1.28 (m, 1 H) 1.94 - 2.11 (m, 1 H) 2.31 - 2.46 (m, 1 H) 2.96 (dd, J = 12.17, 8.41 Hz, 1 H) 3.43 - 3.56 (m, 2 H) 4.12 (br s, 1 H) 4.57 (br s, 1 H) 4.86 - 5.12 (m, 1 H) 6.62 (d, J = 2.01 Hz, 1 H) 7.12 (br s, 1 H) 7.53 (d, J = 7.53 Hz, 1 H) 8.06 - 8.19 (m, 1 H) 11.61 (br s, 1 H). Step 8. 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-fluoropiperidin-1-yl) prop-2-en-1 -one.
[064] To a solution of N - ((3R, 5S) -5-fluoropiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.424 mmol) in THF ( 3 ml) and aqueous NaHCO3 solution (3 ml) at 0 oC was added acryloyl chloride (42 mg, 0.468 mmol) dropwise at 0 oC carefully. The resulting mixture was stirred at 0 ° C for 2 hours. After TLC (DCM / MeOH, 10: 1) shows that the starting material was consumed, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mLx2); the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was also purified by silica gel column chromatography (MeOH / DCM, 0% to 8%) to provide 1 - ((3R , 5S) -3- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-fluoropiperidin-1-yl) prop-2-en-1-one (60 mg, 50% ) as a white solid. The solid was also purified by RP-HPLC to provide pure product (25.7 mg). HPLC: Column: DIKMA Diamonsil (2) C18 200 x 20 mm * 5 μm; Mobile phase: 0% MeCN (0.225% FA) in water (0.225% FA) to 10% MeCN (0.225% FA) in water (0.225% FA). 1H NMR (400 MHz, DMSO-d6) δ 1.75 - 2.13 (m, 1 H) 1.82 - 2.12 (m, 1 H) 2.36 - 2.48 (m, 1 H) 3.25 (br s, 1 H) 4.27 (br s, 3 H) 4.61 - 4.88 (m, 1 H) 5.67 (d, J = 9.03 Hz, 1 H) 6 , 10 (dd, J = 16.81, 2.26 Hz, 1 H) 6.52 (d, J = 2.51 Hz, 1 H) 6.64 - 6.82 (m, 1 H) 6, 90 (d, J = 7.03 Hz, 1 H) 7.08 (br s, 1 H) 8.15 (s, 1 H) 11.35 (br s, 1 H). Example 16: 1 - ((1R, 2R, 5R) -2 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3,2,1] octan-8 -il) prop-2-en-1-one. Step 1. Rac-N- (8-Methyl-8-azabicyclo [3,2,1] octan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. A solution of 4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine, 8-methyl-8-azabicyclo [3,2,1] octan-2-amine (Pharmablock), and DIEA in 1 -butanol (30 mL) was heated to 80 ° C overnight. LCMS showed that pyrrolopyrimidine was consumed, and ionization consistent with the desired product. The reaction was concentrated in vacuo, and the crude material was divided between ethyl acetate (10 ml) and water (20 ml). The mixture was filtered and the solid was washed with ether to provide 6 g of rac-N- (8-methyl-8-azabicyclo [3,2,1] octan-2-yl) -7-tosyl-7H-pyrrole [ 2,3-d] pyrimidin-4-amine. LC / MS (M + H) = 412.1. Step 2. N - (((1R, 2R, 5S) -8-Azabicyclo [3,2,1] octan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine . To a solution of rac-N- (8-methyl-8-azabicyclo [3,2,1] octan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine ( 4.0 g, 9.72 mmol) in DCE (50 mL) at 0 oC NaHCO3 (10 eq, 97.2 mmol, 8.25 g mg) in DCE (50 mL) was added followed by 1-chloroethyl chloroformate (10 eq, 10.6 ml, 97.2 mmol). After 10 min, the reaction was allowed to warm to room temperature. The resulting mixture was heated to 50 ° C for 4 hours. After cooling to room temperature, the reaction mixture was poured into Na2CO3 (2N) and the organic layers were separated. The aqueous layer was extracted with DCM. The combined organic layer was evaporated to dryness. The residue was dissolved in EtOH (120 ml) and refluxed for 4 h. All volatiles were removed in vacuo. The residue was treated with DCM and Na2CO3 (aq). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried (Na2SO4) and the solvent was removed to provide 4.0 g of crude product. The crude product was purified by CombiFlash® (40 g gold column, 0 to 10% 2 M NH3 in MeOH in DCM) to provide 2 g of N - ((1R, 2R, 5S) -8-azabicycles [ 3,2,1] racemic oc-tan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. LC / MS (M + H) = 398.1 (M + H). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.08-8.02 (m, 2H), 7.46-7.48 (m, 1H), 7.33-7, 27 (m, 2H), 6.57-6.52 (m, 1H), 5.03-4.91 (m, 1H), 4.33-4.26 (m, 1H), 3.76 ( bs, 1 H), 3.60 (bs, 1 H), 2.37 (s, 3H), 2.03-1.26 (m, 9H).
[065] N - (((1R, 2R, 5S) -8-azabicyclo [3,2,1] octan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine racemic (1 g) was purified by chiral SFC to provide 400 mg of two peaks: enantiomer 1 (pk 1): N - ((1R, 2R, 5S) -8-azabicyclo [3,2,1] octan-2- il) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine and enantiomer 2 (pk 2): N- ((1S, 2S, 5R) -8-azabicyclo [3,2,1 ] octan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. Column: Chiral Tech AS-H 250 mm x 21.2 mm 5 um Isocratic conditions: Mobile phase A: 80% CO2; Mobile phase B: 20%; Methanol + 0.2% NH4OH; 210 nM detection; Flow: 80.0 mL / min; Back pressure: 120 Bar. Step 3. 1 - ((1R, 2R, 5R) -2 - (((7-Tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicycles [ 3.2.1] octan-8-yl) prop-2-en-1-one. To a solution N - ((1R, 2R, 5S) -8-azabicyclo [3,2,1] octan-2-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (pk1) in chloroform (10 ml) DIPEA was added. The solution was cooled to 0 oC and acryloyl chloride (in 1 ml of CHCl3) was added over 5 min. The reaction was stirred for 30 minutes. Na2CO3 (10%; 5 ml) was added. The reaction was stirred at 0 ° C for 0.5 hr and the organic phase was separated and the solvent was evaporated. The residue (300 mg) was purified by CombiFlash® (12 g gold column, 20 to 100% EA in Hept) to provide 208 mg of 1 - ((1R, 2R, 5R) -2 - ((7- Tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3,2,1] octan-8-yl) prop-2-en-1-one. LC / MS (M + H): 452.2. 1H NMR (400MHz, CDCl3) δ 8.44 (s, 1H), 8.08-8.02 (m, 2H), 7.50-7.45 (m, 1H), 7.31-7.25 (m, 2H), 6.92-6.83 (m, 1H), 6.50-6.41 (m, 2H), 5.805.71 m, 1H), 5.01-4.97 (m, 1H), 4.78-4.73 (m, 1H), 4.69-4.60 (br s, 1H), 4.26-4.16 (m, 1H), 2.40 (s, 3H ), 2.01-1.53 (m, 8H). Step 4. 1 - ((1R, 2R, 5R) -2 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3,2,1] octan-8 -il) prop-2-en-1-one. 1 - (((1R, 2R, 5R) -2 - (((7-Tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3,2,1] octane- 8-yl) prop-2-en-1-one (200 mg) was dissolved in 5 ml of THF. TBAF (1 M in THF, 1.9 ml) was added. The reaction was heated to 60 oC for 48 hrs. The solvent was removed in vacuo and the residue was treated with EtOAc and NH4Cl (10%) (5 ml each). The layers were separated and the organic layer collected, washed with NH4Cl (10%) and saturated NaHCO3 and brine. The organic fraction was collected, dried (Na2SO4) and the solvent removed to provide 200 mg of crude product, which was purified by RP-HPLC to provide 90 mg of product. The product was also purified by CombiFlash® (12 g gold column, 0 to 10% MeOH in DCM) to provide 55 mg of 1 - ((1R, 2R, 5R) -2- ((7H-pyrrole [2 , 3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3,2,1] octan-8-yl) prop-2-en-1-one. LC / MS (M + H) 298.3. 1H NMR (400 MHz, CDCl3) δ 11.58-11.47 (m, 1H) 8.44-8.34 (m, 1H), 7.20-7.15 (m, 1H), 7.04 -7.00 (m, 2H), 6.61-6.42 (m, 2H), 5.84-5.76 (m, 1H) 5.11-5.04 (m, 1H) 4,844.82 (m, 1H), 4.48-4.30 (m, 1H), 2.17-1.69 (m, 8H). Example 17: 1 - (((3R, 5S) -3- (7H-Pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one. Step 1. (3S, 5S) -5 - ((tert-Butyldimethylsilyl) oxy) piperidin-3-ol. (3S, 5S) -1- benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-ol (3.6 g, 11.196 mmol) was taken up in EtOH (30 ml) and the ethanol solution was degassed with argon for 15 minutes after which 10% Pd / C (400 mg) was added and the resulting mixture was hydrogenated using a hydrogen bladder for 16 h. After TLC (5% MeOH in DCM) shows that the starting material was consumed, the reaction mixture was filtered through a bed of Celite®, and the filtrate was concentrated to obtain 3 g of (3S, 5S) -5 - Crude ((tert-butyldimethylsilyl) oxy) piperidin-3-ol as light yellow oil. (3S, 5S) -5 - crude ((tert-butyldimethylsilyl) oxy) piperidin-3-ol was used directly for the next step. Step 2. 3 ((3S, 5S) -tert-butyl ((tert-Butyldimethylsilyl) oxy) -5-hydroxypiperidine-1-carboxylate. To a stirred solution of (3S, 5S) -5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-ol (2.59 g, 11.192 mmol) in DCM (19 ml) at 0 oC was added TEA (3, 12 ml, 22.385 mmol) and Boc2O (3.086 ml, 13.431 mmol in a DCM solution (4 ml)). The reaction mixture was allowed to warm to room temperature for 45 min. After TLC (70% EtOAc in hexane) indicates starting material to be consumed, the reaction mixture was quenched with water (20 ml) and extracted with DCM (2 x 50 ml). The organic layers were combined and dried over Na2SO4 and concentrated to provide the crude product, which was purified by CombiFlash® (EtOAc / hexane, 100% hexane to 35% EtOAc in hexane) to provide 3.2 g (86%) 3 - ((tert-butyldimethylsilyl) oxy) -5-hydroxypiperidine-1-carboxylate (3S, 5S) -tert-butyl as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 0.03 - 0.10 (m, 6 H) 0.87 (s, 9 H) 1.45 (s, 9 H) 1.68 (br s, 1 H) 1.78 - 1.88 (m, 1 H) 3.08 (br s, 1 H) 3.39 (br s, 2 H) 3.57 (dd, J = 13.69, 3.42 Hz, 1 H) 3.87 - 4.11 (m, 2 H). Step 3. 3 - ((tert-Butyldimethylsilyl) oxide) -5 - (3S, 5S) -tert-butyl (3S, 5S) -tert-butyl piperidine-1-carboxylate. To a stirred solution of (3S, 5S) 3 - ((tert-butyldimethylsilyl) oxy) -5-hydroxypiperidine-1-carboxylate (3.5 g, 10.557 mmol) in DCM (25 ml) at 0 oC TEA (4.414 ml, 31.671 mmol) was added followed by mesyl chloride (1.06 ml, 13.724 mmol). The reaction mixture was allowed to stir for 4 h. After TLC (30% EtOAc in hexane) indicates a clear conversion, the reaction mixture was quenched with water and extracted with DCM (2 x 75 ml). The combined organic fractions were dried over Na2SO4 and concentrated to provide 4.5 g of (3S, 5S) 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((methylsulfonyl) oxy) piperidine-1-carboxylate crude butyl as a light yellow oil, which was used for the next step directly. 1H NMR (400 MHz, CDCl3) δ 0.08 (d, J = 1.47 Hz, 6 H) 0.88 (s, 9 H) 1.33 - 1.49 (m, 9 H) 1.85 (br s, 1 H) 2.09 (br s, 1 H) 2.90 - 3.08 (m, 4 H) 3.40 (br s, 1 H) 3.59 - 3.86 (m, 2 H) 3.95 (br s, 1 H) 4.94 (br s, 1 H). Step 4. 3-Azido-5 - ((tert-butyldimethylsilyl) oxy) (3R, 5S) -tert-butyl piperidine-1-carboxylate. To a stirred solution of (3S, 5S) 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((methylsulfonyl) oxy) piperidine-1-carboxylate (4.32 g, 10.546 mmol) in DMF (35 ml) NaN3 (2.057 g, 31.639 mmol) was added. The reaction mixture was heated to 100 ° C for 16 h. The reaction mixture was concentrated to remove DMF and the residue was taken up in EtOAc (200 ml) and washed with water (3 x 50 ml). The organic fractions were dried over Na2SO4 and concentrated to provide crude material, which after Com-biFlash® (EtOAc / hexane, 100% hexane to 20% EtOAc in hexane) provided 1.9 g (51%) of 3-azide -5 - (3R, 5S) ((tert-butyldimethylsilyl) oxy) piperidine-1-carboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.04 - 0.10 (m, 6 H) 0.88 (s, 9 H) 1.40 - 1.46 (m, 9 H) 1.48-1, 45 (m, 1 H) 2.26 (d, J = 12.23 Hz, 1 H) 2.36 - 2.60 (m, 2 H) 3.24 - 3.40 (m, 1 H) 3 , 49 - 3.65 (m, 1 H) 3.88 - 4.36 (m, 2 H). Step 5. (3R, 5S) -tert-butyl 3-Amino-5 - ((tert-butyldimethylsilyl) oxy) piperidine-1-carboxylate. To a stirred solution of 3-azido-5 - ((tert-butyldimethylsilyl) oxy) piperidine-1-carboxylate of (3R, 5S) -tert-butyl (1.9 g, 5.329 mmol) in THF (100 ml) H2O (0.671 ml, 37.303 mmol) and PPh3 (2.097 g, 7.993 mmol) were added. The reaction mixture was refluxed for 16 h. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography using 100-200 silicas and MeOH / DCM as eluent (100% DCM to 5% MeOH in DCM) to provide 1.52 g (86 %) 3-amino-5- ((tert-butyldimethylsilyl) oxy) (3R, 5S) -tert-butyl piperidine-1-carboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.07 (d, J = 0.98 Hz, 6 H) 0.88 (s, 9 H) 1.20 - 1.31 (m, 1 H) 1.44 (s, 9 H) 2.07 (s, 1 H) 2.43 - 2.55 (m, 1 H) 2.60 - 2.71 (m, 1 H) 2.81 (m, J = 9 , 30, 9.30 Hz, 1 H) 3.53 - 3.69 (m, 1 H) 3.78 - 3.97 (m, 2 H). Step 6. 3 - (((tert-Butyldimethylsilyl) oxide) -5 - ((3S, 5R) (3S, 5R ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate ) -tert-butyl. To a stirred solution of 3-amino-5 - ((tert-butyldimethylsilyl) oxy) (3R, 5S) -tert-butyl piperidine-1-carboxylate (1.52 g, 4.598 mmol) in n-butanol (10 ml ) 4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (1.698 g, 5.518 mmol) and DIPEA (1.642 ml, 9.197 mmol) were added. The resulting mixture was refluxed for 36 h, and then the volatiles were removed under reduced pressure. The crude material was purified by CombiFlash® (EtOAc / hexane as eluent, 100% hexane to 60% EtOAc in hexane) to provide 2 g (72%) of 3 - (((tert-butyldimethylsilyl) oxide) -5- ( (7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3S, 5R) -tert-butyl piperidine-1-carboxylate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09 (s, 6 H) 0.87 (s, 9 H) 1.12 - 1.58 (m, 10 H) 2.13 (d, J = 10.76 Hz, 1 H) 2.33 (br s, 3 H) 2.80 - 3.00 (m, 1 H) 3.53 - 3.92 (m, 3 H) 3.98 - 4 , 13 (m, 2 H) 6.61 - 6.88 (m, 1 H) 7.43 (d, J = 8.31 Hz, 2 H) 7.59 (br s, 2 H) 7.96 (d, J = 8.31 Hz, 2 H) 8.25 (s, 1 H). Step 7. N - (((3R, 5S) -5 - (((tert-Butyldimethylsilyl) oxy) piperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a stirred solution of (3S 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate , 5R) -tert-butyl (1 g, 1.662 mmol) in DCM (10 ml) at 0 ° C, TFA (0.763 ml, 9.969 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred for 16 h. The reaction mixture was quenched with aqueous NaHCO3 solution (10 ml) and extracted with DCM (2 x 30 ml). The organic fractions were dried over Na2SO4 and concentrated to provide crude material. The crude material was purified by CombiFlash® using (MeOH / DCM, 100% DCM to 8% MeOH in DCM) to provide 520 mg (62%) of N - ((3R, 5S) -5 - ((tert- butyldimethylsilyl) oxy) piperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.03 (s, 6 H) 0.84 (s, 9 H) 1.25 (br s, 2 H) 1.32 - 1.43 (m, 1 H) 2.01 - 2.20 (m, 2 H) 2.35 (s, 3 H) 2.80 - 3.05 (m, 2 H) 3.53 - 3.70 (m, 1 H ) 4.05 (m, 1 H) 6.88 (d, 1 H) 7.43 (d, 2 H) 7.50 - 7.62 (m, 2 H) 7.96 (s, 2 H) 8.21 (s, 1 H). Step 8. 1 - (((3S, 5R) -3 - ((tert-Butyldimethylsilyl) oxy) -5 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin -1-yl) prop-2-en-1-one. To a stirred solution of N - ((3R, 5S) -5 - ((tert-butyldimethyl-silyl) oxy) piper-idin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin -4-amine (520 mg, 1.036 mmol) in DCM (20 ml) at 0 ° C, TEA (0.437 ml, 3.109 mmol) and acryloyl chloride (0.084 ml, 1.036 mmol) were added. The reaction mixture was allowed to stir at 0 ° C for 30 minutes. The reaction was quenched with water (10 ml) and extracted with DCM (2 x 50 ml). The organic fractions were dried over Na2SO4 and concentrated to provide crude material, which was purified by CombiFlash® (EtO-Ac / hexane, 100% hexane to 70% EtOAc in hexane) to provide 450 mg of 1 - ((3S, 5R) -3 - (((tert-butyldimethylsilyl) oxy) -5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2- en-1-one as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.08 (br s, 6 H) 0.81 - 0.91 (m, 9 H) 1.53 - 1.66 (m, 1 H) 2, 13 - 2.23 (m, 1 H) 2.35 (s, 3 H) 2.69 - 2.98 (m, 1 H) 3.60 - 3.81 (m, 1 H) 3.86 - 4.07 (m, 1 H) 4.10 - 4.25 (m, 1 H) 4.35 - 4.50 (m, 1 H) 5.59 - 5.74 (m, 1 H) 6, 00 - 6.15 (m, 1 H) 6.67 - 6.80 (m, 1 H) 6.86 (m, 1 H) 7.43 (d, 2 H) 7.58 (d, J = 3.91 Hz, 1 H) 7.61 - 7.79 (m, 1 H) 7.96 (d, J = 8.31 Hz, 2 H) 8.21 - 8.30 (m, 1 H) . Step 9. 1 - (((3S, 5R) -3-Hydroxy-5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one. To a stirred solution of 1- ((3S, 5R) -3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino ) piperidin-1-yl) prop-2-en-1-one (450 mg, 0.81 mmol) in THF (5 ml) at 0 oC was added 1 M TBAF in THF (1.21 ml, 1, 21 mmol). The reaction mixture was allowed to come to room temperature and stirred for 4 h. The reaction mixture was quenched with water (10 ml) and extracted with EtOAc (3 x 30 ml). The combined organic fractions were dried over Na2SO4 and concentrated to provide 300 mg of 1 - ((3S, 5R) -3-hydroxy-5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4- il) amino) piperidin-1-yl) prop-2-en-1-one (crude) which was used for the next step without further purification. LC / MS (M + H) = 442.2. Step 10. 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-hydroxypiperidin-1-yl) prop-2-en-1 -one. To a solution of 1 - ((3S, 5R) -3-hydroxy-5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop -2-en-1-one (300 mg, 0.679 mmol) in MeOH (5 ml) at 0 ° C H2O (1 ml) and K2CO3 (132.724 mg, 1.019 mmol) were added. The reaction mixture was allowed to come to room temperature and stirred for 16 h. The volatiles were removed in vacuo and the crude material was taken up in EtOAc (50 ml) and washed with water (2 x 20 ml). The organic fractions were dried over Na2SO4 and concentrated to provide crude material, which after purification by preparative HPLC provided 30 mg of 1 - ((3R, 5S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4 -yl) amino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one as a white solid. Preparative HPLC: Instrument: Waters self-purification instrument; Column: Zorbax SB-C18 (250 x 21.2 mm); Mobile phase: Methanol gradient and 0.05% TFA in H2O; Detector: PDA. LC / MS (M + H) = 288. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.17 - 1.35 (m, 2 H) 1.67 - 1.90 (m, 1 H) 2 , 32 (d, J = 12.72 Hz, 1 H) 3.38 - 3.49 (m, 1 H) 3.77 - 3.96 (m, 1 H) 3.99 - 4.19 (m , 1 H) 4.23 - 4.44 (m, 1 H) 5.47 - 5.81 (m, 1 H) 6.00 - 6.21 (m, 1 H) 6.48 (d, J = 2.93 Hz, 1 H) 6.56 - 6.89 (m, 1 H) 7.08 (br s, 1 H) 8.04 - 8.20 (m, 1 H). Example 18: 1 - (((2S, 5R) -5 - (((5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2 -en-1-one Step 1. 5 - ((2S, 5R) ((5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate - benzyl. Prepared as in Example 13: (2S, 5R) -Benzyl (190 (5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate (190 mg, 56%). LC / MS (M + H) = 400.1. Step 2. 5-Chloro-N - ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a vial containing 5 ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate (2S, 5R) - benzyl (190 mg, 0.47 mmol) DCM (5 ml) and HBr / AcOH (5 ml) were added. After stirring at 25 oC for 3 hrs, 50 ml of diethyl ether was added and the reaction stirred for 15 min and filtered. The solid was dried to provide 5-chloro-N - ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as the HBr salt (170 mg, 83%) LC / MS (M + H) = 266.1 Step 3. Prep of 1 - ((2S, 5R) -5 - ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin -4- yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one
[066] To a vial containing 5-chloro-N - ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine - HBr salt (170 mg, 0.49 mmol) DCM (5 mL) and Hunig's base (0.24 mL, 2.8 mL) were added. The mixture was cooled to 0 oC and then acryloyl chloride in DCM (0.04 ml in 2 ml DCM) was added dropwise. After the addition, the reaction was stirred at room temperature for 1 hr and then poured into water. The layers were separated and the organic layer collected, dried (Na2SO4) and the solvent removed to provide a yellow solid, which was purified by RP-HPLC to provide 1 - ((2S, 5R) -5 - ((5-chloro- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methyl-piperidin-1-yl) prop-2-en-1-one (33 mg, 21%). LC / MS (M + H) = 320.1. 1H NMR (400 MHz, MeOH-d4) d ppm 1.24 - 1.45 (m, 3 H) 1.77 - 1.98 (m, 2 H) 2.01 - 2.16 (m, 2 H ) 3.03 - 3.23 (m, 1 H) 4.12 (br s, 1 H) 4.45 - 4.74 (m, 2 H) 5.80 (dd, 1 H) 6.25 ( dd, 1 H) 6.85 (dd, 1 H) 7.37 (s, 1 H) 8.32 (s, 1 H). Example 19: 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methoxypiperidin-1-yl) prop-2-en-1 -one. Step 1. 3 ((3S, 5R) (3S, 5R) ((tert-Butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) ) -tert-butyl. To a solution of 3-amino-5 - ((tert-butyldimethyl-silyl) oxy) piperidine-1-carboxylate of (3R, 5S) -tert-butyl (ex 17: Step 6) (700 mg, 2.117 mmol) in n-BuOH (10 mL) 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine (1.257 g, 3.176 mmol) was added, followed by DIPEA (802 mg, 6.351 mmol) at room temperature . The resulting mixture was heated to 120 ° C overnight. After TLC (Petroleum ether: EtOAc, 2: 1) shows the starting material to be consumed, the mixture was concentrated to dryness to provide the crude product which was purified by column chromatography (silica, EtOAc / petroleum ether). , 0-45%) to provide 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (3S, 5R) -tert-butyl (708 mg, 48%) as a white solid. LC / MS (M + H) 690.9. Step 2. (3S, 5R) -tert-butyl (3S, 5R) -tert-butyl 3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of (3S, 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate 5R) -tert-butyl (708 mg, 1.026 mmol) in THF (15 mL) TBAF (536.5 mg, 2.052 mmol) was added at room temperature. The resulting solution was heated and stirred at 40 ° C overnight. After TLC (EtOAc) shows the starting material to be consumed, the reaction mixture was separated between EtOAc (20 ml) and H2O (20 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to provide 3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine- Crude (3S, 5R) -tert-butyl 1-carboxylate (550 mg, 93%) as a white solid, which was used directly for the next step without further purification. LC / MS (M + H) 576.3. Step 3. 3-Methoxy-5 - ((3S, 5R) -tert-butyl ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of (3S, 5R) -tert-butyl (3S, 5R) -tert-butyl 3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) 550 mg, 0.955 mmol)) in anhydrous THF (10 mL) NaH (84 mg, 2.101 mmol) was added at 0 oC under N2. The resulting suspension was stirred at 0 ° C for 10 min. MeI (162.8 mg, 1.146 mmol) in anhydrous THF (40 mL) was added. The resulting mixture was stirred at room temperature overnight. After TLC (EtOAc) showed the starting material to be consumed, the reaction mixture was quenched with water, and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to provide the crude product which was purified by column chromatography (silica, EtOAc: petroleum ether, 0-60%) to provide 3-methoxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3S, 5R) -tert-butyl piperidine-1-carboxylate (400 mg, 71%) as a solid White. LC / MS (M + H) = 590.3. Step 4. N - (((3R, 5S) -5-Methoxypiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine
[067] To a solution of 3-methoxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate of (3S, 5R) -terc -butyl (400 mg, 0.68 mmol) in anhydrous DCM (4 ml) 4 M HCl / dioxane (4mL) was added dropwise at 0 oC. The resulting solution was stirred at 0 ° C for 1 h. After TLC (EtOAc) showed the starting material to be consumed, the mixture was concentrated to dryness to provide N- ((3R, 5S) -5-methoxypiperidin-3-yl) -7-trityl-7H-pyrrole [2, 3-d] pyrimidin-4-amine (356 mg, 100%) as a white solid. Step 5. 1 - (((3S, 5R) -3-Methoxy-5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one. To a solution of N - (((3R, 5S) - 5-methoxypiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (356 mg, 0.68 mmol) in THF (10 mL) and sat. NaHCO3. (aq) (10 ml) acryl-Cl (73.3 mg, 0.815 mmol) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 h. TLC (EtOAc) showed that the starting material was completely consumed. The reaction mixture was separated between THF and water. The aqueous layer was extracted with EtOAc (10 ml x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to provide 1 - ((3S, 5R) -3-methoxy-5 - (((7-trityl-7H-pyrrole [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one crude (348 mg, 100%) as a white solid that was directly used for the next step without further purification. LC / MS (M + H) = 544.0. Step 6. 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methoxypiperidin-1-yl) prop-2-en-1 -one. A solution of 1 - ((3S, 5R) -3-methoxy-5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one (348 mg, 0.64 mmol) in TFA (5 ml) was stirred at 40 ° C overnight. TLC (EtOAc) showed that the starting material was completely consumed. The mixture was diluted with THF and concentrated to dryness to provide the crude product which was purified by column chromatography (silica, MeOH: EtOAc = 0-33%) and RP-HPLC to provide 1 - ((3R, 5S) - 3 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methoxypiperidin-1-yl) prop-2-en-1-one (12.1 mg, 6.3% ) as a white solid. LC / MS (M + H) = 302.1. 1H NMR (400 MHz, DMSO-d6) δ 1.43 - 1.66 (m, 1 H) 2.36 (d, 1 H) 2.57 - 3.05 (m, 2 H) 3.19 - 3.35 (m, 3 H) 4.18 (d, 2 H) 4.45 (d, 1 H) 5.61 - 5.76 (m, 1 H) 6.02 - 6.17 (m, 1 H) 6.51 (d, 1 H) 6.63 - 6.97 (m, 1 H) 7.10 (d, 1 H) 7.19 - 7.33 (m, 1 H) 8.05 - 8.17 (m, 1 H) 11.56 (br s, 1 H). Example 20: (R) -2- (4 - ((1-Acryloylpiperidin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) acetonitrile.
[068] Similar to the preparation of Example 12, except using Het-Cl as 2- (4-chloro-7H-pyrrolo [2,3-d] pyrimidin-5-yl) acetonitrile. LC / MS (M + H) = 311.1. Example 21: rac-1 - ((3aR, 7aR) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H ) -yl) prop-2-en-1-one.
[069] Similar to the preparation of rac-1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin -6 (2H) -yl) prop-2-en-1-one (ex 8), except using hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) - rac- (3aR, 7aR) -benzyl through the synthetic sequence. LC / MS (M + H) = 298.1. 1H NMR (400 MHz, DMSO-d6) δ 11,583 (s, 1H) 8.09-8.07 (d, J = 9.2Hz, 1H) 7.11 (s, 1H), 6.82-6 , 78 (m, 1H), 6.510 (m, 1H), 6.05-6.01 (m, 1H), 5.665-5.851 (m, 1H), 4.69-4.68 (m, 0.5H ), 4.27 (s, 1H), 3.90-3.74 (m, 3H), 3.13-3.24 (m, 2H), 2.74-2.71 (m, 0.5H ), 2.19-1.74 (m, 4.5H). Example 22: rac-cis-1 - ((3R, 5S) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2 -en-1-one. See Example 14 (Step 7). To a solution of rac-cis-N - ((3R, 5S) -5-methylpiperidin-3-yl) - 7H-pyrrolo [2,3-d] pyrimidin-4-amine (400 mg, 1.494 mmol) in THF (20 ml) saturated aqueous NaHCO3 (15 ml) was added at 0 ° C, acryloyl chloride (149 mg, 1.643 mmol, 1.1 eq.) Was added slowly. The reaction was stirred at 0 ° C for 2 hours. After TLC (EtOAc: MeOH = 10: 1) shows the reaction to be complete, the reaction mixture was diluted with water (80 ml), and extracted with EtOAc (80 ml * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc / MeOH, 10: 1) to provide rac-cis-1 - ((3R, 5S) -3- ((7H-pyrrolo [2,3-d] pyrimidin-4 -yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (300 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (br s, 1H), 8.10 (d, J = 14.3 Hz, 1H), 7.39 - 7.22 (m, 1H), 7.07 (br s, 1H), 6.94 - 6.78 (m, 1H), 6.56 (br s, 1H), 6.12 (dd, J = 8.9, 16.2 Hz, 1H), 5.69 (t, J = 10.4 Hz, 1H), 4.71 (d, J = 10.0 Hz, 1H), 4.47 - 4.29 (m, 1H), 4, 03 (d, J = 11.0 Hz, 2H), 2.73 (t, J = 11.5 Hz, 1H), 2.58 (t, J = 12.3 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.19 (t, J = 11.5 Hz, 1H), 2.05 (d, J = 11.8 Hz, 1H), 1.36 - 1.17 (m , 1H), 0.97 - 0.89 (m, 3H). LCMS (M + H) 285.9. Examples 23-40


[070] Examples 23-40 were prepared as described in the diagram below using parallel methods known to those skilled in the art, and in light of the description contained herein.
FIGURE LEGENDS: dioxane Step 1: Suzuki coupling. A 0.16 M solution of 3 - ((5-iodo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine- (R) -tert-butyl 1-carboxylate in dioxane is prepared. A 0.63 M solution of K3PO4 in H2O is prepared. A boronate / boronic acid monomer (225 μmol, 1.8 eq) is dispensed in 8 ml reaction vials. A volume of 800 μL of a solution of 3 - ((5-iodine-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine- (R) -tert-butyl 1-carboxylate (125 μmol, 1.0 eq) is then dispensed into the flask, followed by 400 μL of K3PO4 solution (250 μmol, 2.0 eq) and then Pd-118 ((1,1'-bis (di-tert-butylphosphine) ferrocene palladium dichloride) (4.9 mg, 7.5 μmol, 0.06 eq), all under N2 atmosphere. 110 oC for 16 hours Reaction progress is checked by LC-MS After completion, each reaction mixture is filtered and concentrated by Speedvac® The residue is washed with H2O and extracted with EtOAc (1 ml x 3). Organic compounds were collected, dried over anhydrous Na2SO4, filtered and concentrated by Speedvac® to provide a crude intermediate, which was used in the next step directly. Step 2: Deprotection. A mixed solution of concentrated HCl (37% aqueous solution) in EtOH ( v / v 1: 6) is prepared. One ml of the HCl solution is dispensed in 8 ml vials containing the crude intermediate from Step 1. The vials are buffered and stirred at 80 oC for 16 hours. Solvent is evaporated by Speedvac®. A mixed solution of NH3H2O in MeOH (v / v 1: 4) is prepared, and 1 ml is dispensed into each vial. The frasconette is plugged and stirred at 30 oC for 16 hours. Reaction progress is checked by LC-MS. Upon completion, the reaction is filtered and concentrated to provide the crude intermediate, which was used for the final step directly. Step 3: Acylation. A saturated solution of NaHCO3 in H2O is pre-stopped and one ml is dispensed into the vials containing the product from Step 2. One ml of EtOAc is then dispensed into each vial, followed by acryloyl chloride (250 μmol, 2, 0 eq). The chips are buffered and stirred at 30 oC for 2 hours. Reaction progress is checked by LC-MS. Upon completion, the mixture is concentrated. The residue is purified by preparative HPLC to provide the final product. Example 41: 1 - ((3aS, 7aS) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) - yl) -2- (trifluoromethyl) prop-2-en-1-one. Step 1. 1 - ((3aS, 7aS) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) - yl) -2- (trifluoromethyl) prop-2-en-1-one. To a round-bottom flask containing the amine (Example 8; 4 - ((3aR, 7aS) - octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d ] pyrimidine, 150 mg, 0.47 mmol) were added DCM (5 ml) and DIPEA (0.33 ml, 1.90 mmol). The reaction mixture was cooled to 0 ° C and BOP (238 mg, 0.52 mmol) and 2- (trifluoromethyl) acrylic acid (73.0 mg, 0.52 mmol) were added. After 1 hr, the reaction was poured into water / ethyl acetate and the layers separated. The organic layer was dried (Na2SO4), filtered and solvent removed to provide an oil, which was purified by column chromatography (silica, DCM / MeOH, 25 g) to provide a larger fraction. This was also purified by RP-HPLC to provide 1 - ((3aS, 7aS) -1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) -2- (trifluoromethyl) prop-2-en-1-one (114 mg, 65%). LC / MS (M + H) 366.2. Examples 42-46:
where R = F, Me, Et, CN, CH2CH2OMe
[071] Examples 42-46 were prepared as described in Examples 1-3, but using Het-Cl = 4-chloro-5-fluoro-7H-pyrrolo [2,3-d] pyrimidine or 4-chloro-5-methyl -7H-pyrrolo [2,3-d] pyrimidine or 4-chloro-5-ethyl-7H-pyrrolo [2,3-d] pyrimidine or 4-chloro-5- (2-methoxyethyl) -7H-pyrrole [2 , 3- d] pyrimidine.
Example 47: 1 - {(3R) -3 - [(3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) amino] piperidin-1-yl} prop-2-en-1- ona. LC / MS (M + H) 285. Example 48: 1 - [(3aS, 7aS) -1- (5-ethynil-7H-pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrole [2,3-c] pyridin-6-yl] prop-2-en-1-one. Step 1. 1- (2,2,2-trifluoroacetyl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) - (3aS, 7aS) -benzyl carboxylate
[072] To a solution of hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) - (-) - (3aS, 7aS) -benzyl carboxylate (3.85 g, 14.8 mmol) in DCM (15 ml) at 0 ° C DIPEA (5.72 ml, 32.5 mmol) was added followed by trifluoroacetic anhydride (2.2 ml, 15.5 mmol). The reaction mixture was stirred at room temperature for 2 hours and then poured into saturated NaHCO3 / DCM. The layers were separated and the organic layer dried (Na2SO4) and the solvent removed to provide 1- (2,2,2-trifluoroacetyl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -crude (3aS, 7aS) -benzyl carboxylate, which was used without purification in the following step. LC / MS (M + H) 357.1. Step 2. 2,2,2-Trifluoro-1 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) ethanone. To a Parr flask were added (3a (7S, 7aS) -benzyl (1- (2,2,2-trifluoroacetyl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate (5.27 g , 14.8 mmol), ethanol (30 mL) and 5% Pd / C (500 mg). The mixture was stirred overnight at 2.81 kg / cm2 (40 psi) at 25 ° C. The reaction mixture was filtered through Celite® and the solvent removed to provide 2,2,2-trifluoro-1 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl ) ethanone. The material was used in the next step without further purification. LC / MS (M + H) 223.1. Step 3. Hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate (3aS, 7aS) -2- (trimethylsilyl) ethyl. To a vial containing 2,2,2-trifluoro-1- ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) ethanone (3.29, 14.8 mmol) DCM (30 ml), TEA (10.3 ml, 73.9 mmol) and Teoc-OSuc (4.19 g, 16.3 mmol) were added. The reaction mixture was stirred at 25 ° C overnight and then poured into saturated NaHCO3 / DCM. The layers were separated and the organic layer dried (Na2SO4) and the solvent removed to provide (3aS, 7aS) -2- (trimethylsilyl) (3aS, 7aS) -2- (trimethylsilyl) hexahydro-1H-pyrrolo [2,3-c] pyridine ethyl. To the hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate (3aS, 7aS) -2- (trimethylsilyl) ethyl (5.42 g, 14.8 mmol) was added MeOH (25 mL) and K2CO3 (4.09 g, 29.6 mmol). The mixture was stirred at room temperature for 4 hours and then filtered and concentrated. The residue was taken up in DCM and washed with saturated NaHCO3 and brine. The organic extract was dried (Na2SO4) and the solvent removed to provide the desired product (3.2 g, 80%). LC / MS (M + H) 271.2. 1H NMR (400 MHz, CDCl3) δ -0.17 - 0.03 (m, 9 H) 0.80 - 1.00 (m, 2 H) 1.26 (dd, 1 H) 1.33 - 1 72 (m, 4 H) 1.77 - 1.94 (m, 1 H) 1.99 - 2.16 (m, 1 H) 2.80 - 3.14 (m, 3 H) 3.34 (dd, 1 H) 3.56 - 3.76 (m, 2 H) 4.04 - 4.21 (m, 2 H) 5.27 (s, 1 H). Step 4. 4-Chloro-5 - ((trimethylsilyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidine. To a flask were added 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (5.0 g, 17.89 mmol), CuI (681 mg, 3.58 mmol), TMS-acetylene (3.79 ml, 26.8 mmol), Pd (PPh3) 4 (1.06 g, 0.89 mmol), THF (100 ml), DMF (33 ml) and TEA (1.28 ml). The reaction was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up in DCM (300 ml). The mixture was washed with water (3 x 75 mL), dried (Na2SO4) and the solvent removed to provide an oil, which after chromatography (silica, 70% EtOAc / Hep) provided the desired product (3.8 g, 85 %). LC / MS (M + H) 250.0. 1H NMR (400 MHz, DMSO-d6) δ 0.26 (br s, 9 H), 8.09 (d, J = 2.34 Hz, 1 H), 8.64 (s, 1 H). Step 5. 1- (5 - ((Trimethylsilyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) - (3aS, 7aS) -2- (trimethylsilyl) ethyl carboxylate. To a round-bottom flask containing hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate (3aS, 7aS) -2- (trimethylsilyl) ethyl (1.94 g, 7.17 mmol ) i-PrOH (20 ml), DIPEA (1.89 ml, 10.8 mmol) and 4-chloro-5 - ((trimethylsilyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidine (1 , 79 g, 7.17 mmol). The reaction mixture was heated to 80 ° C for 2 hrs (LC / MS shows desired product; tms intact). The solvent was removed in vacuo and the residue diluted with DCM / H2O. The layers were separated and the organic layer collected, dried (Na2SO4) and the solvent removed to provide the crude, which was purified by chromatography (silica, EtOAc / MeOH) to provide 1- (5 - ((trimethylsilyl) ethynyl) -7H (3aS, 7aS) -2- (trimethylsilyl) ethyl pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyridine [2,3-c] pyridine-6 (2H) -2- (trimethylsilyl) ethyl (1 , 3 g, 38%). LC / MS (M + H) 484.2. 1H NMR (400 MHz, CDCl3) δ -0.07 (s, 9 H) 0.42 (s, 9 H) 0.63 - 1.11 (m, 2 H) 1.19 - 1.36 (m , 1 H) 1.60 - 2.15 (m, 4 H) 2.38 - 2.63 (m, 1 H) 3.25 - 3.73 (m, 2 H) 3.90 - 4.22 (m, 4 H) 4.26 - 4.48 (m, 1 H) 4.51 - 4.76 (m, 1 H) 7.48 (s, 1 H) 8.33 (s, 1 H) 11.86 (br s, 1 H). Step 6. 5-Ethinyl-4 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine.
[073] To a vial containing 1- (5 - ((trimethylsilyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) (3aS, 7aS) -2- (trimethylsilyl) ethyl (800 mg, 1.65 mmol) -carboxylate (800 mg, 1.65 mmol) were added THF (10 mL) and TBAF (3.64 mL, 1 M in THF). After stirring at room temperature for 48 hours, the reaction was poured into water and the mixture extracted with ethyl acetate. The organic extracts were collected, dried (Na2SO4) and the solvent removed to provide an oil (not product). The aqueous layer was adjusted to pH ~ 10 and then extracted with DCM. The organic extracts were combined, dried (Na2SO4) and the solvent removed to provide 1 - ((3aS, 7aS) - 1- (5-ethynyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro- Crude 1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one (442 mg), which was used in the next step without purification. Step 7. 1 - ((3aS, 7aS) -1- (5-Ethinyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one. To the vial containing 5-ethinyl-4 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine (442 mg, 1.65 mmol) DCM (7 mL) and TEA (0.51 mL, 3.64 mmol) were added. The flask was cooled to 0 ° C and acryloyl chloride (189 mg in 5 ml of DCM) was added dropwise over 5 minutes. After the addition was complete, the reaction was stirred for 30 minutes. The reaction mixture was poured into water and the layers separated. The organic layer was collected, washed with brine, dried (Na2SO4) and the solvent removed to provide an oil, which was purified by RP-HPLC to provide 1 - ((3aS, 7aS) -1- (5-ethynyl- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one (197 mg, 37%). LC / MS (M + H) 322.1. 1H NMR (400 MHz, DMSO-d6) δ 1.49 - 2.03 (m, 4 H) 3.40 - 3.93 (m, 4 H) 4.05 (s, 1 H) 4.15 - 4.59 (m, 3 H) 5.42 (d, 1 H) 5.97 - 6.19 (m, 1 H) 6.39 (dd, 1 H) 6.80 (dd, 1 H) 7 , 66 (d, 1 H) 8.10 - 8.27 (m, 1 H) 12.13 (br s, 1 H). Example 49: 1 - [(3aS, 7aR) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6-yl] prop -2-en-1-one. Step 1. 3- Dimethyl cyano ((diphenylmethylene) amino) methyl) pentanedioate. To a flask containing 2 - ((diphenylmethylene) amino) acetonitrile (4.0 g, 18.16 mmol) in THF at -78 ° C were added DBU (1.6 mL, 9.08 mmol) and pent-2- (E) -dimethyl enodioate. The mixture was stirred at -78 ° C overnight and then at room temperature for 24 hrs. The solvent was removed in vacuo and the crude material purified by chromatography (silica, EtOAc / Hep, 0 to 30%) to provide 3.9 g of dimethyl 3- (cyano ((diphenylmethylene) amino) methyl) pentanedioate. GC / MS 378. 1H NMR (400 MHz, CDCl3) δ 2.48 - 2.57 (m, 1 H) 2.66 (d, J = 6.25 Hz, 2 H) 2.78 - 2.89 (m, 2 H) 3.59 (s, 6 H) 4.51 (d, J = 4.49 Hz, 1 H) 7.17 - 7.22 (m, 2 H) 7.30 - 7, 37 (m, 2 H) 7.40 - 7.46 (m, 1 H) 7.47 - 7.53 (m, 3 H) 7.58 - 7.63 (m, 2 H). Step 2. Methyl 2- (1-Benzhydryl-2-cyano-5-oxopyrrolidin-3-yl) acetate. To a flask containing dimethyl 3- (cyan ((diphenylmethylene) amino) methyl) pentanedioate were added HOAc (5.0 mL) and Na (OAc) 3BH (5.3 g, 24 mmol). The reaction mixture was stirred overnight and then concentrated and diluted with saturated NaHCO3 / EtOAc. The layers were separated and the organic layer washed with water, brine and dried (MgSO4). The solvent was removed to provide crude material, which after chromatography (silica, EtOAc / Hep, 0 to 50%) gave methyl 2- (1-benzhydryl-2-cyano-5-oxopyrrolidin-3-yl) acetate (2, 5 g, 73%). LC / MS (M + H) 349.2. 1H NMR (400 MHz, CDCl3) δ 2.34 - 2.46 (m, 2 H) 2.64 - 2.77 (m, 2 H) 2.89 - 3.10 (m, 2 H) 3, 64 (s, 3 H) 3.88 (d, J = 3.12 Hz, 1 H) 4.53 (d, J = 7.61 Hz, 1 H) 6.54 (d, J = 13.27 Hz, 1 H) 7.05 - 7.17 (m, 1 H) 7.25 - 7.43 (m, 8 H). Step 3. 1-Benzhydryltetrahydro-1H-pyrrolo [2,3-c] pyridine-2,5 (3H, 6H) -dione. To a Parr flask were added 2- (1-benzhydryl-2-cyano-5-oxopyrrolidin-3-yl) methyl acetate (2.5 g, 7.2 mmol), MeOH (10 mL) and PtO2 (200 mg ). The reaction was stirred overnight at 2.81 kg / cm2 (40 psi) of H2, 60 ° C for 30 hours. The reaction mixture was filtered through Celite® and the solvent removed in vacuo to provide crude 1-benzhydryltetrahydro-1H-pyrrolo [2,3-c] pyridine-2,5 (3H, 6H) -dione (2.2 g , 96%), which was used without further purification. LC / MS (M + H) 321.2. Step 4. 1-Benzhydryloctahydro-1H-pyrrolo [2,3-c] pyridine. To a flask containing 1-benzhydryltetrahydro-1H-pyrrolo [2,3-c] pyridine-2,5 (3H, 6H) -dione (1.0 g, 3.1 mmol) was added THF (5 mL) and LAH (474 mg, 12.5 mmol). The reaction was stirred at 60 ° C overnight. The reaction mixture was prepared using a Fisher preparation. The reaction mixture was filtered through Celite® and washed with methanol. The solvent was concentrated to provide crude 1-benzhydryloctahydro-1H-pyrrolo [2,3-c] (900 mg, 98%), which was used without further purification. LC / MS (M + H) 293.2. Step 5. 1-Benzhydryl-6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridine. To a flask containing 1-benzhydryl-6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridine (900 mg, 3.08 mmol) were added DCM (10 mL), TEA (0.89 mL, 6.16 mmol) and TsCl (719 mg, 3.69 mmol). The reaction was stirred at room temperature overnight and poured into DCM / water. The layers were separated and the organic layer collected, dried (Na2SO4). The solvent was removed to provide crude, which was purified by chromatography to provide 1-benzhydryl-6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridine (400 mg, 29%). LC / MS (M + H) 447.2. Step 6. 1-Benzhydryl-6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridine. To a Parr flask containing 1-benzhydryl-6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridine (400 mg, 0.89 mmol) in ethanol / acetic acid (10 mL / 1mL) was added Pd (OH) 2 (60 mg). The reaction was stirred at 2.81 kg / cm2 (40 psi) of H2 overnight. The reaction mixture was filtered through Celite® and the solvent removed to provide crude 1-benzhydryl-6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridine, which was used without further purification. LC / MS (M + H) 281.1. Step 7. 7-Tosyl-4 - ((3aS, 7aR) -6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine.
[074] To a flask containing 4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (276 mg, 0.89 mmol) were added n-BuOH (5 mL), 1-benzhydryl-6 -tosyloctahydro-1H-pyrrolo [2,3-c] pyridine (251 mg, 0.89 mmol) and DIPEA (1.14 mL, 6.53 mmol). The reaction was heated to 80 ° C for 4 hours and then diluted with water / ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to provide the crude, which was purified by chromatography (silica, EtOAc / Hep, 0 to 40%) to provide two peaks with the same molecular weight. Pk1 (cis-isomer, 25 mg), compared to Example 8, Step 8, material treated with TsCl. LC / MS (M + H) 552.0. Pk2 (transisomer, 85 mg): LC / MS (M + H) 552.1. Step 8. 4 - ((3aR, 7aR) -Octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine. To a vial containing 7-tosyl-4 - ((3aS, 7aR) -6-tosyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] piramidine pk2 (100 mg, 0.18 mmol) in MeOH (5 mL) NaHPO4 (109 mg, 0.90 mmol) and Na / Hg (20-30 beads) were added. The reaction mixture was stirred at room temperature overnight and then filtered through Celite®. The solvent was removed and the crude material diluted with ethyl acetate / water. The pH of the aqueous layer was adjusted to pH ~ 9 and then extracted with ethyl acetate (3x). The organic extracts were combined and washed with water, brine and dried (Na2SO4). The solvent was removed to provide 4 - ((3aR, 7aR) - octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine (35 mg, 80 %). LC / MS (M + H) 244.2. Step 9. 1 - ((3aS, 7aR) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) - il) prop-2-en-1-one. To a vial containing 4- ((3aR, 7aR) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3- d] pyrimidine (20 mg, 0.08 mmol) in DCM at 0 ° C DI-PEA (0.06 mL, 0.33 mmol) and acryloyl chloride (8.0 mg, 0.08 mmol) were added. The mixture was stirred for 3 hours at 0 ° C and then diluted with water / DCM. The layers were separated and the organic layer collected and dried (Na2SO4). The solvent was removed to provide crude material, which after chromatography (silica, MeOH / DCM, 0 to 10%) provided 1- ((3aS, 7aR) -1- (7H-pyrrolo [2,3-d] pyrimidin-4 -yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one (6.5 mg, 27%). LC / MS (M + H) 298.2. Example 50: 1 - [(3R, 4S) -4-methyl-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one . Preparation of rac-1 - ((3R, 4S) - 3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en- 1- one (from Example 11, Step 4). To a solution of N - (((3R, 4S) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (410 mg, 1.530 mmol) in THF (20 mL) and aq. (15 mL) at 0 ° C, acryloyl chloride (152 mg, 1.683 mmol, 1.1 eq.) Was added. The reaction mixture was stirred at 0 ° C for 2 hours. After TLC (EtOAc / MeOH, 10: 1) shows the reaction to be complete, the reaction mixture was diluted with water (50 ml), and extracted with EtOAc (50 ml * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (MeOH / EtOAc, 2% ~ 10%) and lyophilized to provide rac-1 - ((3R, 4S) -3 - ((7H-pyrrolo [2,3- d] pyrimidin -4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1-one (150 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.08 (d, J = 15.1 Hz, 1H), 7.32 - 7.20 (m, 1H), 7.08 (br s, 1H), 6.81 (dt, J = 10.5, 17.3 Hz, 1H), 6.59 (br s, 1H), 6.12 (d, J = 14, 8 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 4.65 - 4.39 (m, 1H), 4.27 - 4.04 (m, 1H), 3, 94 - 3.71 (m, 1H), 3.16 (d, J = 5.3 Hz, 1H), 3.08 - 2.96 (m, 1H), 2.89 - 2.77 (m, 1H), 2.71 - 2.60 (m, 1H), 2.46 - 2.28 (m, 1H), 1.82 (d, J = 12.3 Hz, 2H), 1.29 - 1 , 12 (m, 1H), 0.94 (dd, J = 6.0, 12.3 Hz, 3H). LCMS (M + H) 286.1. Example 51: rac-1 - [(3aR, 7aR) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6-yl ] prop-2-en-1-one. Prepared as in Example 8, except using rac- (3aR, 7aR) -benzyl hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -benzyl instead of optically active material in Step 7. LC / MS (M + H) 298.2. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H) 8.09-8.07 (d, J = 9.2Hz, 1H) 7.115 (s, 1H), 6.82-6, 78 (m, 1H), 6.51 (m, 1H), 6.05-6.01 (m, 1H), 5.69-5.85 (m, 1H), 4.69-4.68 ( m, 0.5H), 4.27 (s, 1H), 3.90-3.74 (m, 3H), 3.13-3.24 (m, 2H), 2.74-2.71 ( m, 0.5H), 2,191.74 (m, 4.5 H). Example 52: 1- [2- (Hydroxymethyl) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one (rac-cis / trans). Prepared as in Example 7, except no separation of diastereomers or enantiomers is performed. LC / MS (M + H) 302.2. Example 53: (R) (- 1- (3 - ((5- (2-hydroxy-2-methylpropyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl ) prop-2-en-1-one Step 1. 1- (4-Chloro-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methylpropan-2-ol. NaH (343 mg, 8.57 mmol) in 20 ml of THF cooled with an ice bath, 5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidine (1000 mg, 4.32 mmol) was added After 10 min, the reaction was cooled with an acetone / dry ice bath. BuLi (1.6 M; 4.02 mL, 6.43 mmol) was added. After 30 min, 2,2-dimethyloxirane (927 mg , 12.9 mmol) was added slowly The reaction was allowed to warm to room temperature slowly, then it was stirred at room temperature overnight NH4Cl (10%, 20 mL) was slowly added The reaction was stirred for 15 min. The mixture was concentrated in vacuo to remove organic solvent. The aqueous solution was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried and concentrated. The residue was purified by Comb i- Flash® (40 g column, 10 to 100% EA in heptane) to provide 549 mg of 1- (4-chloro-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2- methylpropan-2-ol (56.5%). LC / MS (M + H) 226.2. 1H NMR (400 MHz, CDCl3) δ 10.63 (br, 1H), 8.59 (s, 1H), 7.33 (s. 1H), 3.14 (s, 2H), 1.29 (s , 6H). Step 2. (R) -tert-butyl ((5- (2-hydroxy-2-methylpropyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate . To a solution of pyrrolopyrimidine1- (4-chloro-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methylpropan-2-ol (140 mg, 0.62 mmol) in 5 mL of dioxane / H2O (8: 4) (R) -tert-butyl 3-aminopiperidine-1-carboxylate (124 mg, 0.62 mmol) and potassium carbonate (172 mg, 1.24 mmol) were added. The resulting reaction mixture was heated to 110 ° C for 5 days. After cooling, the reaction mixture was concentrated. The aqueous mixture was diluted with 5 ml of water and extracted with EtOAc (3 x). The combined organic layer was washed with water (4 x), brine and dried (Na2SO4), then filtered and concentrated. The residue was purified by silica gel column chromatography (0-100% EtOAc in heptanane) to provide 3 - ((5- (2-hydroxy-2-methylpropyl) -7H-pyrrole [2,3- d] (R) -tert-butyl pyrimidin-4-yl) amino) piperidine-1-carboxylate (85 mg, 35% yield). LC / MS (M + H) 390.4. Step 3. (R) -2-Methyl-1- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propan-2-ol. To a solution of (R) -tert- 3 - ((5- (2-hydroxy-2-methylpropyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate butyl (85 mg, 0.22 mmol) in 5 ml of THF HCl (4 M in dioxane) (5 ml) was added and the resulting mixture stirred at room temperature for 3 h. The reaction was concentrated. The residue was dissolved in DCM and concentrated. The process was repeated 3 times to provide 65 mg of (R) -2-methyl-1- (4- (piperidin-3-ylamino) - 7H-pyrrolo [2,3-d] pyrimidin-5-yl) propan- 2-ol as an HCl salt. LC / MS (M + H) 290.3. Step 4. (R) -1- (3 - ((5- (2-Hydroxy-2-methylpropyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one. To a vial containing (R) -2-methyl-1- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propan-2-ol (65 mg, 0.2mmol), DIPEA (10 eq required to obtain the neutralized and homogeneous salt) and DCM (5 ml) at 0 oC, acryloyl chloride (18 mg, 0.200 mmol of solution in 1 ml of DCM) was added. After 45 min, the reaction mixture was quenched with a saturated solution of NaHCO3 (5 ml) and the layers were divided. The aqueous layer was extracted (2x) with DCM and the combined organic layers were concentrated to provide the crude product as a white solid. The solid was purified by reverse phase HPLC to provide 15 mg of desired product. LC / MS (M + H) 344.2. 1H NMR (400 MHz, MeOH-d4) δ 8.19 (s, 1H), 7.12 (s. 1H), 6.88-6.76 (m, 1H), 6.22-6.14 ( m, 1H), 5.78-5.73 (m, 1H), 4.15-3.99 (m, 1H), 3.92-3.84 (m, 1H) 3.79-3.50 (3H), 2.89-2.74 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.769 (m, 2H), 1.731.58 (m, 1H), 1.30-1.15 (m, 3H), 1.18-1.149m, 3H). Example 54: 1 - (((3S, 4R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-fluoropiperidin-1-yl) prop-2-en-1 -one. Step 1. (3S, 4R) -Benzyl (3S, 4R) -benzyl ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine (308 mg, 0.779 mmol) and cesium fluoride (474 mg, 3.12 mmol) in DMSO (3.0 mL ) (3S, 4R) -benzyl 3-amino-4-fluoropiperidine-1-carboxylate (prepared according to WO2010 / 16005 and WO2011 / 101161) (225 mg, 0.779 mmol) was added. The reaction mixture was heated to 120 ° C for 16 hours. After LCMS showed that 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine was completely consumed, the reaction mixture was diluted with a 1: 1 mixture of DCM / water (200 ml). The organic layer was extracted and the aqueous layer was extracted again with DCM (2 x 50 ml). The organic extracts were combined, washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to produce a crude product that was loaded dry with Celite® onto an HP 80 g Silicycle® column and purified using normal phase column chromatography (25-75% EtO-Ac / heptanes over 10 column volumes) to provide 4-fluoro-3- ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3S, 4R) -benzyl piperidine-1-carboxylate (400.0 mg, 84%) as a colorless solid. LCMS (M + H) 532.56. Step 2. N - ((3S, 4R) -4-Fluoropiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a dry hydrogenation flask, 10% Pd / C (175 mg) was added under a nitrogen atmosphere. A solution of 4-fluoro-3 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3S, 4R) -benzyl (400 mg, 0.654 mmol) in anhydrous ethanol (13.0 mL) was added and the resulting mixture was hydrogenated under 3.51 kg / cm2 (50 psi) of H2 at room temperature for 3 hours. After LCMS showed the starting material to be completely consumed, the reaction mixture was filtered through a thin pad of Celite® and the filter cake was washed with ethanol. The combined filtrate was evaporated, azeotroped with toluene (5 x) at 75 ° C to provide compound N - ((3S, 4R) -4-fluoropiperidin-3-yl) -7-trityl-7H-pyrrole [2,3- d] pyrimidin-4-amine (312 mg, 100%) as a colorless solid, which was used directly in the next step without further purification. Step 3. 1 - (((3S, 4R) -4-Fluoro-3 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one. To a solution of N - ((3S, 4R) - 4-fluoropiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (312 mg, 0.653 mmol) in CHCl3 anhydrous (15.0 ml) Hunig's base (0.6 ml, 4.0 mmol) is added. The reaction mixture was cooled to 2 ° C, and then treated dropwise with a solution of acrylic chloride (0.053 ml, 0.653 mmol) in anhydrous CHCl3 (3.0 ml). The reaction mixture was allowed to warm to room temperature and after 35 minutes, LCMS showed that compound N - ((3S, 4R) -4-fluoropiperidin-3-yl) -7-trityl-7H-pyrrole [2,3-d ] pyrimidin-4-amine was completely consumed. The reaction mixture was cooled to 2 ° C and quenched with 10% aqueous sodium bicarbonate (15 mL). The organic layer was extracted and the aqueous layer was extracted again with chloroform (2 x 10 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to produce crude product which was loaded dry with Celite® onto an HP 80 g Silicycle® column and purified by normal phase column chromatography ( 50-85% EtOAc / heptanes over 10 column volumes) to provide 1 - ((3S, 4R) -4-fluoro-3 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4 -yl) amino) piperidin-1-yl) prop-2-en-1-one (280.0 mg, 81%) as a colorless solid. LCMS (M + H) 532.56. Step 4. 1 - (((3S, 4R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-fluoropiperidin-1-yl) prop-2-en-1 -one. A solution of 1 - ((3S, 4R) -4-fluoro-3 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one (270.0 mg, 0.508 mmol) in trifluoroacetic acid (5.00 mL) was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo and loaded dry with Celite® onto an HP 80 g Silicycle® column and purified by normal phase column chromatography (0-20% MeOH / DCM over 10 volumens) column) to provide 1 - ((3S, 4R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-fluoropiperidin-1-yl) prop-2-en -1-one (146.0 mg, 99%) as a colorless solid. LCMS (M + H) 290.41. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (S, 1H), 8.13 (s, 1H), 7.47 (s, 1H), 7.11 (s, 1H), 6.91 - 6.70 (m, 2H), 6.12 (t, J = 20 Hz, 1 H), 5.78 - 5.61 (m, 2H), 5.16 - 4.98 (m, 1H) , 4.51 - 4.36 (m, 1H), 4.21 - 2.97 (m, 5H). Example 55: (R) -1- (3 - ((5- (2-Hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2- en-1-one. Prepared as in Examples 1-3, except using 5- (2 - ((tert-butyldimethylsilyl) oxy) ethyl) -4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine as Het's partner -Cl. LC / MS (M + H) 316.3. 1H NMR (400 MHz, DMSO-d6) δ 1.31 - 2.06 (m, 4 H) 2.78 (d, J = 11.13 Hz, 2 H) 2.94 - 3.18 (m, 1 H) 3.47 - 3.87 (m, 3 H) 3.96 - 4.21 (m, 2 H) 5.11 - 5.67 (m, 2 H) 5.90 - 6.14 ( m, 1 H) 6.50 - 6.90 (m, 2 H) 7.02 - 7.38 (m, 1 H) 8.03 (d, J = 13.08 Hz, 1 H) 11.25 (br s, 1 H). Example 56: 1- (2 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -8-azabicyclo [3,2,1] octan-8-yl) prop-2-en -1-one. Prepared as described in Example 16, except no chiral SFC performed. Example 57: 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5- (dimethylamino) piperidin-1-yl) prop-2- en-1-one. Step 1. (R) -tert-butyl (R) -tert-butyl 3-oxo-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate
[075] To a solution of 3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate of (3S, 5R) -tert -butyl (5.0 g, 8.68 mmol) in DCM (100 mL) DessMartin periodinane (4.0 g, 9.55 mmol) was added, then the mixture was stirred at room temperature for 18 hours. After TLC (DCM / MeOH, 10: 1) shows that the starting material was completely consumed, the reaction mixture was concentrated to provide the crude product (7.8 g) as a yellow solid, which was purified by preparative HPLC for provide (R) -tert-butyl 3-oxo-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (3.7 g, 74%) as a white solid. LC / MS (M + H) 574.5. Step 2. 3- (Dimethylamino) -5 - ((3S, 5R) -tert-butyl (3S, 5R) -tert-butyl ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate . To a dry hydrogenation flask, 10% dry Pd / C (300 mg) was added under Ar atmosphere. A solution of 3-oxo-5 - ((7-trityl-7H-pyrrole [2,3-d] pyrimidin-4-yl) amino) (R) -tert-butyl piperidine-1-carboxylate (600 mg, 1.05 mmol) in 2 M NHMe2 / MeOH (20 mL) was added and the resulting mixture was hydrogenated to 3.16 kg / cm2 (45 psi) of H2 at 20 ° C overnight. After TLC (DCM / MeOH / NH3OH = 10: 1: 1) indicates starting material to be completely consumed, and two new spots are formed, the reaction solution was filtered through a pad of Celite® and the mass was washed with MeOH three times. The combined filtrate was concentrated to provide the crude product, which was purified by column chromatography (silica, MeOH / NH3 / DCM, 0-8%) to provide 3- (dimethylamino) -5 - ((7-trityl-7H- pyrrole [2,3-d] pyrimidin-4-yl) amino) (3S, 5R) -tert-butyl piperidine-1-carboxylate (100 mg, 15.8%) as an oil and 3- (dimethylamino) - (3S, 5S) -tert-butyl 5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (300 mg, 47.6%) like a white solid. LC / MS (M + H) 603.5 (pk1); LC / MS (M + H) 603.5 (pk2). Step 3. (3S, 5R) -N3, N3-Dimethyl-N5- (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3,5-diamine. To a solution of 3- (dimethylamino) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate of (3S, 5R) -tert- butyl (100 mg, 0.660 mmol) in dioxane (10 ml) was added 4 N HCl / dioxane (6 ml) dropwise at 0 ° C and stirred at room temperature for 4 h. After TLC (DCM / MeOH, 10: 1) indicating the reaction was complete, the reaction mixture was concentrated to provide the crude product, which was purified by column chromatography (silica, MeOH / DCM, 0-10%) to provide (3S, 5R) -N3, N3-dimethyl- N5- (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3,5-diamine (100 mg, 100% ) as a white solid. LC / MS (M + H) 503.5. Step 4. 1 - ((3S, 5R) -3- (Dimethylamino) -5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one. To a stirred solution of (3S, 5R) -N3, N3-dimethyl-N5- (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3,5-diamine (100 mg , 0.199 mmol) in THF (10 mL) / aqueous NaHCO3 solution (10 mL) was added acryloyl chloride (19.8 mg, 0.219 mmol) dropwise at 0 ° C. After addition, the resulting mixture was stirred at 0 ° C for 2 hours. After TLC (DCM / MeOH, 10: 1) shows that the starting material was completely consumed, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mLx2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was used for the next step directly without further purification. LC / MS (M + H) 557.5. Step 5. 1 - (((3R, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5- (dimethylamino) piperidin-1-yl) prop-2- en-1-one. 1 - (((3S, 5R) -3- (Dimethylamino) -5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2 -en-1-one (50 mg, 0.089 mmol) in TFA (3 mL) was stirred at 30 ° C overnight. After TLC (DCM / MeOH / NH4OH, 10: 1: 1) indicates that the starting material was completely consumed, the reaction mixture was concentrated in vacuo to provide the crude product, which was purified by chromatography (silica, MeOH / NH3 / DCM, 0-10%) and also purified by preparative HPLC to provide 1- ((3R, 5S) -3 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) - 5- (dimethylamino) piperidin-1-yl) prop-2-en-1-one (17 mg, 30.3%) as a white solid. LC / MS (M + H) 315.2. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.16 - 8.07 (m, 1H), 7.49 - 7.31 (m, 1H), 7.12 - 7.06 (m, 1H), 6.81 (dd, J = 10.5, 16.8 Hz, 1H), 6.55 (br s, 1H), 6.13 (d, J = 16, 8 Hz, 1H), 5.71 (d, J = 10.8 Hz, 1H), 4.68 - 4.49 (m, 1H), 4.27 (d, J = 12.0 Hz, 0, 69H), 4.11 (br s, 1.51H), 2.98 - 2.81 (m, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.44 (d, J = 12.5 Hz, 1H), 2.36 - 2.16 (m, 6H), 1.72 - 1.50 (m, 1H). Example 58: (3S, 5R) -5 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1- acryloylpiperidine-3-carbonitrile. Step 1. (5R) -tert-butyl 3-Cyano-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate
[076] To a mixture of (R) -tert-butyl 3-oxo-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (see Example 57) (1.0 g, 1.74 mmol) and TOSMIC (693.7 mg, 3.83 mmol) in DME (30 ml) at 0 ° C t-BuOK (624.4 mg, 5.58 mmol) and EtOH (176.3 mg, 3.83 mmol) portion by portion. The resulting mixture was stirred at 0 ° C for 0.5 hour, then the mixture was warmed to room temperature and stirred for 2 hours. After TLC (DCM / MeOH, 10: 1) indicates the reaction to be complete, the reaction solution was filtered, and concentrated to dryness to provide a crude product which was purified by preparative TLC (petroleum ether / EtOAC, 2: 1) to provide (5R) -tert-butyl 3-cyano-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (200 mg , 20%) as a yellow solid. LC / MS (M + H) 585.7. Step 2. (5R) -5 - ((7-Trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile. To a solution of (5R) -tert-butyl 3-cyano-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (235 mg , 0.41 mmol) in DCM (1.5 ml) at 0 ° C was added TFA (229.0 mg, 2.0 mmol). The reaction was stirred at room temperature for 12 hours. After TLC (petroleum ether / EtOAC, 1: 1) indicates the reaction to be complete, the reaction mixture was concentrated in vacuo to provide (5R) -5 - ((7-trityl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (235 mg, 100%) as a yellow solid. LC / MS (M + H) 485.2. Step 3. (5R) -1-Acryloyl-5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile. To a stirred solution of (5R) -5- ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (100 mg, 0.206 mmol) in THF ( 3 ml) / aqueous NaHCO3 solution (2.5 ml) at 0 ° C was added acryloyl chloride (22.4 mg, 0.247 mmol) dropwise. The resulting mixture was stirred at 0 ° C for 2 hours. After TLC (DCM / MeOH, 20: 1) indicates the reaction to be complete, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mLx2), the combined organic extracts were washed with brine, dried (Na2SO4 ) and concentrated to provide the crude product, which was also purified by preparative TLC (petroleum ether / EtOAC, 1: 1) to provide (5R) -1-acryloyl-5 - (((7-trityl-7H-pyrrole [2 , 3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (80 mg, 72%) as a yellow solid. LC / MS (M + H) 539.2. Step 4. (3S, 5R) -5 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1- acryloylpiperidine-3-carbonitrile. A solution of (5R) -1-acryloyl-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-3-carbonitrile (80 mg, 0.272 mmol) in TFA (1 ml) was stirred at room temperature for 12 hours. After TLC (petroleum ether / EtOAC, 1: 1) indicates 20% of starting material remaining, the reaction was heated to 30 ° C for an additional 5 h. After LCMS indicated completion, the reaction mixture was concentrated to provide the crude product, which was also purified by preparative TLC (petroleum ether / EtOAc, 1: 1) to provide (5R) -5 - ((7H-pyrrole [2 , 3-d] pyrimidin-4-yl) amino) -1-acryloylpiperidine-3-carbonitrile (12 mg, 10% for 3 steps) as a white solid. Chiral HPLC showed that it was a trans / cis mixture, which was purified by SFC providing 1.4 mg of peak 1 (trans) and 3.3 mg of peak 2 (cis): SFC separation conditions: Column: ChiralPak AD (250 mm x 30 mm, 20 μm), Mobile phase: 50% EtOH + NHβH2θ, 80 mL / min. Analytical SFC conditions: Column: Chiralpak AD-H 250x4.6 mm ID, 5 μm Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL / min; Wavelength: 220 nm. Peak 2: 1H NMR (400 MHz, MeOH-d4) δ 8.20 (br s, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.90 - 6.54 (m, 2H), 6.32 - 6.07 (m, 1H), 5.90 - 5.57 (m, 1H), 4.71 - 4.41 (m, 2H), 4.40 - 4.01 ( m, 2H), 3.71 - 3.40 (m, 2H), 2.39 (br s, 1H), 2.17 (d, J = 9.0 Hz, 1H). LC / MS (M + H) 297.1. Example 59: 1 - ((3aS, 7aS) -3a-Methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one (racemic-cis). Step 1. rac- (3aS, 7aS) -6-Benzyl-3a-methylhexahydro-1H-pyrrolo [2,3-c] pyridin-7 (7aH) -one. A mixture of (3aS, 7aS) -1,6-dibenzyl-3-methylhexahydro-1H-pyrrolo [2,3-c] pyridin-7 (7aH) -one (975 mg, 2.92 mmol), cyclohexene (7 , 5 ml, 73 mmol) and 10% Pd / C (175 mg, 0.16 mmol) in ethanol (14 ml) was stirred at reflux for 1.5 h. After TLC indicates complete conversion of starting material, the reaction was cooled, diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under reduced pressure, providing (3aS, 7aS) -6-benzyl-3-methylhexahydro-1H-pyrrolo [2,3-c] pyridin-7 (7aH) -one (683 mg, 95%) as a cloudy oil. LC / MS (M + Na) 267.2. Step 2. rac- (3aS, 7aS) -6-Benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridine. To a vial containing 3aS, 7aS) -6-benzyl-3a-methylhexahydro-1H-pyrrolo [2,3-c] pyridin-7 (7aH) -one (677 mg, 2.77 mmol) in THF (10 mL) at 0 ° C LAH (150 mg, 3.95 mmol) was added. The reaction was heated to reflux for 1 h. The reaction was cooled and quenched by the addition of water (0.15 ml), 15% NaOH (0.15 ml) and water (0.45 ml). The suspension was diluted with ethyl acetate and filtered through Celite®. Concentration under reduced pressure gave (3aS, 7aS) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridine (607 mg, 95%) as a yellow oil. LC / MS (M + H) 231.2. Step 3. rac-4 - ((3aS, 7aR) -6-Benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7-tosyl-7H-pyrrole [2,3 -d] pyrimidine. To a vial containing (3aS, 7aS) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridine (607 mg, 2.64 mmol) were added n-butanol (8.5 mL), 4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (815 mg, 2.65 mmol) and DIPEA (3.8 mL, 22 mmol). The reaction mixture was stirred at 85 ° C for 16 h. The reaction was cooled to room temperature and the solvent removed in vacuo. The crude material was purified by chromatography (silica, EtO-Ac / Heptane) to provide 4 - ((3aS, 7aR) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl ) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (913 mg, 69%) as an off-white solid. LC / MS (M + H) 502.2. Step 4. rac-4 - ((3aS, 7aR) -6-Benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine . To a vial containing 4- ((3aS, 7aR) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7-tosyl-7H-pyrrole [2,3- d] pyrimidine (908 mg, 1.81 mmol) MeOH (14.4 mL), water (4.0 mL) and LiOH (124 mg, 5.1 mmol) were added. The reaction was stirred at 60 ° C for 1 h. The reaction was diluted with water (30 ml) and dichloromethane (30 ml) and the pH was adjusted to ~ 5 with 1 M HCl. The layers were separated and the aqueous solution was extracted with dichloromethane (20 ml x 2) . The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide 4 - ((3aS, 7aR) -6-benzyl-3-methyloctahydro-1H-pyrrole [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine (628 mg) as a pale yellow solid. LC / MS (M + H) 348.2. Step 5. Chiral separation of rac-4 - ((3aS, 7aR) -6-benzyl-3-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrole [2,3- d] pyrimidine. 4 - ((3aS, 7aR) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine racemate (622 mg ) was purified by chiral SFC (Chiralpak AD-H, 60/40 CO2 / MeOH, 0.2% i-PrNH2) to provide two peaks, pk1 assigned as (4 - ((3aS, 7aR) -6- benzyl-3-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine, 263 mg, room temperature = 3.97 min) and assigned pk 2 as (4- ((3aR, 7aS) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine, 233 mg room temperature = 5.31 min). Step 6. 4 - ((3aR, 7aS) -3a-Methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) - 7H-pyrrolo [2,3-d] pyrimidine. To a vial containing (4 - ((3aR, 7aS) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine ethanol (8.0 mL), cyclohexene (2.0 mL, 20 mmol) and Pd (OH) 2 on carbon (263 mg, 0.38 mmol) were added in. The reaction was stirred at reflux for 1.5 h. The reaction was cooled, diluted with methanol and filtered through Celite® The filtrate was concentrated and the product precipitated from ethyl acetate to provide 4 - ((3aR, 7aS) -3a- methyloctahydro-1H-pyrrole [2,3- c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidine (184 mg, 96%) as a colorless solid LC / MS (M + H) 258.2. Step 7. 1- ( (3aS, 7aS) -3a-Methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one To a flask containing 4 - ((3aR, 7aS) -3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrole [2, 3-d] pyrimidine (50 mg, 0.19 mmol) in DCM (3.0 mL) at 0 ° C, DIPEA (0.2 mL, 0.96 mL) and acryloyl chloride (19 mg, 0, 20 mmol) .The reaction was stirred at 0 ° C for 3 h and se-g diluted with water / DCM (25/25 mL). The pH was adjusted to pH ~ 5 and the layers separated. The organic extract was combined, dried (Na2SO4) and the solvent removed to provide the crude product. The product was precipitated with ethyl acetate / heptanes to provide 1- ((3aS, 7aS) -3a-methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H- pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one (49.6 mg, 83%) as a colorless solid. LC / MS (M + H) 312.2. Example 60: 1 - (((3R, 5R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-hydroxypiperidin-1-yl) prop-2-en-1 -one. Step 1. N - (((3R, 5R) -1-Benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) - 7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4 -the mine. To a stirred solution of (3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-amine (4 g, 12.479 mmol) in n-butanol (25 ml) was added 4-chlorine -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (4.608 g, 14.974 mmol) and DIPEA (4.443 ml, 24.957 mmol). The resulting mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature. After TLC (70% EtOAc in hexane) indicates starting material to be consumed, the solvent was removed in vacuo to provide the crude compound, which was purified by chromatography (silica, EtOAc / hexane 0-20%) to provide 5 g ( 68%) of N - ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin- 4- amine as a light yellow solid. LC / MS (M + H) 592.0. 1H NMR (400 MHz, CDCl3) δ -0.07 (s, 6 H) 0.87 (s, 9 H) 1.44 (d, J = 18.10 Hz, 1 H) 1.93 - 2, 31 (m, 3 H) 2.37 (s, 3 H) 2.65 (d, J = 10.76 Hz, 1 H) 2.94 (br s, 1 H) 3.36 - 3.71 ( m, 2 H) 3.81 - 3.98 (m, 1 H) 4.43 (br s, 1 H) 5.63 (br s, 1 H) 6.43 (d, J = 3.91 Hz , 1 H) 7.13 - 7.35 (m, 7 H) 7.47 (d, J = 3.91 Hz, 1 H) 8.06 (d, J = 8.31 Hz, 2 H) 8 , 39 (s, 1 H). Step 2. N - (((3R, 5R) -1-Benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) - 7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a stirred solution of N- ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin -4-amine (3 g, 5.069 mmol) in MeOH (15 ml) at 0 ° C H2O (3 ml) and K2CO3 (1.053 g, 7.603 mmol) were added. The reaction was allowed to warm to room temperature and stirred for 16 h. After TLC (70% EtOAc in hexane) indicates starting material to be completely consumed, the solvent was removed in vacuo and the crude was purified by chromatography (silica, EtOAc / hexane, 0 to 70%) to provide 1.5 g (68%) of N - ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4- amine as a white solid. LC / MS (M + H) 437.8. 1H NMR (400 MHz, DMSO-d6) δ -0.01 (s, 6 H) 0.86 (s, 9 H) 1.74 (d, J = 4.89 Hz, 2 H) 2.11 - 2.45 (m, 3 H) 2.80 (d, J = 8.31 Hz, 1 H) 3.38 - 3.70 (m, 2 H) 4.11 (br s, 1 H), 4 , 62 (br s, 1 H) 6.60 (br s, 1 H) 6.94 (d, J = 8.31 Hz, 1 H) 7.07 (t, J = 2.69 Hz, 1 H ) 7.15 - 7.40 (m, 5 H) 8.06 (s, 1 H) 11.47 (br s, 1 H). Step 3. N - (((3R, 5R) -5 - ((tert-Butyldimethylsilyl) oxy) piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. A solution of N - ((3R, 5R) -1-benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (600 mg, 1.371 mmol) in ethanol was degassed with argon for 15 min and then loaded with 10% Pd / C (60 mg). The mixture was hydrogenated using a hydrogen balloon for 16 h. After TLC (10% MeOH / DCM) indicates no starting material is present, the reaction mixture was filtered through Celite®, and the filtrate was concentrated to provide the crude material. The crude material was purified by column chromatography (100-200 silicas, MeOH / DCM, 0 to 8%) to provide 380 mg (80%) of N - ((3R, 5R) -5- ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.00 (br s, 6 H) 0.82 (s, 9 H) 1.65 - 1.88 (m, 2 H) 2.56 - 2.42 (m, 3 H) 2.70 (d, J = 11.74 Hz, 1 H) 2.91 - 3.06 (m, 1 H) 3.96 (br s, 1 H) 4.40 (br s, 1 H) 6.57 (d, J = 1.47 Hz, 1 H) 6.88 - 7.12 (m, 2 H) 8.06 (s, 1 H) 11.46 (br s, 1 H). Step 4. 1 - (((3R, 5R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5 - (((tert-butyldimethylsilyl) oxy) piperidin-1-yl ) prop-2-en-1-one. To a stirred solution of N - ((3R, 5R) -5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (400 mg, 1.151 mmol) in DCM (10 ml) at 0 ° C TEA (0.481 ml, 3.453 mmol) was added, followed by acryloyl chloride (0.093 ml, 1.15 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes. After TLC (10% MeOH / DCM) indicates starting material to be consumed, the reaction mixture was quenched with water (10 ml) and extracted with DCM (2 x 50 ml). The combined organics were washed with aq. (10 ml) and then with brine, dried (Na2SO4) and concentrated to provide the crude material, which was purified by chromatography (silica, MeOH / DCM 0 to 5%) to provide 180 mg (39%) of 1- ( (3R, 5R) -3- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5 - ((tert-butyldimethylsilyl) oxy) piperidin-1-yl) prop-2-en -1-one as a light yellow solid. LC / MS (M + H) 401.8. 1H NMR (400 MHz, DMSO-d6) δ -0.11 - 0.18 (m, 6 H) 0.76 - 0.92 (m, 9 H) 1.64 - 2.07 (m, 2 H ) 2.55 - 2.63 (m, 1 H) 3.06 - 3.28 (m, 1 H) 3.77 - 4.26 (m, 3 H) 4.44 (br s, 1 H) 4.64 (d, J = 11.25 Hz, 1 H) 5.50 - 5.74 (m, 1 H) 5.96 - 6.15 (m, 1 H) 6.57 (d, J = 10.27 Hz, 1 H) 6.71 (td, J = 16.51, 10.51 Hz, 1 H) 7.08 (br s, 1 H) 7.13 - 7.30 (m, 1 H ) 7.99 - 8.19 (m, 1 H) 11.51 (br s, 1 H) Step 5. 1 - ((3R, 5R) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one. To a stirred solution of 1- ((3R, 5R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5 - ((tert-butyldimethylsilyl) oxy) piperidin -1-yl) prop-2-en-1-one (100 mg, 0.249 mmol) in THF (1 ml) 6 N HCl (1 ml) was added at 0 ° C. The resulting mixture was allowed to come to room temperature, and stirred for 4 h. After TLC (10% MeOH / DCM) indicates starting material to be consumed, the reaction mixture was basified with saturated aqueous NaHCO3 solution and extracted with 20% IPA in DCM (5 x 30 ml). The organic extracts were dried (Na2SO4) and filtered. The solvent removed to provide the crude compound, which was purified by RP-HPLC to provide 25 mg of 1 - ((3R, 5R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) - 5-hydroxypiperidin-1-yl) prop-2-en-1-one as a white solid. LC / MS (M + H) = 288.0. 1H NMR (400 MHz, MeOH-d4) δ 1.78 - 2.28 (m, 3 H) 2.83 - 3.01 (m, 1 H) 3.33 - 3.63 (m, 2 H) 3.76 - 3.97 (m, 1 H) 4.00 - 4.22 (m, 2 H) 4.45 - 4.67 (m, 1 H) 5.46 - 5.79 (m, 1 H) 5.97 - 6.26 (m, 1 H) 6.46 - 6.70 (m, 2 H) 6.78 (dd, J = 16.87, 10.51 Hz, 1 H) 7, 06 (t, J = 3.18 Hz, 1 H) 8.06 - 8.23 (m, 1 H). Example 61: 1 - [(5R) -2,2-Dimethyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one . Step 1. N- (1-Benzyl-6,6-dimethylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. One vial containing 4-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (212 mg 0.688 mmol), 1-benzyl-6,6-dimethyl-piperidin-3-amine (200 mg, 0.688 mmol ), DIEA (1.22 ml, 6.88 mmol) and n-BuOH (2.5 ml) was heated to 110 ° C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (CombiFlash®, 12 g gold column, 10 to 50% EA in heptane) to provide 140 mg (41.6%) of N- (1-benzyl-6,6-dimethylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. LC / MS (M + H) 490.1. Step 2. N- (6,6-Dimethylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a solution of N- (1-benzyl-6,6-dimethylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.204 mmol) in 5 ml of EtOH was added 20 mg of Pd / C (5%, 50% water) followed by HCOONH4 (64.4 mg, 1.02 mmol). The reaction was heated to reflux for 24 hours. The reaction was allowed to cool to room temperature and filtered. The filtrate was concentrated. The residue was dissolved in DCM and washed with water. The organic layer was separated and concentrated to provide 70 mg of N- (6,6-dimethylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. LC / MS (M + H) 400.1. Step 3. 1- (2,2-Dimethyl-5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en- 1-one. To a solution of N- (6,6-dimethylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (70 mg, 0.18 mmol) in chloroform (5 mL )) DIPEA (0.124 ml, 0.700 mmol) was added. The solution was cooled to 0 ° C and acryloyl chloride (23.7 mg, 0.26 mmol) in 1 ml of CHCl3 was added. After 30 min, saturated NaHCO3 (5 ml) was added and the reaction mixture was stirred for 30 minutes. The organic layer was separated and concentrated to provide 80 mg of 1- (2,2-dimethyl-5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin -1-yl) prop-2-en-1-one. 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.00 (d, 2H), 7.41 (d, 1H), 7.22 (d, 2H), 6.36 (d .1H), 6.35-6.28 (m, 1H), 6.07-6.02 (m, 1H), 5.42-5.39 (m, 1H), 5.04-5.02 (m, 1H), 4.31 - 4.27 (m, 1H), 3.71 - 3.67 (m, 1H), 3.30 - 3.25 (m, 1H), 2.30 (s , 3H), 2.06-2.03 (m, 1H), 1.61-1.58 (m, 2H), 1.45 (d, 6H); m / z 454.1 (M + H). Step 4. (R) -1- (5 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2,2-dimethylpiperidin-1-yl) prop-2-en-1 -one. To a vial containing 1- (2,2-dimethyl-5 - (((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en -1-one (80 mg, 0.17) THF (2 ml) was added. The reaction mixture was cooled to 0 oC and t-BuOK (0.348 ml, 0.3 mmol) was added. The ice bath was removed after 1 hr. After 1.5 hr, 0.5 mL (0.5 mmol) of more t-BuOK was added and the reaction stirred at room temperature. After 2 hours, the reaction was quenched with NH4Cl (aq) and the mixture extracted with DCM. The DCM layer was dried and the solvent removed to provide the crude product, which was purified by chromatography (silica, MeOH / DCM) to provide rac-1- (5 - (((7H-pyrrolo [2,3-d] pyrimidin -4-yl) amino) -2,2-dimethylpiperidin-1-yl) prop-2-en-1-one. The racemate was separated by chiral HPLC to provide two peaks. Example 61a: Enantiomer 1, 3.2 mg, room temperature 3.27, m / z 299.9 (M + H). Example 61b: Enantiomer 2, 4.4 mg, room temperature 3.92, m / z 299.8 (M + H). Example 62: 3- (4 - {[(3R) -1-Acryloylpiperidin-3-yl] amino} -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile. Step 1. (R) -tert-butyl (- ((5- (2-cyanoethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. (a) A vial containing 3 ((5- (2-hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) -tert-butyl piperidine-1-carboxylate (400 mg, 1.11 mmol) in DCM (6.0 mL) at 0 ° C, CH3SO2Cl (0.10 mL, 1.33 mmol) and DIPEA (0.6 mL, 3.32 mmol) were added. The mixture was stirred at 0 ° C for 30 minutes and then poured into water / DCM. The layers were separated and the organic extracts collected and dried (Na2SO4). The solvent was removed to provide 3 - ((5- (2- ((methylsulfonyl) oxy) ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) piperidine-1-carboxylate ) crude tert-butyl (540 mg), which was used in the next step without purification. (b) Ao (3) - ((5- (2 - ((methylsulfonyl) oxy) ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate crude tert-butyl (540 mg, 1.23 mmol) DMF (5 mL) and NaCN (303 mg, 6.1 mmol) were added. The reaction was stirred at 50 ° C for 30 minutes and then poured into water / ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to provide the crude, which after chromatography (silica, 0 to 5% MeOH / DCM) provided 3 - ((5- (2-cyanoethyl) -7H-pyrrolo [2,3-d] pyrimidin-4- il) (R) -tert-butyl amino) piperidine-1-carboxylate (302 mg, 66%). LC / MS (M + H) 371.4. Step 2. (R) -3- (4- (Piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile. (c) To a vial containing 3 ((5- (2-cyanoethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) -tert-butyl piperidine-1-carboxylate (302 mg, 0.82 mmol) DCM (2 mL) and TFA (0.32 mL) were added. The mixture was stirred at room temperature for 4 hours and the solvent removed to provide (R) -3- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile crude, which was used without further purification. LC / MS (M + H) 271.3. Step 3. 3- (4 - {[(3R) -1-Acryloylpiperidin-3-yl] amino} -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile. To a vial containing (R) -3- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile (53 mg, 0.20 mmol) in DCM ( 1.5 ml) at 0 ° C DIPEA (0.10 ml, 0.58 mmol) was added. After 30 min, acryloyl chloride (14.2 mg, 0.157 mmol) was added and the reaction stirred for 1 hr. The reaction was diluted with saturated NaHCO3 / DCM and the layers separated. The organic layer was collected, dried (Na2SO4) and the solvent removed. The crude material was purified by chromatography (silica, MeOH / DCM, 5 - 8%) to provide (R) -3- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile (32 mg, 50%). LC / MS (M + H) 325.4. 1H NMR (400 MHz, DMSO-d6) δ 1.29 - 1.52 (m, 1 H) 1.60 - 2.05 (m, 3 H) 2.59 - 2.76 (m, 2 H) 2.82 - 2.95 (m, 1 H) 2.99 - 3.24 (m, 3 H) 3.60 - 3.86 (m, 1 H) 3.95 - 4.22 (m, 2 H) 5.38 - 5.73 (m, 1 H) 5.86 - 6.21 (m, 2 H) 6.55 - 6.87 (m, 1 H) 6.97 (s, 1 H) 7.94 - 8.18 (m, 1 H) 11.42 (br s, 1 H). Example 63: 1 - [(3R) -3 - {[2- (Pyridin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] prop- 2-en-1-one. Step 1. 2,4-Dichloro-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine. To a suspension of sodium hydride (60 weight%, 510 mg, 12.76 mmol) in DMF (15 mL) at 0 ° C was added a solution of 2,4-dichloro-7H-pyrrole [2, 3-d] pyrimidine (2 g, 10.63 mmol) in anhydrous DMF (5 ml). When the addition was complete, 2- (trimethylsilyl) ethoxymethyl chloride (2.45 ml, 13.83 mmol) was added dropwise and the reaction mixture stirred at 0 ° C. After 1.5 hours, the reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic extract washed with brine and dried (Na2SO4). The solvent was removed in vacuo to provide the crude material, which after chromatography (silica, EtOAc / Hex, 0-5%) provided 3.1 g (92%) of 2,4-dichloro-7 - ((2- ( trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3- d] pyrimidine as a light yellow liquid. LC / MS 318.0. Step 2. 3 ((((2-chloro-7 - (((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate R) -tert-butyl. To a stirred solution of 2,4-dichloro-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine (2.85 g, 8.95 mmol) in n- butanol (100 ml) (R) -tert-butyl 3-aminopiperidine-1-carboxylate (1.79 g, 8.95 mmol) and DIPEA (7.80 ml, 44.77 ml) were added. The reaction mixture was heated to 80 ° C for 16 hours. After TLC indicated completion of the reaction with traces of unreacted SM, the crude mixture was concentrated in vacuo and purified by CombiFlash® chromatography (using 0-30% ethyl acetate / hexane) to provide 2.5 g (58%) of (R) - ((2-chloro-7 - (((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate tert-butyl as a colorless sticky solid. LC / MS (M + H) 482.4. Step 3. 3 - ((2- (pyridin-3-ylamino) -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine (R) -tert-butyl -1-carboxylate. To a stirred solution of 3 - ((2-chloro-7 - ((2- (trimethylsilyl) ethoxy) methyl) - 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate of (R) -tert-butyl (1.4 g, 2.90 mmol) in dioxane (30 mL) were added pyridin-3-amine (314 mg, 3.34 mmol), Cs2CO3 (2.36 g, 7 , 26 mmol) and Xantphos (67 mg, 0.116 mmol). The reaction mixture was degassed by the argon subsurface flow for 30 minutes. Pd2 (dba) 3 (53 mg, 0.058 mmol) was added to the reaction mixture which was then heated to 150 ° C in a sealed tube for 16 hours. After TLC (40% EtOAc in hexane) indicates completion of the reaction, the reaction mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by CombiFlash® chromatography (using 0-80% ethyl acetate / hexane) to obtain 1.3 g (83%) of 3 - ((2- (pyridin-3-ylamino) - (R) -tert-butyl 7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate as an off-white solid. LC / MS (M + H) 540.2. Step 4. (R) -N4- (Piperidin-3-yl) -N2- (pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-2,4-diamine. To a stirred solution of 3 - ((2- (pyridin-3-ylamino) -7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino ) (R) -tert-butyl piperidine-1-carboxylate (300 mg, 0.556 mmol) in DCM (5 ml) TFA (5 ml) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 3 hours. After TLC (50% EtOAc in hexane) indicates completion of the reaction, the reaction was concentrated under reduced pressure. The crude material was dissolved in methanol (6 ml) and ethylene diamine (0.5 ml) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and divided between DCM and water. The organic layer was separated and washed with water, brine, dried over Na2SO4 and concentrated to provide 210 mg (~ 100%) of (R) -N4- (piperidin-3-yl) -N2- (pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-2,4-diamine as a brown sticky solid. LC / MS (M + H) 310.4. Step 5. (R) -1- (3 - ((2- (Pyridin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one. To a stirred solution of (R) - N4- (piperidin-3-yl) -N2- (pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-2,4-diamine (210 mg, 0.679 mmol) in DCM (5 mL) were added DI-PEA (0.356 mL, 2.04 mmol) and acryloyl chloride (0.06 mL, 0.747 mmol) at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C. After TLC (5% MeOH in DCM) indicates completion of the reaction, the reaction mixture was diluted with DCM / water. The organic extracts were separated and washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by CombiFlash® chromatography (using 0-3% MeOH / DCM) followed by trituration with ether-pentane to obtain 38 mg (16%) of (R) -1- (3- ((2- ( pyridin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (br, 1H), 8.89-8.86 (m, 2H), 8.32-8.23 (m, 1H), 8.00- 8.01 (m, 1H), 7.19-7.17 (m, 1H), 6.83-6.81 (m, 1H), 6.90-6.60 (m, 1H), 6, 47 (br, 1H), 6.15-5.99 (m, 1H), 5.72-5.47 (m, 1H), 4.55-4.15 (m, 2H), 4.10- 3.90 (1H), 3.21-2.60 (m, 2H), 2.20-1.92 (m 1H), 1.90-1.82 (m, 1H), 1.75-1 , 32 (m, 2H); m / z 364.2 (M + H). Example 64: 1 - [(3S, 4R) -4-Hydroxy-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one ) (rac-cis). Step 1. tert-Butyl 5,6-dihydropyridine-1 (2H) -carboxylate. Boc-anhydride (61.4 mL, 267.7 mmol) was added to a stirred solution of 1,2,3,6-tetrahydropyridine (22 g, 265 mmol) in 10% Na2CO3 (74.8 mL) at 0 ° C. The reaction mixture was stirred for 1 h at 0 ° C and then at room temperature for 3 h. Saturated NaCl solution was added to the reaction mixture and the aqueous mixture extracted with diethyl ether. The organic layer was dried (Na2SO4), and concentrated to provide tert-butyl 5,6-dihydropyridine-1 (2H) -carboxylate (39.6 g, 81.8%) as a pale yellow liquid. TLC system: Rf = 0.5 (20% ethyl acetate in petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ 5.75-5.85 (m, 1H), 5.6-5.72 (m, 1H), 3.8 (d, 2H), 3.6 ( dt, 2H), 2.15 (d, 2H), 1.4 (s, 9H). GCMS: (m / z) = 82.2 (M + -Boc) +; (Purity: 87.95%). Step 2. tert-Butyl 7-Oxa-3-azabicyclo [4,1,0] heptane-3-carboxylate. Sodium bicarbonate (29 g, 346.2 mmol) was added portionwise to a solution of tert-butyl 5,6-dihydropyridine-1 (2H) -carboxylate (39.6 g, 216.3 mmol) in DCM ( 871 ml) at 0 ° C. M-Chloroperbenzoic acid (78 g, 454.4 mmol) was then added portion by portion at 0 ° C and stirred for 2 hours at the same temperature, and then at room temperature for an additional 2 h. The insoluble material was filtered and the filtrate was washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography over silica (100200 mesh), eluting with 10% ethyl acetate in petroleum ether to provide tert-7-oxa-3-azabicyclo [4,1,0] heptane-3-carboxylate - butyl (29.25 g, 69%) as a pale yellow liquid. TLC system: Rf = 0.3 (30% ethyl acetate in petroleum ether). 1H NMR (300MHz, DMSO-d6) δ 3.7 (t, 2H), 3.05-3.45 (overlap signals, 4H), 1.7-2.0 (m, 2H), 1.4 (s, 9H). GCMS: (m / z) 199.2 (M +); (Purity: 98%). Step 3. tert-Butyl 4-azido-3-hydroxypiperidine-1-carboxylate and tert-butyl 3-azido-4-hydroxypiperidine-1-carboxylate. To a solution of tert-butyl 7-oxa-3-azabicyclo [4,1,0] heptane-3-carboxylate (29 g, 145.7 mmol) in 1,4-dioxane (406 mL), water was added (81 ml) and sodium azide (13.8 g, 212.7 mmol) at room temperature and the resulting mixture was heated to 110 ° C for 12 h. After cooling to room temperature, water was added to the reaction mixture and the resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography on silica (100200 mesh) by gradient elution with 10% to 20% ethyl acetate in petroleum ether to provide tert-4-azido-3-hydroxypiperidine-1-carboxylate. butyl (16.9 g) as a pale yellow liquid and tert-butyl 3-azido-4-hydroxypiperidine-1-carboxylate (4 g) as a yellow liquid. (Combined production: 59%). TLC system: Rf = 0.3 (40% ethyl acetate in petroleum ether). 4-Azido-3-hydroxypiperidine-1-tert-butyl carboxylate: 1H NMR (300 MHz, DMSO-d6) δ 5.55 (d, 1H), 3.9 (dd, 1H), 3.8 (dd , 1H), 3.35-3.45 (m, 1H), 3.2-3.35 (m, 1H), 2.65-2.85 (br, 1H), 2.5-2.65 (br, 1H), 1.8 (dd, 1H), 1.4 (s, 9H). LCMS: (m / z) 143.1 (M + H-Boc) +; (Purity: 98.5%). 3-Azido-4-hydroxypiperidine-1-tert-butyl carboxylate: 1H NMR (300MHz, DMSO-d6) δ 5.35 (d, 1H), 3.7-3.85 (broad, 1H), 3, 6-3.7 (am-plo, 1H), 3.4-3.55 (m, 1H), 3.2-3.35 (broad, 1H), 2.6-3.0 (overlap, 2H ), 1.70-1.85 (m, 1H), 1.40 (s, 9H). LCMS: (m / z) = 143.1 (M + H-Boc) +; (Purity: 98.7%). Step 4. Rac- (3S, 4S) - tert-butyl 4-Amino-3-hydroxypiperidine-1-carboxylate. 10% Pd-C (5 g) was added portion by portion to a solution of tert-butyl 4-azido-3-hydroxypiperidine-1-carboxylate (23 g, 181 mmol) in methanol (200 mL) over 45 min under nitrogen. The resulting mixture was stirred for 12 h under hydrogen balloon pressure. The mixture was filtered through Celite® and the pad washed with methanol. The filtrate was concentrated and the crude dissolved in DCM, and filtered again through Celite® to remove residual Pd. The filtrate was concentrated to provide rac- (3S, 4S) -tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (11.5 g, 76%) as yellow syrup. TLC system: Rf = 0.3 (10% MeOH in DCM). 1H NMR (400 MHz, DMSO-d6) δ 4.9-5.1 (br s, 1H), 3.60-4.0 (2H), 2.85-2.95 (m, 2H), 2 , 60-2.80 (br, 1H), 2.35-2.45 (m, 1H), 1.501.80 (overlap, 3H), 1.40 (s, 9H). LCMS: (m / z) = 217.15 (M + H) +; (Purity: 96.5%). Step 5. 3 - ((2-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidine-1-carboxylate of Rac- (3S, 4S) -tert-butyl. To a flask containing rac- (3S, 4S) - tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (460 mg, 2.13 mmol) were added n-butanol (4 mL), 2,4- dichloro-7H-pyrrolo [2,3-d] pyrimidine (400 mg, 2.13 mmol) and DIPEA (2 mL, 10 mmol). The mixture was heated to 95 ° C overnight. The reaction was poured into EtOAc / brine and the layers separated. The organic extract was washed with brine, dried (Na2SO4) and the solvent removed to provide the crude, which after chromatography (silica, EtOAc / Heptane) provided 3 - ((2-chloro-7H-pyrrole [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidine-1-carboxylate of rac- (3S, 4S) -tert-butyl (549 mg, 70%). LC / MS (M + H) 368.1. 1H NMR (400 MHz, CHCl3) δ 1.10 - 1.72 (m, 10 H) 1.96 - 2.11 (m, 1 H) 2.74 - 3.19 (m, 2 H) 3, 59 - 4.37 (m, 4 H) 5.69 (br s, 1 H) 6.29 (br s, 1 H) 6.82 - 7.07 (m, 1 H) 10.82 (br. s, 1 H). Step 6. 3 - (((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4 - ((4-nitrobenzoyl) oxy) piperidine-1-carboxylate , 4R) -tert-butyl. To a mixture of rac- (3S, 4S) -tert-butyl 3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidine-1-carboxylate (0.4 g, 1.09 mmol) in toluene (6 mL) were added 4-nitrobenzoic acid (0.254 g, 1.52 mmol) and triphenylphosphine (0.451 g, 1.74 mmol)). The mixture was degassed with nitrogen and sealed in a vial with a septum top. DEAD (0.316 mL, 1.74 mmol) was added dropwise to the suspension. All solids dissolved and the mixture was stirred at room temperature for 4 h. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic phase washed with 1 N HCl, saturated sodium bicarbonate and then brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (silica, EtOAc / Heptane) to provide 3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4 - ((4- nitrobenzoyl) oxy) piperidine-1-carboxylate of rac- (3S, 4R) -tert-butyl (499.5 mg, 88%). LC / MS (M + H) 517.2. Step 7. Rac - (3S, 4R) -tert-butyl (- ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidine-1-carboxylate. To a vial containing 3 ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4 - ((4-nitrobenzoyl) oxy) piperidine-1-carboxylate (3S, 4R) -tert-butyl (499 mg, 0.96 mmol) dioxane (8 mL) and NaOH (5 mL, 1 M solution) were added. The mixture was heated to 50 ° C for 1 h and poured into brine / EtOac. The layers were separated and the aqueous phase extracted twice with 25 ml of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide crude, which was purified by chromatography (silica, EtOAc / Hep, 0 to 100%) to provide 3- Rac ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidine-1-carboxylate (3S, 4R) -tert-butyl (183 mg, 51% ). LC / MS (M + H) 368.2. 1H NMR (400 MHz, CHCl3) δ 1.37 - 1.49 (m, 10 H) 1.60 - 1.88 (m, 3 H) 3.08 - 3.90 (m, 4 H) 4, 34 - 4.48 (m, 1 H) 6.35 (br s, 1 H) 6.47 (br s, 1 H) 7.03 (s, 1 H) 10.42 (br s, 1 H) . Step 8. Rac- (3S, 4R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-4-ol. To a mixture of rac - (3S, 4R) - tert-butyl 3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidine-1-carboxylate (0.1826 g) in ethanol (2 ml) cyclohexene (2 ml) and 1.25 M HCl in methanol (1 ml) were added. The mixture was placed under nitrogen and 10% Pd / C was added and refluxed overnight. After cooling to room temperature, the mixture was filtered through Celite® and the filtrate concentrated to provide rac- (3S, 4R) - 3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-4-ol (150 mg, 98%). LC / MS (M + H) 234.2. 1H NMR (400 MHz, MeOH-d4) δ 1.89 - 2.20 (m, 3 H) 3.03 - 3.22 (m, 1 H) 3.36 - 3.53 (m, 2 H) 4.12 - 4.28 (m, 1 H) 4.51 - 4.73 (m, 1 H) 7.02 (br s, 1 H) 7.36 (br s, 1 H) 8.38 ( br s, 1 H). Step 9. Rac-1 - ((3S, 4R) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidin-1-yl) prop-2-en -1-one. To a mixture of rac- (3S, 4R) -3- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-4-ol (75 mg, 0.24 mmol) in DCM (2 ml) and acetonitrile (2 ml) NMM (0.083 ml, 0.73 mmol) was added. The mixture was stirred in an ice bath for 10 minutes, during which time a solution of acryloyl chloride (0.02 ml, 0.24 mmol) in DCM (0.5 ml) was added dropwise over 10 minutes . The mixture was stirred at 0 ° C for 1.5 h. DMF (3 ml) was added and the reaction stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to provide rac-1 - ((3S, 4R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-hydroxypiperidin-1-yl) prop-2-en-1-one (7.1 mg). LC / MS (M + H) 288.18. Example 65: Rac-1 - ((3R, 5R) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en -1-one. Step 1. Rac-N - ((3R, 5R) -5-Methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a dry Parr flask was added Pd / C (200 mg) under N2 atmosphere. Then a solution of rac- (3R, 5R) -benzyl 3 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidine-1-carboxylate (see Example 14, Step 5, rac-trans, 559 mg, 1.398 mmol) in MeOH / THF (30 mL / 10 mL) was added and the resulting mixture was heated to 40 oC under 3.51 kg / cm2 ( 50 psi) of H2 for 3 days. LCMS indicated that the reaction has been completed. The reaction mixture was filtered and the filter cake was washed with MeOH. The combined filtrate was evaporated to provide rac-N - ((3R, 5R) -5-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (rac-trans, 413 mg, 100%) as a pink solid. Step 2. Rac-1 - (((3R, 5R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en -1-one. To a solution of rac-N - ((3R, 5R) - 5-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine ((413 mg, 1.542 mmol) in THF ( 20 mL) saturated aqueous NaHCO3 (15 mL) and acryloyl chloride (154 mg, 1.70 mmol, 1.1 eq.) Were added at 0 ° C. After 2 hours at 0 ° C, TLC (EtOAc: MeOH = 10: 1) indicated that the reaction was complete, the reaction mixture was diluted with water (50 ml), and extracted with EtOAc (50 ml * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc: MeOH = 10: 1) to provide rac-1 - ((3R, 5R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (221 mg, 50%) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 11.48 (br s , 1H), 8.30 - 8.04 (m, 1H), 7.13 - 6.96 (m, 2H), 6.83 (dd, J = 10.3, 16.8 Hz, 1H), 6.69 - 6.54 (m, 1H), 6.36 (dd, J = 10.5, 16.6 Hz, 1H), 6.08 (d, J = 17.8 Hz, 1H), 5 , 89 (d, J = 17.1 Hz, 1H), 5.66 (d, J = 8.8 Hz, 1H), 5.35 (d, J = 10.5 Hz, 1H), 4.47 - 4.20 (m, 1H), 4.04 - 3.84 (m, 2H), 3.61 - 3.37 (m, 2H), 2.88 - 2.75 (m, 1H ), 2.15 (br s, 1H), 1.93 - 1.76 (m, 1H), 1.71 - 1.53 (m, 1H), 0.98 - 0.88 (m, 3H) . LC / MS (M + H) 285.9. Example 66. (R) -1- (3 - ((5- (6-Methylpyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one. Prepared like the derivatives in Examples 23-40. LC / MS (M + H) 363.2. Example 67. 1- (5 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2,2-dimethylpiperidin-1-yl) prop-2-en-1-one. Prepared as described in Example 61, except no chiral separation. Example 68. 1 - ((2R, 5S) -5 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1 -one. Prepared as described in Example 5, Step 9; pk1: 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 7.30 (dd, J = 6.8 , 18.8Hz, 1H), 7.10 (br s, 1H), 6.89 - 6.71 (m, 1H), 6.56 (d, J = 1.8 Hz, 1H), 6.10 (dd, J = 2.1, 16.7 Hz, 1H), 5.72-5.61 (m, 1H), 4.81 (br s, 0.5H), 4.56 (d, J = 10.3 Hz, 0.5H), 4.37 (br s, 0.5H), 4.20 - 3.95 (m, 1.5H), 2.96 (t, J = 11.9, 10 Hz, 0.5H), 2.60 (t, J = 12.0 Hz, 0.5H), 1.92 - 1.59 (m, 4H), 1.30 - 1.07 (m, 3H) . 19 H's obs; 19 exp. LC / MS (M + H) 286.2. OR = [a] D20 = +0.34 (c = 0.6, MeOH). Example 69: 1- (5 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one. Prepared as in Example 7, except no separation of diastereomers or enantiomers. LC / MS (M + H) 302.2. See Example 52. Examples 70, 71 and 72: Example 70: (S) -1- (3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1- il) prop-2-en-1-one. Example 71: 1- (3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one. Example 72: (R) -1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one . Step 1. 3-Methyl 1-tert-butyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-tert-butyl 3-methyl piperidine-1,3-dicarboxylate (15 g, 0.062 mol) in THF (250 ml) was added LHMDS (74.4 ml, 0.074 mol) dropwise -65 ° C under N2 protection. The reaction mixture was stirred at -65 ° C for 1 h. MeI (10.5 g, 0.074 mol) was added dropwise. The resulting solution was stirred at -65 ° C for 2 h and at room temperature for 1 h. The resulting solution was quenched with NH4Cl sat. (aq) (200 ml). The organic layer was separated and the aqueous layer was extracted with MTBE (200 ml x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to provide 1-tert-butyl 3-methylpiperidine-1,3-dicarboxylate (15.86 g, 100%) as yellow oil . 1H NMR (400 MHz, DMSO-d6) δ 1.08 (s, 3 H) 1.32 - 1.47 (m, 12 H) 1.94 (br s, 1 H) 3.05 (d, J = 12.30 Hz, 2 H) 3.42 (br s, 1 H) 3.61 (br s, 3 H) 3.82 (br s, 1 H). Step 2. 3-Methyl-1-tert-butyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of 3-methyl-1-tert-butyl 3-methylpiperidine-1,3-dicarboxylate (15.86 g, 0.062 mol) in THF (100 ml) and H2O (10 ml) was added LiOH ^ O (7.76 g, 0.186 mol) at room temperature. The mixture was refluxed at 70 ° C for 6 h. After TLC (petroleum ether / EtOAc, 4: 1, stained by iodine) shows the starting material to be consumed, the mixture was concentrated to dryness. The residue was diluted with H2O (300 ml) and then extracted with MTBE (100 ml x 2). The organic layers were discarded. The resulting aqueous layer was acidified to pH 1 with 1 M HCl (aq.) And then extracted with MTBE twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to provide 1-tert-butyl 3-methylpiperidine-1,3-dicarboxylate (13.97 g, 93%) as a solid White. Step 3. tert-Butyl 3-isocyanate-3-methylpiperidine-1-carboxylate. To a solution of 3-methyl-1-tert-butyl 3-methylpiperidine-1,3-dicarboxylate (5.97 g, 24.5 mmol) in anhydrous toluene (65 mL) were added TEA (3.5 mL, 24.5 mmol) and DPPA (6 mL, 27 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then refluxed at 90 ° C for 2 h. The reaction was poured into ice water (100 ml) and extracted with MTBE (100 ml x 3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to dryness to provide tert-butyl 3-isocyanate-3-methylpiperidine-1-carboxylate (5.9 g, 100%) as a yellow oil, which was used without purification in the next step. Step 4. tert-Butyl 3-Amino-3-methylpiperidine-1-carboxylate. To a solution of tert-butyl 3-isocyanate-3-methylpiperidine-1-carboxylate (5.89 g, 24.54 mmol) in THF (140 ml) was added 2 M NaOH (aq) (140 ml). The resulting solution was stirred vigorously at room temperature overnight. TLC showed that the desired product was formed. The reaction mixture was acidified to pH 1 with 1 M HCl (aq) and then extracted with MTBE (200 ml x 3). The organic layers were discarded. The resulting aqueous layer was basified to pH 10 with 1 M NaOH (aq.) And then extracted with MTBE (250 ml x 3). The combined organic layers were washed with brine at neutral pH, dried over Na2SO4 and concentrated to dryness to provide tert-butyl 3-amino-3-methylpiperidine-1-carboxylate (3.7 g, 36%) as a colorless oil that was directly used for the next step without further purification. 1H NMR (400 MHz, CHCl3) δ d 1.09 (s, 3 H) 1.27 - 1.40 (m, 2 H) 1.46 (s, 10 H) 1.53 - 1.65 (m , 2 H) 3.04 - 3.56 (m, 4 H). Step 5. tert-Butyl 3-methyl-3 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. Tert-Butyl 3-Amino-3-methylpiperidine-1-carboxylate (3.3 g, 15.398 mmol) and tert-butyl 3-amino-3-methylpiperidine-1-carboxylate (3.9 g, 12.7 mmol ) were stirred at 140 ° C overnight. After TLC showed tert-butyl 3-amino-3-methylpiperidine-1-carboxylate, the mixture was diluted with DCM (80 ml). The DCM layer was washed with saturated NaHCO3 (aq) and brine and concentrated to dryness to provide the crude product which was purified by chromatography (silica, EtOAc / petroleum ether, 0-40%) to provide 3-methyl-3 - tert-butyl ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (2.4 g, 40%) as a white solid. Step 6. N- (3-Methylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a solution of tert-butyl 3-methyl-3 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (3g, 6.2 mmol ) in dioxane (30 ml) 4 M HCl / dioxane (30 ml) was added dropwise at 0 ° C. Then, the reaction mixture was warmed to room temperature and stirred for 2 h. After LC-MS showed the starting material to be consumed, the reaction mixture was concentrated to dryness to provide the crude product (2.6 g, 100%) as a white solid that was directly used for the next step without further purification . Step 7. 1- (3-Methyl-3 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1- ona. To a solution of N- (3-methylpiperidin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (2.5g, 5.93 mmol) in THF (100 ml ) / NaHCO3 (aq) sat. (100 ml) acryloyl chloride (0.64 g, 7.115 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. After TLC showed the starting material was consumed, the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined organic layers were concentrated to dryness to provide the crude product which was purified by chromatography (silica, EtOAc / petroleum ether = 066%) to provide 1- (3-methyl-3 - ((7-tosyl-7H- pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one (1.618 g, 62%) as a white solid. LC / MS (M + H) 440.2. Step 8. 1- (3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one. To a solution of 1- (3-methyl-3 - ((7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1 -one (1 g, 2.277 mmol) in THF (10 ml) and H2O (2 ml) were added Li-OH ^ H2O (0.2 g, 4.554 mmol) and t-BuOK (0.5 g, 4.554 mmol) . The reaction mixture was refluxed at 65 ° C for 7 h. After TLC showed the starting material was consumed most of the time, the mixture was neutralized with AcOH and concentrated to dryness to provide the crude product, which was purified by chromatography (silica, MeOH / EtOAc, 0-6 %, 6-8%) to provide 1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1 -one (180 mg) (97% purity by LC-MS). The crude product was also purified by SP1 (MeOH / EtOAc, 02%) to provide 70 mg (12%) of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.51 (s, 3 H) 1.58 (br s, 1 H) 1.75 (d, J = 8.53 Hz, 2 H) 3.12 - 3.26 (m, 3 H) 3.59 (d, J = 11.80 Hz, 1 H) 3.81 (br s, 1 H) 5.44 (br s, 1 H) 5.93 (br s, 1 H) 6.23 (br s, 1 H) 6.60 (br s, 2 H) 7.03 (d, J = 3.26 Hz, 1 H) 8.13 (s, 1 H) 11.00 - 11.57 (m, 1 H). Step 9. (R) -1- (3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one and (S) -1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one. Seventy milligrams of 1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one were separated by chiral SFC to provide two arbitrarily assigned peaks: pk1, (R) -1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl ) prop-2-en-1-one (17 mg) and pk 2, (S) -1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3- methylpiperidin-1-yl) prop-2-en-1-one (21.3 mg). Pk1: (R) -1- (3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one: 1H NMR (400 MHz, DMSO-d6) δ 1.51 (d, J = 1.25 Hz, 3 H) 1.58 (br s, 1 H) 1.68 - 1.83 (m, 2 H) 1.76 (d, J = 8.78 Hz, 2 H) 3.07 (br s, 2 H) 3.30 (br s, 1 H) 3.60 (d, J = 13.55 Hz, 1 H) 3.78 (br s, 1 H) 5.50 (br s, 1 H) 5.96 (br s, 1 H) 6.20 (br s, 1 H) 6.57 (br s, 2 H) 7.03 (br s, 1 H) 8.13 (s, 1 H) 11.24 (br s, 1 H). Pk2: (S) -1- (3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -3-methylpiperidin-1-yl) prop-2-en-1-one. 1H NMR (400 MHz, DMSO-d6) δ 1.51 (s, 3 H) 1.59 (br s, 2 H) 1.75 (d, J = 8.28 Hz, 2 H) 3.06 ( br s, 2 H) 3.31 (br s, 1 H) 3.60 (d, J = 13.30 Hz, 1 H) 3.78 (br s, 1 H) 5.48 (br s, 1 H) 5.96 (br s, 1 H) 6.19 (br s, 1 H) 6.57 (br s, 2 H) 7.03 (d, J = 2.51 Hz, 1 H) 8, 13 (s, 1 H) 11.25 (br s, 1 H). Example 73: 1 - [(3aS, 7aS) -1- (2-Amino-7H-pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6 -il] prop-2-en-1-one. Step 1. 1- (2-Amino-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate 7aS) -benzyl. A (3aS, 7aS) -benzyl hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate (Example 8, Step 7, pk2) (464 mg, 1.786 mmol), DIPEA (1.15 g, 8.928 mmol) and 4-chloro-7H-pyrrolo [2,3-d] pyrimidin-2-amine (300 mg, 1,786 mol) in n-BuOH (6mL) was heated to 130 ° C for 8 hours. After TLC (DCM / MeOH, 10: 1) indicates the reaction to be complete, the reaction mixture was cooled to room temperature and evaporated to dryness and the residue was purified by chromatography (silica, DCM / MeOH, 1% -12% ) to provide 1- (2-amino-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate (3aS, 7aS) -benzyl (350 mg, 50%) as a brown solid. LC / MS (M + H) 393.4. 1H NMR (400 MHz, CHCl3) δ 1.73-1.76 (m, 1H), 2.17-2.04 (m, 3 H), 2.51 (br. S, 1H), 3.05 -2.41 (m, 2 H), 4.11 - 3.81 (m, 3 H), 4.81 - 4.47 (m, 3 H), 5.29-5.07 (m, 3 H), 6.79-6.35. Step 2. 4 - ((3aR, 7aS) -Octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine. To a dry Parr flask, Pd / C (50 mg) was added under Ar atmosphere. Then, a solution of 1- (2-amino-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro -1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate from (3aS, 7aS) -benzyl (200 mg, 0.510 mol) in EtOH (15 mL) was added and the resulting mixture was hydrogenated under 3 , 16 kg / cm2 (45 psi) of H2 at 25 oC for 18 hours. After TLC (DCM / MeOH, 10: 1) indicates starting material to be consumed, the reaction mixture was filtered and the filter mass was washed with EtOH. The combined filtrate was evaporated to provide 4 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (120 mg, 91.6%) as a white solid. LC / MS (M + H) 259.2. Step 3. 1 - [(3aS, 7aS) -1- (2-Amino-7H-pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6 -il] prop-2-en-1-one. To a stirred solution of 4 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (150 mg, 0.58 mol) and NaHCO3 (150 mg, 1.74 mmol) in H2O (8 mL) was added acryloyl chloride (63 mg, 0.70 mmol) dropwise at 0 ° C carefully. After the addition, the resulting mixture was stirred at room temperature for 6 hours. After LC-MS shows 4 - ((3aR, 7aS) -octahydro-1H-pyrrolo [2,3-c] pyridin-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine is consumed , the reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (20 ml x4), the combined organic layer was concentrated to provide the crude product, which was purified by column chromatography to provide 1- [(3aS, 7aS) -1- (2-amino-7H-pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6-yl] prop-2-en- 1-one (56 mg, 30.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.655 (s, 1H) 6.72-6.71 (d, 2H) 6.41 (s, 1H), 6.09-6.05 (d, 1H) , 5.64-5.61 (m, 1H), 5.33 (s, 2H), 4.28-3.69 (m, 5H), 3.34-3.29 (d, 1H), 3 , 20 (s, 1H), 2.09-1.72 (m, 5H). Examples 74 and 75: Example 74: 1 - [(3R, 5R) -3-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2- en-1-one. Example 75: 1 - (((3S, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1 -one. See Example 14 (Step 5) and Example 65 (Step 2). Step 1. 1 - [(3R, 5R) -3-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one and 1 - (((3S, 5S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one . rac-trans: 1 - ((3R, 5R) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en- 1-one (see Example 14, Step 5; Example 65, Step 2) (150 mg) was separated by chiral SFC to provide two arbitrarily assigned peaks: 1 - ((3R, 5R) -3 - ((7H- pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (pk 1, 60 mg, 80%) as a white solid and 1 - (((3S, 5S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1-one (pk 2.60 mg, 80%) as a white solid. SFC conditions: ChiralPak AD (250 mm x 30 mm, 5 μm); 20% EtOH, NH3H2O; 60 ml / min. Pk1: 1 - (((3R, 5R) -3- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1- ona: 1H NMR (400 MHz, DMSO-d6) δ 11.51 (br s, 1H), 8.19 - 8.07 (m, 1H), 7.06 (d, J = 6.0 Hz, 2H ), 6.84 (dd, J = 10.2, 16.4 Hz, 1H), 6.70 - 6.55 (m, 1H), 6.35 (dd, J = 10.4, 16.7 Hz, 1H), 6.08 (d, J = 18.6 Hz, 1H), 5.88 (dd, J = 2.3, 16.8 Hz, 1H), 5.66 (d, J = 10 , 3 Hz, 1H), 5.35 (dd, J = 2.3, 10.5 Hz, 1H), 4.41 - 4.21 (m, 1H), 4.06 - 3.84 (m, 2H), 3.61 - 3.42 (m, 1H), 2.85 - 2.75 (m, 1H), 2.15 (br s, 1H), 1.99 - 1.78 (m, 1H ), 1.73 - 1.50 (m, 1H), 1.23 (s, 1H), 1.00 - 0.86 (m, 3H). LCMS (M + H) 286.1. Pk 2: 1 - (((3S, 5S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methylpiperidin-1-yl) prop-2-en-1 -one: 1H NMR (400 MHz, DMSO-d6) δ 11.51 (br s, 1H), 8.19 - 8.05 (m, 1H), 7.06 (br s, 1H), 6.84 (dd, J = 10.3, 16.8 Hz, 1H), 6.69 - 6.55 (m, 1H), 6.35 (dd, J = 10.5, 16.6 Hz, 1H), 6.08 (d, J = 16.6 Hz, 1H), 5.88 (d, J = 15.1 Hz, 1H), 5.66 (d, J = 9.3 Hz, 1H), 5, 35 (d, J = 10.0 Hz, 1H), 4.42 - 4.19 (m, 1H), 4.06 - 3.82 (m, 1H), 3.62 - 3.44 (m, 1H), 2.86 - 2.73 (m, 1H), 2.15 (br s, 1H), 1.96 - 1.77 (m, 1H), 1.72 - 1.53 (m, 1H ), 1.23 (br s, 1H), 1.01 - 0.64 (m, 3H). LCMS (M + H) 286.1. Example 76: 1 - [(3aR, 7aR) -1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6-yl] prop -2-en-1-one. Prepared as in Example 8, except using rac- (3aS, 7aS) -benzyl hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -benzyl in Step 7. LC / MS (M + H) 298.0. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H) 8.09-8.07 (d, J = 9.2Hz, 1H) 7.11 (s, 1H), 6.82- 6.78 (m, 1H), 6.51 (m, 1H), 6.05-6.01 (m, 1H), 5.69-5.85 (m, 1H), 4.69-4, 68 (m, 0.5H), 4.27 (s, 1H), 3.90-3.74 (m, 3H), 3.13-3.24 (m, 2H), 2.74-2, 71 (m, 0.5H), 2.19-1.74 (m, 4.5H). Examples 77 and 78: Example 77: 1 - [(3R, 5R) -3-Methoxy-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2- en-1-one. Example 78: 1 - {(3R, 5R) -3-Methoxy-5- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} prop-2-en -1-one. Step 1. N - (((3R, 5R) -1-Benzyl-5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) - 7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4 -the mine. To a mixture of 4-chloro-7-trityl-7H-pyrrolo [2,3-d] pyrimidine (16.3 g, 41.18 mmol) and (3R, 5R) -1- benzyl-5 - ((tert -butyldimethylsilyl) oxy) piperidin-3-amine (12 g, 37.44 mmol) in n-BuOH (250 mL) DIPEA (14.5 g, 112.32 mmol) was added. The mixture was heated to 110 ° C for 3 days. After TLC (DCM / MeOH, 10: 1) indicates the reaction to be complete, the reaction mixture was cooled to room temperature and evaporated to dryness. The residue was diluted in EtOAc (800 ml) and water (500 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by chromatography (silica, EtOAc / PE, 0% to 30%) to provide N - (((3R, 5R) - 1-benzyl-5- ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (15 g, 65%) as a solid yellow. 1H NMR (400 MHz, CHCl3) δ -0.02 (s, 6 H), 0.82 (s, 9 H), 1.50-1.45 (m, 1H), 2.31-2.29 (m, 2 H), 2.75-2.73 (m, 1 H), 2.97 (br. S, 1 H), 3.69-3.49 (m, 2 H), 4,003.98 (m, 1 H), 4.49 (br. s, 1 H), 5.57 (br s, 1 H), 6.32 (s, 1 H), 6.90 (s, 1 H), 7.17-7.15 (m, 5 H), 7.33-7.26 (m, 15 H), 7.99 (s, 1 H). Step 2. 3 - (((tert-butyldimethylsilyl) oxy) -5 - ((3R, 5R) (3R, 5R ) -tert-butyl. To a Parr flask, 10% dry Pd / C (1.5 g) was added under Ar atmosphere. Then, a solution of N - ((3R, 5R) -1-benzyl-5 - ((tert- butyldimethylsilyl) oxy) piperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (14.8 g, 21.76 mmol) and (Boc) 2O (5.22 g, 23.94 mmol) in MeOH (300 mL) was added. The resulting mixture was hydrogenated under 3.51 kg / cm2 (50 psi) of H2 at 40 ° C for 12 hours. After TLC (PE / EtOAc, 4: 1) indicates the reaction to be complete, the reaction solution was filtered through a pad of Celite® and the filter mass was washed three times with MeOH. The combined filtrate was concentrated to provide 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (3R, 5R) -tert-butyl (14.8 g, ~ 100%) as a yellow solid, which was used directly in the next Step without further purification. 1H NMR (400 MHz, CHCl3) δ 0.06 (s, 6 H), 0.86 (s, 9 H), 1.53 (s, 9 H), 1.83 (br. S, 1 H) , 2.28 - 2.04 (m, 1 H), 3.09 (br s 1 H), 3.49 (br s, 2 H), 3.93-3.71 (m, 4 H), 4.44 (br. S, 1 H), 6.30 (s, 1 H), 6.80 (s, 1 H) 7.26-7.14 (m, 15 H), 8.00 (s , 1 H). Step 3. 3-Hydroxy-5 - ((3R, 5R) -tert-butyl ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of (3R, 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate 5R) -tert-butyl (15 g, 21.74 mmol) in anhydrous THF (300 mL) was added n-Bu4NF (11.38 g, 43.47 mmol) and then heated to 40 ° C overnight. After TLC (PE / EtOAc, 4: 1) shows the reaction to be complete, the reaction solution was diluted with water (300 ml) and then extracted with EtOAc (200 ml x 2). The combined organic layers were washed with water and brine in cycles, dried over Na2SO4 and concentrated to provide 3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3R, 5R) -tert-butyl piperidine-1-carboxylate (14.6 g, ~ 100%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CHCl3) δ 8.01 (s, 1H), 7.37 - 7.08 (m, 17H), 6.91 (d, J = 3.5 Hz, 1H), 6.30 (br s, 1H), 4.48 (d, J = 3.5 Hz, 1H), 4.05 (br s, 1H), 3.83 - 3.51 (m, 4H), 3.23 ( br s, 1H), 1.58 - 1.29 (m, 10H). Step 4. 3-Methoxy-5 - ((3R, 5R) -tert-butyl ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate and 3 -methoxy-5- (3R, 5R) -tert-butyl (methyl (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a solution of (3R, 5R) -tert-butyl (3-hydroxy-5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate ( 0.6 g, 1.043 mmoL) in DMF (1 ml) Ag2O (0.48 g, 2.086 mmol) was added, followed by MeI (0.6 g, 4.22 mmol). The reaction mixture was sealed and heated to 30 oC for 48 hours. After LC-MS showed the starting material to be consumed, and ~ 20% dimethylation product was formed, the mixture was filtered through a pad of Celite® and the mass was washed with EtOAc. The combined filtrates were washed with water, brine, dried (Na2SO4) and the solvent removed to provide the crude product, which was purified by chromatography (silica, EtOAc / PE, 0% to 50%) to provide 3-methoxy-5- ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3R, 5R) -tert-butyl piperidine-1-carboxylate and 3-methoxy-5- (methyl (7 (3R, 5R) -tert-butyl-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (250 mg, 50%) as a white solid. LC-MS showed that the monomethylation and dimethylation ratio was ~ 1: 1. LC / MS (M + H) 590 and 604. Step 5. N - (((3R, 5R) -5-Methoxypiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4 -amine and N - ((3R, 5R) -5-methoxypiperidin-3-yl) -N-methyl-7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a solution of mono and dimethylated compound (250 mg, 0.36 mmol) in DCM (2 ml) was added 4 M HCl (g) / dioxane (2 ml) at 10 ~ 15 ° C. After stirring for 2 h, LC-MS showed that the reaction was complete. The reaction solution was concentrated to provide N - (((3R, 5R) -5-methoxypiperidin-3-yl) -7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine and N- ((3R, 5R) -5-methoxypiperidin-3-yl) -N-methyl-7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (208 mg, 100%), which were used directly in the next step without further purification. LC / MS (M + H) 490.1 and 504.1. Step 6. 1 - (((3R, 5R) -3-Methoxy-5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop- 2-en-1-one and 1 - ((3R, 5R) -3-Methoxy-5- (methyl (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin- 1-yl) prop-2- en-1-one. To a stirred solution of mono / dimethylated compound (208 mg, 0.36 mmol) in THF (5 mL) and saturated aqueous NaHCO3 solution (5 mL) was added acryloyl chloride (40 mg, 0.43 mmol) dropwise drop at 0 to 5 ° C. After the resulting mixture was stirred at 0 ~ 10 ° C for 2 hours, TLC (DCM / MeOH / NH4OH, 10: 1: 1) indicated the amine consumed completely. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (30 ml x 3), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to provide 1 - ((3R, 5R) -3- methoxy-5 - crude (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one and 1 - ((3R , 5R) -3-methoxy-5- (methyl (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2- en-1-one (240 mg, ~ 100%), which were used directly in the next step without further purification. Step 7. 1 - (((3R, 5R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-methoxypiperidin-1-yl) prop-2-en-1 -one and 1 - ((3R, 5R) -3-Methoxy-5- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en -1-one. A solution of mono / dimethylated compound (240 mg, 0.44 mmol) in TFA (3 ml) was stirred at room temperature (10 ~ 20 ° C) overnight. After TLC (DCM / MeOH / NH4OH, 10: 1: 1) shows ~ 30% of starting material left, the reaction was heated to 40 ° C for an additional 6 h, over which LC-MS showed that the starting material was consumed. The reaction solution was diluted with THF and concentrated to provide the crude product, which was purified by preparative HPLC directly to provide 1 - ((3R, 5R) -3 - ((7H-pyrrolo [2,3-d] pyrim- idin-4-yl) amino) -5-methoxypiperidin-1-yl) prop-2-en-1-one (32 mg, 24% for 3 steps) and 1- ((3R, 5R) -3-methoxy- 5- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one (25 mg) as a white solid. Pk1 (mono-Me): 1H NMR (400 MHz, DMSO-d6) δ 11.32 (br s, 1H), 8.14 (s, 1H), 7.13 - 6.94 (m, 2H), 6.69 (d, J = 16.1 Hz, 1H), 6.59 (br s, 1H), 6.07 (d, J = 15.6 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.40 (br s, 1H), 4.14 (br s, 1H), 3.65 (br s, 1H), 3.32 (s, 3H), 3.20 (d, J = 14.1 Hz, 2H), 2.15 (br s, 1H), 1.85 (br s, 1H). Pk2 (di-Me): 1H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 8.19 - 8.04 (m, 1H), 7.18 (d, J = 8 , 6 Hz, 1H), 6.85 - 6.69 (m, 1H), 6.68 - 6.53 (m, 1H), 6.10 (dd, J = 7.2, 16.6 Hz, 1H), 5.73 - 5.58 (m, 1H), 5.03 - 4.80 (m, 1H), 4.72 (d, J = 13.7 Hz, 1H), 4.45 (d , J = 11.7 Hz, 1H), 4.19 (d, J = 14.1 Hz, 1H), 4.03 (d, J = 12.1 Hz, 1H), 3.69 - 3.55 (m, 2H), 3.28 - 3.10 (m, 6H), 2.96 (t, J = 11.5 Hz, 1H), 2.78 - 2.68 (m, 1H), 2, 18 - 1.90 (m, 2H). Example 79: 1 - [(1S, 2S, 5S) -2- (7H-Pyrrolo [2,3-d] pyrimidin-4-ylamino) - 8-azabicyclo [3,2,1] oct-8-yl] prop-2-en-1-one. Prepared as described in Example 16, except pk2 after chiral separation is carried out by steps 3 and 4. Examples 80-87: The following compounds were prepared as in Example 41, using the appropriate acid or acid chloride.
Example 88: 1 - [(3R, 5R) -3- (Dimethylamino) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one. Prepared as in Example 57, except using the trans isomer. Step 1. (3R, 5R) -N3, N3-Dimethyl-N5- (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3,5-diamine
[077] To a solution of 3- (dimethylamino) -5 - ((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3R, 5R) piperidine-1-carboxylate - tert-butyl (300 mg, 0.498 mmol) in dioxane (15 mL) 4 N HCl / dioxane (10 mL) was added dropwise at 0 ° C and stirred at room temperature for 4 h. TLC (CH2Cl2 / MeOH = 10: 1) indicated that the reaction was complete. The reaction solution was concentrated to provide (3R, 5R) -N3, N3-dimethyl-N5- (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3,5-diamine crude (300 mg, 100%) as a yellow solid. Step 2. 1 - (((3R, 5R) -3- (Dimethylamino) -5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one. To a stirred solution of (3R, 5R) -N3, N3-dimethyl-N5- (7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-3,5-diamine (300 mg , 0.597 mmol) in THF (18 mL) and aqueous NaHCO3 solution (18 mL) at 0 ° C was added acryloyl chloride (59.4 mg, 0.657 mmol) dropwise. After the resulting mixture was stirred at 0 ° C for 2 hours, TLC (DCM / MeOH, 10: 1) indicated that the reaction was complete. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (30 ml x 2), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was used for the next step directly without further purification. Step 3. 1 - (((3R, 5R) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5- (dimethylamino) piperidin-1-yl) prop-2- en-1-one. 1 - (((3R, 5R) -3- (Dimethylamino) -5 - (((7-trityl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2 -en-1-one (170 mg, 0.305 mmol) in TFA (5 ml) was stirred at 30 ° C overnight. TLC (DCM / MeOH / NH4OH, 10: 1: 1) indicated that the starting material was completely consumed. The reaction mixture was concentrated in vacuo to provide the crude product, which was purified by chromatography (silica, MeOH / NH3 / DCM = 0-10%) and also purified by means of preparative HPLC to provide 1- ((3R , 5R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5- (dimethylamino) piperidin-1-yl) prop-2-en-1-one (59 mg , 61.4%) as a white solid. LC / MS (M + H) 315.2. 1H NMR (400 MHz, DMSO-d6) δ 11.26 (br s, 1H), 8.13 (s, 1H), 7.04 (br s, 1H), 6.81 (br s, 1H), 6.60 (br s, 2H), 5.98 (d, J = 15.8 Hz, 1H), 5.49 (br s, 1H), 4.47 (br s, 1H), 3.59 ( br s, 4H), 2.66 - 2.53 (m, 1H), 2.29 (s, 6H), 2.08 (br s, 1H), 1.87 (br s, 1H). Example 89: 1 - {(3aS, 7aS) -1- [5- (2-Methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] octahydro-6H-pyrrolo [2,3-c ] pyridin-6-yl} prop-2-en-1-one. Prepared as in Example 8, except using rac- (3aS, 7aS) -benzyl and 4-chloro-5- (2-methoxyethyl) hexahydro-1H-pyrrolo [2,3-c] pyridine-6 (2H) -carboxylate -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine in Step 7. LC / MS (M + H) 356.2. 1H NMR (400 MHz, CHCl3) δ 1.44 - 1.99 (m, 5 H) 2.42 - 2.58 (m, 1 H) 2.83-2.77 (m, 1 H) 2, 89 - 3.06 (m, 2 H) 3.24 - 3.38 (m, 4 H) 3.59-3.42 (m, 3 H) 3.98-3.91 (m, 1 H) 4.25 - 4.41 (m, 1 H) 4.45 - 4.65 (m, 2 H) 5.21 (dd, J = 9.37, 3.32 Hz, 1 H) 5.89 - 6.15 (m, 2 H) 6.95 (s, 1 H) 8.33 (br s, 1 H) 10.25 (br s, 1 H). Example 90: 1 - [(4aR, 8aS) -4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-2H-pyrido [4,3-b] [1,4] oxazin- 6 (5H) -yl] prop-2-en-1-one.
Step 1. 4- (7-Tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-2H-pyrido [4,3-b] [1,4] oxazine-6 (7H) - (4aR, 8aS) -tert-butyl carboxylate. To a vial containing hexahydro-2H-pyrido [4,3-b] [1,4] oxazine-6 (7H) - (4aR, 8aS) -tert-butyl carboxylate (500 mg, 2.06 mmol) and 4 -iodo-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (800 mg, 2.0 mmol) in n-butanol (2 mL) DIPEA (0.9 mL, 5 mmol) was added. The reaction was heated to 85 oC overnight and then poured into brine / ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 12 g, EtOAc / Hep) to provide 4- (7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-2H-pyrido [ 4,3-b] [1,4] oxazine-6 (7H) -carboxylate (4aR, 8aS) -tert-butyl (877 mg, 85%). Step 2. 1 - ((4aR, 8aS) -4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-2H-pyrido [4,3-b] [1,4] oxazin- 6 (7H) -yl) prop-2-en-1-one. Similar to Example 12 (steps 2-4). LC / MS (M + H) 314.2. 1H NMR (400 MHz, CHCl3) δ 1.70 - 2.07 (m, 2 H) 2.90 (t, J = 12.59 Hz, 1 H) 3.16 - 3.65 (m, 3 H ) 3.70 - 3.99 (m, 3 H) 4.15 (d, J = 8.98 Hz, 1 H) 4.36 (d, J = 11.13 Hz, 1 H) 4.48 - 4.87 (m, 2 H) 5.52 - 5.77 (m, 1 H) 6.32 (d, J = 16.79 Hz, 1 H) 6.44 - 6.70 (m, 2 H ) 7.13 (d, J = 3.71 Hz, 1 H) 8.18 - 8.42 (m, 1 H) 10.95 (br s, 1 H). Examples 91-107:
[078] Prepared as in Example 12, except for the final step, the corresponding acid or acid chloride was used.

Examples 108-111:
[079] Prepared as in Example 12, except in the final step, the corresponding acid or acid chloride was used.

Example 111: 1 - [(3aR, 7aR) -1- (5-Acetyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6 -il] prop-2-en-1-one. Step 1. 1 - [(3aR, 7aR) -1- (5-Acetyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6 -il] prop-2-en-1-one. To a vial containing 1 - ((3aR, 7aR) -1- (5-ethynyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin- 6 (2H) -yl) prop-2-en-1-one (30 mg, 0.1 mmol) was added acetonitrile / water 0.1% TFA (5 mL). The mixture was stirred at room temperature for 2 hours and then the solvent removed in vacuo to provide the crude product, which was purified by RP-HPLC to provide 1 - [(3aR, 7aR) -1- (5-acetyl -7H- pyrrolo [2,3-d] pyrimidin-4-yl) octahydro-6H-pyrrolo [2,3-c] pyridin-6-yl] prop-2- en-1-one (9.4 mg) . LC / MS (M + H) 340.2. Example 112: 1 - [(3S, 4R) -4-Methyl-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one . Prepared as in Example 11, Step 5. 1 - (((3R, 4S) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop -2-en-1-one (pk 1) and 1 - ((3S, 4R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1 -il) prop-2-en-1-one (pk 2). rac-1 - (((3R, 4S) -3 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1- one (120 mg) was separated by chiral chromatography to provide 1 - ((3R, 4S) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidine- 1-yl) prop-2-en-1-one (peak 1, 47.8 mg, 80%) as a white solid and 1 - ((3S, 4R) -3 - ((7H-pyrrole [2,3 -d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1-one (peak 2, 48.2 mg, 80%) as a white solid. Chiral SFC: ChiralPak AD (250 x 30 mm, 5 μm); 30% EtOH / NH4OH; 30% EtOH (0.05% NH3 in H2O) in CO2, 60 mL / min. Peak 1 data (Example 11): 1H NMR (400 MHz, DMSO-d6) δ 11.50 (br s, 1H), 8.08 (d, J = 14.3 Hz, 1H), 7.33 - 7.16 (m, 1H), 7.08 (br s, 1H), 6.88 - 6.72 (m, 1H), 6.59 (br s, 1H), 6.12 (d, J = 16.1 Hz, 1H), 5.68 (d, J = 10.5 Hz, 1H), 4.60 (d, J = 9.5 Hz, 1H), 4.43 (d, J = 12, 5 Hz, 1H), 4.21 (d, J = 10.5 Hz, 1H), 4.06 (d, J = 14.6 Hz, 1H), 3.93 - 3.71 (m, 1H) , 3.09 - 2.97 (m, 1H), 2.83 (t, J = 11.8 Hz, 1H), 2.66 (t, J = 12.8 Hz, 1H), 2.46 - 2.35 (m, 1H), 1.82 (d, J = 11.5 Hz, 2H), 1.28 - 1.13 (m, 1H), 0.94 (dd, J = 6.1, 11.7 Hz, 3H). LCMS (M + H) = 285.9. Peak 2 Data (Example 112): 1H NMR (400 MHz, DMSO-d6) δ 11.50 (br s, 1H), 8.09 (d, J = 14.1 Hz, 1H), 7.33 - 7.16 (m, 1H), 7.08 (br s, 1H), 6.89 - 6.72 (m, 1H), 6.59 (br s, 1H), 6.12 (d, J = 16.6 Hz, 1H), 5.68 (d, J = 10.3 Hz, 1H), 4.60 (d, J = 8.8 Hz, 1H), 4.43 (d, J = 13, 1 Hz, 1H), 4.21 (d, J = 10.5 Hz, 1H), 4.06 (d, J = 13.3 Hz, 1H), 3.93 - 3.70 (m, 1H) , 3.02 (t, J = 13.3 Hz, 1H), 2.83 (t, J = 11.7 Hz, 1H), 2.66 (t, J = 12.0 Hz, 1H), 2 , 42 (t, J = 11.5 Hz, 1H), 1.82 (d, J = 11.3 Hz, 2H), 1.30 - 1.12 (m, 1H), 0.94 (dd, J = 6.0, 11.5 Hz, 3H). LCMS (M + H) 285.9. Example 113: rac-1 - [(3S, 4S) -4-Hydroxy-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one. Prepared as in Example 5, except using rac- (3R, 4R) -tert-butyl amine (3-amino-4-hydroxypiperidine-1-carboxylate). 1 - [(3S, 4S) - 4-Hydroxy-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2- en-1-one. To a solution of rac- (3R, 4R) -3 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-4-ol (100 mg, 0.33 mmol) in DCM (5 ml) at 0 ° C DBU (0.20 ml, 1.3 mmol) was added, followed by acryloyl chloride (29.6 mg, 0.33 mmol). The reaction mixture was stirred at 60 ° C for 4 hours. The reaction mixture was concentrated and a portion of the crude material (50 mg) purified by RP-HPLC to provide rac-1- [(3S, 4S) -4-hydroxy-3- (7H-pyrrole [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one (5.0 mg). LC / MS (M + H) 288.2. Examples 114 and 115: Example 114: 1 - [(2S, 5S) -2-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2- en-1-one. Example 115: 1 - [(2R, 5R) -2-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one . Prepared as in Example 5, except using rac-trans- (2S, 5S) -tert-butyl 5-amino-2-methylpiperidine-1-carboxylate. Step 1. (2R, 5R) ((2R, 5R) -benzyl ((2R, 5R) -benzyl (2-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate) A mixture of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (266.5 mg, 1.425 mmol), DIPEA (613 mg, 4.75 mmol) and 5-amino-2-methylpiperidine-1 rac- (2R, 5R) -benzyl carboxylate (270 mg, 0.950 mmol) in n-BuOH (10 mL) was heated to 130 ° C overnight. LC-MS indicated that rac- (2R, 5R) -benzyl 5-amino-2-methylpiperidine-1-carboxylate was consumed completely. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo and the residue purified by chromatography (silica, PE / EA, 12% -100%) to provide 5 - ((2-chloro-7H-pyrrole [2 , 3-d] pyrimidin-4-yl) amino) -2-methylpiperidine-1-carboxylate (2R, 5R) -benzyl (290 mg, 76.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 7.57 (d, J = 5.8 Hz, 1H), 7.21 - 6.98 (m, 6H), 6.78 (br s, 1H), 5.04 - 4.92 (m, 1H), 4.92 - 4.79 (m, 1H), 4.34 (br s, 1H), 4.29 - 4.14 (m, 2H), 3.19 (d, J = 12.3 Hz, 1H), 2.27 - 2.12 (m, 1H), 2.08 - 1.95 (m, 1H) , 1.66 (d, J = 11.5 Hz, 1H), 1.44 - 1.30 (m, 1H), 1.22 - 1.10 (m, 3H). Step 2. N - (((3R, 6R) -6-Methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a Parr flask, 10% Pd / C (100 mg) was added under Ar atmosphere. Then, a solution of 5 - ((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4- il) (2R, 5R) -benzyl amino (-2R, 5R) -benzyl (290R, 0.727mmol) in MeOH (20ml) was added and the resulting mixture was hydrogenated under 3.16 kg / cm2 (45) psi) of H2 at 25 oC for 18 hours. After TLC (DCM / MeOH, 10: 1) indicates the starting material to be consumed, the reaction mixture was filtered and the filter mass was washed with MeOH. The combined filtrate was evaporated to provide rac-N - ((3R, 6R) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (180 mg, 100% ) as a white solid. Step 3. rac-1 - (((2R, 5R) -5 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en -1-one. To a stirred solution of rac-N- ((3R, 6R) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (130 mg, 0.563 mmol) in solution of Aqueous NaHCO3 (1 ml) and THF (1 ml) at 0 ° C were added acryloyl chloride (55.7 mg, 0.619 mmol) dropwise. After the addition, the resulting mixture was stirred at 0 ° C for 3 hours. TLC (CH2Cl2 / MeOH / NH4OH = 10: 1: 1) indicated that rac-N- ((3R, 6R) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4- amine was consumed completely. The reaction mixture was diluted with H2O (5 ml) and extracted with EtOAc (5 ml * 4), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by preparative TLC. provide rac-1 - (((2R, 5R) -5 - (((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1 -one (30 mg, 18.75%). Step 4. 1 - [(2S, 5S) -2-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one and 1 - [(2R, 5R) -2-methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one. rac-1- ((2R, 5R) -5 - (((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1- one was purified by chiral SFC to provide two peaks, arbitrarily assigned stereochemistry: Pk1, 1 - [(2S, 5S) -2-methyl- 5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin -1-yl] prop-2-en-1-one (5.1 mg) and Pk2, 1 - [(2R, 5R) -2-methyl-5- (7H-pyrrolo [2,3-d] pyrimidin -4-ylamino) piperidin-1-yl] prop-2-en-1-one (5.2 mg). SFC conditions: Column: ChiralPak IC 250 x 4.6 mm ID, 5 μm; Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL / min; Wavelength: 215 nm Pk1: 1H NMR (400 MHz, MeOH-d4) δ 8.15 (s, 1H), 7.06 (d, J = 3.5 Hz, 1H), 6.64 (d, J = 3.3 Hz, 1H), 6.28 (br s, 1H), 5.95 (br s, 1H), 5.34 (br s, 1H), 4.59 (br s, 1H), 4.38 (br s, 2H), 3.53 - 3.34 (m, 1H), 2.25 - 2.09 (m, 2H), 1.80 (br s, 1H), 1.57 - 1.45 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H). Pk2: 1H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 1H), 7.07 (d, J = 3.5 Hz, 1H), 6.65 (d, J = 3.3 Hz , 1H), 6.30 (br s, 1H), 5.96 (br s, 1H), 5.35 (br s, 1H), 4.59 (s, 1H), 4.50 - 4.22 (m, 2H), 3.52 - 3.34 (m, 1H), 2.23 - 2.17 (m, 2H), 1.89 - 1.76 (m, 1H), 1.57 - 1 , 48 (m, 1H), 1.29 (s, 3H). Example 116: Rac-1 - ((1R, 4R, 5S) -4- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-azabicyclo [3,2,1] octan-2- il) prop-2-en-1-one. For preparation of a similar ring system see (Tetrahedron, 2012, 68, 7848). Step 1. Rac- (1R, 3S, 4S) -methyl 2-benzyl-2-azabicyclo [2,2,1] heptane-3-carboxylate. To a Parr flask were added rac- (1S, 3S, 4R) 2-benzyl-2-azabicyclo [2,2,1] hept-5-ene-3-carboxylate (1.0 g, 4.11 mmol), EtOAc / HOAc (10: 1, 20 mL) and 10% Pd / C (50 mg). The reaction was stirred for 4 hours at 2.81 kg / cm2 (40 psi) of H2. The reaction was filtered through a pad of Celite® and the solvent removed to provide rac- (1R, 3S, 4S) 2-benzyl-2-azabicyclo [2,2,1] heptane-3-carboxylate -methyl (990 mg). GC / MS 245. 1H NMR (400 MHz, CHCl3) δ 1.16 - 1.51 (m, 3 H) 1.53 - 1.75 (m, 2 H) 1.89 - 2.08 (m, 2 H) 2.56 (d, J = 3.90 Hz, 1 H) 2.72 (s, 1 H) 3.36 (s, 1 H) 3.68 - 3.87 (m, 4 H) 7.12 - 7.45 (m, 5 H). Step 2. Rac - ((1R, 3S, 4S) -2-Benzyl-2-azabicyclo [2,2,1] heptan-3-yl) methanol. To a solution of rac- (1R, 3S, 4S) -methyl 2-benzyl-2-azabicyclo [2,2,1] heptane-3-carboxylate (2.2 g, 9.0 mmol) in THF (20 ml) at 0 ° C LAH (9.05 ml, 1 M in THF) was added. After the addition, the reaction was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was poured into 1 N NaOH / Et2O and the layers separated. The organic layer was collected and the aqueous layer extracted (2 x) with ethyl acetate. The organic extracts were combined, washed with brine and dried (Na2SO4). The solvent was removed to provide an oil (1.52 g, 78%), which was used without further purification. GC / MS 217. 1H NMR (400 MHz, CHCl3) δ 1.11 - 1.43 (m, 3 H) 1.51 - 1.72 (m, 2 H) 1.81 (d, J = 9, 76 Hz, 1 H) 1.95 - 2.12 (m, 1 H) 2.17 - 2.28 (m, 2 H) 3.17 - 3.38 (m, 2 H) 3.60 - 3 , 81 (m, 2 H) 4.16 (q, J = 7.15 Hz, 1 H) 7.18 - 7.41 (m, 5 H). Step 3. Rac- (1R, 4R, 5S) -4-azido-2-benzyl-2-azabicyclo [3,2,1] octane. To a vial containing rac - ((1R, 3S, 4S) -2-benzyl-2-azabicyclo [2,2,1] heptan-3-yl) methanol (2.0 g, 9.20 mmol) in DCM ( 150 ml) at room temperature Bu4N3 (2.97 g, 10.1 mmol) was added. The reaction was cooled to -78 ° C and Xtal-FluorE (2.37 g, 4.25 mmol) was added. The reaction mixture was allowed to warm to room temperature for 2 hours. After 2 hours, the reaction was quenched with 3.75 N NaOH (100 mL). The layers were separated and the organic layer collected, dried (Na2SO4) and the solvent removed to provide the crude product, which was purified by chromatography (silica, EtOAc / Hep, 5 to 45%) to provide rac- (1R, 4R, 5S) -4-azido-2-benzyl-2-azabicyclo [3.2.1] octane (1.0 g, 45%). GC / MS 242. 1H NMR (400 MHz, CHCl3) δ 1.08 - 1.51 (m, 3 H) 1.69 - 1.99 (m, 2 H) 2.15 (d, J = 11, 32 Hz, 1 H) 2.33 - 2.48 (m, 2 H) 2.73 (d, J = 13.27 Hz, 1 H) 3.19 (br s, 1 H) 3.34 - 3 , 60 (m, 3 H) 7.14 - 7.44 (m, 5 H). Step 4. Rac- (1R, 4R, 5S) -2-benzyl-2-azabicyclo [3,2,1] octan-4-amine. To a flask containing rac- (1R, 4R, 5S) -4-azido-2-benzyl-2-azabicyclo [3.2.1] octane (1.9 g, 7.84 mmol) was added THF: H2O ( 10: 1, 20 mL) and PPh3 (2.3 g, 8.62 mmol). The reaction was heated to 50 ° C overnight and then cooled to room temperature. The solvent was removed in vacuo to provide a white solid. The crude material was purified by chromatography (silica, MeOH / DCM / NH4OH (10: 1 MeOH / NH4OH), 5 to 20%) to provide rac- (1R, 4R, 5S) -2-benzyl-2-azabicycl [ 3.2.1] octan-4-amine (1.25 g, 73%) as an oil. GC / MS 216. 1H NMR (400 MHz, CHCl3) δ 1.12 - 1.47 (m, 3 H) 1.68 - 1.94 (m, 2 H) 2.06 (d, J = 12, 10 Hz, 1 H) 2.17 - 2.30 (m, 1 H) 2.36 - 2.52 (m, 2 H) 2.74 (br s, 1 H) 3.13 (t, J = 4.68 Hz, 1 H) 3.35 - 3.55 (m, 3 H) 7.15 - 7.45 (m, 5 H). Step 5. Rac-N - ((1R, 4R, 5S) -2-Benzyl-2-azabicyclo [3,2,1] octan-4-yl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-amine. To a flask containing rac- (1R, 4R, 5S) -2-benzyl-2-azabicyclo [3.2.1] octan-4-amine (1.23 g, 5.68 mmol) was added n-BuOH ( 10 ml), DIPEA (2.2 ml, 12.5 mmol) and 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (1.07 g, 5.69 mmol). The mixture was heated to 80 ° C overnight. The reaction mixture was concentrated and the residue diluted with DCM / H2O. The layers were separated and the aqueous layer extracted (2 x EtOAc). The organic extracts were combined, washed with brine, dried (Na2SO4) and the solvent removed to provide an oil, which after chromatography (silica, EtOAc / Hep, 80 to 100%) provided rac-N - ((1R, 4R , 5S) -2-benzyl-2-azabicyclo [3,2,1] octan-4-yl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (1.44 g, 68%). LC / MS (M + H) 368.1. 1H NMR (400 MHz, CHCl3) δ 1.24 - 1.34 (m, 2 H) 1.37 - 1.61 (m, 3 H) 1.71 (s, 2 H) 1.76 - 2, 04 (m, 4 H) 2.65 (br s, 3 H) 3.21 (br s, 1 H) 3.38 - 3.57 (m, 2 H) 4.16 (q, J = 7, 41 Hz, 1 H) 6.42 (br s, 1 H) 7.09 (br s, 1 H). Step 6. Rac-N - ((1R, 4R, 5S) -2-Azabicyclo [3,2,1] octan-4-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a round-bottomed flask containing rac-N - ((1R, 4R, 5S) -2-benzyl-2-azabicyclo [3,2,1] octan-4-yl) -2-chloro-7H-pyrrole [2 , 3-d] pyrimidin-4-amine (1.22 g, 3.3 mmol) were added EtOH (40 mL), 10% Pd / C (400 mg) and ammonium formate (1.08 g, 16 , 6 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction was filtered through a pad of Celite® and the solvent removed to provide rac-N - ((1R, 4R, 5S) -2-azabicyclo [3,2,1] octan-4-yl) -7H- pyrrolo [2,3-d] crude pyrimidin-4-amine, which was used without further purification. LC / MS (M + H) 244.1. 1H NMR (400 MHz, MeOH-d4) δ 1.29 - 1.63 (m, 4 H) 1.80 (d, J = 9.76 Hz, 1 H) 2.09 (d, J = 12, 10 Hz, 1 H) 2.69 (d, J = 3.90 Hz, 1 H) 2.84 (d, J = 14.05 Hz, 1 H) 3.29 (d, J = 4.68 Hz , 1 H) 3.49 (br s, 1 H) 4.04 (t, J = 4.10 Hz, 1 H) 6.65 (d, J = 3.51 Hz, 1 H) 7.12 ( d, J = 3.51 Hz, 1 H) 8.12 (s, 1 H). Step 7. Rac-1 - (((1R, 4R, 5S) -4 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-azabicyclo [3,2,1] octan -2-yl) prop-2-en-1-one. To a vial containing rac-N - ((1R, 4R, 5S) -2-azabicyclo [3,2,1] octan-4-yl) -7H-pyrrolo [2,3- d] pyrimidin-4-amine ( 129 mg, 0.53 mmol) in DCM at 0 ° C DIPEA (0.31 ml, 1.75 ml) was added. After 30 min, acryloyl chloride (59.3 mg, 0.64 mmol in 5 ml DCM) was added. The reaction was stirred at room temperature for 1 hour and then poured into water / DCM. The layers were separated and the aqueous layer extracted (2 x DCM). The organic extracts were combined, dried (Na2SO4) and the solvent removed to provide rac-1 - ((1R, 4R, 5S) -4- ((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino ) -2-azabicyclo [3,2,1] octan-2-yl) prop-2-en-1-one crude (110 mg), one portion (50 mg) was purified by RP-HPLC to provide (6, 5 mg) of pure material. LC / MS (M + H) 298.2. Example 117: 1 - [(2S, 5S) -2- (Hydroxymethyl) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one. Example 118: 1- [2- (Hydroxymethyl) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one. Example 118: Prepared as described in Example 7, except 5 - ((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2- (hydroxymethyl) piperidine-1 (2S, (55) enzila carboxylate (another cis isomer, pk 2) was performed through steps 7 - 10. LC / MS (M + H) 302.2.1H NMR (400 MHz, MeOH-d4 ) δ 1.72 - 2.22 (m, 4 H) 2.81 - 2.99 (m, 1 H) 3.65 - 3.85 (m, 2 H) 3.88 - 4.17 (m , 2 H) 4.25 - 4.45 (m, 1 H) 5.80 (d, J = 12.10 Hz, 1 H) 6.26 (d, J = 16.78 Hz, 1 H) 6 , 80 - 6.99 (m, 2 H) 7.39 (br s, 1 H) 8.21 - 8.40 (m, 1 H) Example 119: 1 - [(4aS, 8aS) -4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-2H-pyrido [4,3-b] [1,4] oxazin-6 (5H) -yl] prop-2-en-1 -one Prepared as in Example 1, except using (4aS, 8aS) -tert-butyl hexahydro-2H-pyrido [4,3- b] [1,4] oxazine-6 (7H) -tert-butyl instead of 3 - (R) -tert-butyl aminopiperidine-1-carboxylate LC / MS (M + H) 314.2.1H NMR (400 MHz, CHCl3) δ 1.32 - 1.58 (m, 2 H) 2 , 45 - 2.76 (m, 2 H) 3.46 - 3.95 (m, 3 H) 3.98 - 4.14 (m, 2 H) 4.80 (d, J = 12.49 Hz , 1 H) 5.10 (d, J = 12.88 Hz, 1 H) 5.74 (d, J = 11.52 Hz, 1 H) 6.22 - 6.57 (m, 2 H) 6.90 (dd, J = 16.88, 10.44 Hz, 1 H ) 7.08 - 7.29 (m, 2 H) 8.50 (s, 1 H) 9.98 (br s, 1 H). Example 120: 1- (4 - {[(3S, 4R) -1-Acryloyl-4-fluoropiperidin-3-yl] amino} -7H-pyrrolo [2,3-d] pyrimidin-5-yl) prop-2 -en-1-one. Example 121: rac-1 - ((2R, 3S) -3 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en -1-one. Prepared as in Example 12, except rac- (2R, 3S) -benzyl 3-amino-2-methylpiperidine-1-carboxylate was used instead of (R) -tert-butyl 3-aminopiperidine-1-carboxylate. LC / MS (M + H) 286.4. Example 122: 1 - ((3aR, 7aR) -3a-Methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -yl) prop-2-en-1-one. 1- ((3aR, 7aR) -3a-methyl-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) hexahydro-1H-pyrrolo [2,3-c] pyridin-6 (2H) -il) prop-2-en-1-one was prepared as in Example 59, except using (4 - ((3aS, 7aR) -6-benzyl-3a-methyloctahydro-1H-pyrrolo [2,3-c] pyridin -1-yl) -7H-pyrrolo [2,3-d] pyrimidine in Step 5. LC / MS (M + H) 312.2 Example 123: 1 - [(5S) -2,2-Dimethyl-5 - (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one. For preparation, see Example 61 and Example 67. Examples 124 and 125: Example 124: 1 - [(2R, 5R) -2-Ethyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one. Example 125: 1 - [(2S, 5S) -2-Ethyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one Prepared as Example 9 for cis derivative, starting from optically pure trans-amines isolated by chiral SFC (Peaks 1 and 2) Pk1: 1 - [(2R, 5R) -2-ethyl-5- (7H-pyrrole [2 , 3- d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one LC / MS (M + H) 300.3.1HNMR appeared to show two sets of signals possibly derived from script eros at room temperature. 1HNMR at 345 K: (500 MHz, DMSO-d6) δ 11.22 (br s, 1H), 8.05 (br s, 1H), 6.96 - 6.94 (m, 1H), 6.69 - 6.63 (m, 1H), 6.58 - 6.55 (m, 1H), 6.35 (s, 1H), 5.82 - 5.78 (m, 1 H), 5.30 - 5.28 (m, 1H), 4.30 - 4.24 (m, 3H), 3.07 (apparent br s, water + 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.62 (m, 2H), 1.55 - 1.35 (m, 2H), 0.75 (t, J = 10 Hz, 3H). Pk2: 1 - [(2S, 5S) -2-ethyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one. LC / MS (M + H) 300.3. 1H NMR at 345 K: (500 MHz, DMSO-d6) δ 11.22 (br s, 1H), 8.05 (br s, 1H), 6.96 - 6.94 (m, 1H), 6, 69 - 6.63 (m, 1H), 6.58 - 6.55 (m, 1H), 6.35 (s, 1H), 5.82 - 5.78 (m, 1 H), 5.30 - 5.28 (m, 1H), 4.30 - 4.24 (m, 3H), 3.07 (apparent br s, water + 1H), 2.05 (m, 1H), 1.95 (m , 1H), 1.62 (m, 2H), 1.55 - 1.35 (m, 2H), 0.75 (t, J = 10 Hz, 3). Examples 126 and 127: Example 126: 1 - ((1S, 4S, 5R) -4- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-azabicyclo [3,2,1] octan -2-yl) prop-2-en-1-one. Example 127: 1 - ((1R, 4R, 5S) -4- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-azabicyclo [3,2,1] octan-2-yl) prop-2-en-1-one. Examples 126 and 127 were prepared by purifying the racemic product of Example 116 by chiral RP-HPLC (IA, 21 x 250 mm, 5 µm, CO2 / 0.1% NH4OH in EtOH, 80:20 A / B retained for 10 min, 40 oC, 75 mL / min), arbitrarily assigned absolute stereochemistry. Pk1: room temperature = 5.67 min (IA, 4.6 x 100 mm, 5 µm, CO2 / 0.1% NH4OH in EtOH, 800: 20 retained for 10 min), Example 126: LC / MS (M + H) 297.9. Pk2: room temperature = 5.72 min (the same as above), Example 127: LC / MS (M + H) 297.9. Example 128: 1 - [(3R, 5S) -3-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one . For preparation of 1- [(3R, 5S) -3-methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1-one , see Example 14, Step 8. Peak 2: 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.10 (d, J = 14.6 Hz, 1H), 7, 38 - 7.23 (m, 1H), 7.08 (br s, 1H), 6.94 - 6.79 (m, 1H), 6.56 (br s, 1H), 6.12 (dd, J = 7.8, 16.8 Hz, 1H), 5.75 - 5.64 (m, 1H), 4.71 (d, J = 11.8 Hz, 1H), 4.49 - 4.30 (m, 1H), 4.03 (d, J = 11.5 Hz, 1H), 2.81 - 2.54 (m, 1H), 2.42 - 2.15 (m, 1H), 2, 06 (d, J = 12.3 Hz, 1H), 1.62 (br s, 1H), 1.38 - 1.18 (m, 1H), 0.99 - 0.88 (m, 3H). LCMS (M + H) 285.9. Example 129: rac-1 - [(2S, 5R) -2-Methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one. For the preparation of rac-1- [(2S, 5R) -2-methyl-5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one, see Example 5, Step 8. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 7.30 (dd, J = 6.8, 18.8 Hz, 1H), 7.10 (br s, 1H), 6.89-6.71 (m, 1H), 6.56 (d, J = 1, 8 Hz, 1H), 6.10 (dd, J = 2.1, 16.7 Hz, 1H), 5.72-5.61 (m, 1H), 4.81 (br s, 0.5H) , 4.56 (d, J = 10.3 Hz, 0.5H), 4.37 (br s, 0.5H), 4.20 - 3.95 (m, 1.5H), 2.96 ( t, J = 11.9Hz, 0.5H), 2.60 (t, J = 12.0 Hz, 0.5H), 1.92 - 1.59 (m, 4H), 1.30 - 1, 07 (m, 3H). Example 130: 1 - {(3R, 4R) -4-Methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} prop-2-en -1-one. Prepared as in Example 12, Step 4, except using N-methyl-N - ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as amine partner. LC / MS (M + H) 300.1. 1H NMR (400 MHz, DMSO-d6) δ 0.82 - 1.19 (m, 3 H) 1.49 - 1.85 (m, 2 H) 2.41 (br s, 1 H) 3.34 (s, 3 H) 3.39 - 4.08 (m, 4 H) 4.86 (br s, 1 H) 5.48 - 5.78 (m, 1 H) 6.12 (d, J = 16.39 Hz, 1 H) 6.56 (br s, 1 H) 6.74 - 6.93 (m, 1 H) 7.14 (br s, 1 H) 8.10 (s, 1 H) 11.66 (br s, 1 H). Example 131: 1 - [(1S, 6R) -8- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [4,2,0] oct-3-yl] prop-2-en-1-one. Prepared as in Example 12, except using (1S, 6R) 3-diazabicyclo [4,2,0] octane-3-carboxylate in Step 1. LC / MS (M + H) 284.1 . Example 132: rac-1 - [(3S, 4S) -4-Methyl-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one. Prepared as in Example 12, except using rac- (3R, 4R) -tert-butyl 3-amino-4-methylpiperidine-1-carboxylate in Step 1. LC / MS (M + H) 286.2. 1H NMR (400 MHz, DMSO-d6) δ 0.97 (d, J = 6.87 Hz, 3 H) 1.39 - 1.63 (m, 1 H) 1.84 (d, J = 10, 44 Hz, 1 H) 2.00 - 2.22 (m, 1 H) 2.89 (t, J = 10.30 Hz, 1 H) 3.98 - 4.19 (m, 1 H) 4, 26 - 4.52 (m, 1 H) 5.33 (d, J = 9.34 Hz, 1 H) 5.66 (d, J = 8.79 Hz, 1 H) 5.89 (d, J = 16.21 Hz, 1 H) 6.06 (d, J = 15.66 Hz, 1 H) 6.33 (dd, J = 16.76, 10.44 Hz, 1 H) 6.60 - 6 , 87 (m, 2 H) 7.07 (br s, 1 H) 7.97 - 8.21 (m, 1 H) 11.46 (br s, 1 H). Example 133: 1 - {(3R) -3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} prop-2-en-1-one. Prepared as in Example 12, except using (R) - tert-butyl 3- (methylamino) piperidine-1-carboxylate in Step 1. LC / MS (M + H) 285.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49-1.53 (m, 1 H), 1.80-1.82 (d, J = 9.28 Hz, 2 H), 1.90 -1.95 (m, 1 H), 2.55-2.63 (m, 1 H), 2.85-2.90 (t, J = 11.48 Hz, 0.5 H), 2, 99-3.04 (t, J = 12.7 Hz, 0.5 H), 3.22-3.24 (d, J = 11.72 Hz, 3 H), 4.03 (m, 1 H ), 4.44 (m, 1 H), 4.67 (m, 1 H), 5.64-5.69 (t, J = 13.2 Hz, 1 H), 6.09-6.12 (dd, J = 2,0,16,7 Hz, 1 H), 6,55-6,57 (d, J = 9,28 Hz, 1 H), 6,75-6,84 (m, 1 H), 7.13 (t, 1 H), 8.06-8.11 (m, 1 H), 11.65 (br s, 1 H). Example 134: 1 - [(1R, 6S) -8- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [4,2,0] oct-3-yl] prop-2-en-1-one. Prepared as in Example 12, except using 3,8-diazabicyclo [4,2,0] octane-3-carboxylate (1R, 6S) -tert-butyl in Step 1. LC / MS (M + H) 284.1 . Examples 135 and 136: Example 135: (2E) -1 - [(3R) -3 - {[5- (2-Methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] (methyl) amino} -piperidin-1-yl] but-2-en-1-one. Example 136: 1 - [(3R) -3 - {[5- (2-Methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] (methyl) amino} piper-idin-1-yl ] prop-2-en-1-one. Prepared as in Example 12, except using (R) -tert-butyl 3- (methylamino) piperidine-1-carboxylate and 4-chloro-5- (2-methoxyethyl) -7-tosyl-7H-pyrrole [2 , 3- d] pyrimidine in Step 1 and for Step 4, (E) -but-2-enoic acid and acrylic acid were used in combination with EDCI / DIEA / DCM. Ex 135: LC / MS (M + H) 358.1. Ex 136: LC / MS (M + H) 344.1. Example 137: 1 - [(3R) -3 - {[5- (4-Hydroxybenzyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] prop-2- en-1-one. Prepared as in Example 12, except using 5- (4- (benzyloxy) benzyl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidine in step 1 and the additional step of removing benzyl protecting group after displacement of chlorine. For Step 4, acrylic acid was used in combination with EDC / DIPEA / DMAP / DMF. LC / MS (M + H) 378.1. Example 138: (2E) -1 - [(3R) -3 - {[5- (4-Hydroxybenzyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] but-2-en-1-one. Prepared as in Example 12, except using 5- (4- (benzyloxy) benzyl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidine in Step 1 and the additional step of removing benzyl protecting group after displacement of chlorine. For Step 4, (E) -but-2-enoic acid was used in combination with EDC / DIPEA / DMAP / DMF. Ex 138: LC / MS (M + H) = 392.0. Example 139: 1 - [(3R) -3 - {[5- (4-hydroxybenzyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] -2-methylprop -2-en-1-one. Pre-stopped as in Example 12, except using 5- (4- (benzyloxy) benzyl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidine in step 1 and the additional step of removing protection group benzyl after displacement of chlorine. For Step 4, (E) -but-2-enoic acid was used in combination with EDC / DIPEA / DMAP / DMF. Ex 139: LC / MS (M + H) 392.3. Examples 140-148:
[080] Examples 140-148 were prepared according to the diagram below
Example 140 Step 1. 4-Chloro-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide. To a flask were added 4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-carboxylic acid (200 mg, 1.01 mmol), dimethyl amine (82.5 mg, 1.01 mmol) and CH3CN (2 mL). After 10 min, HATU (476 mg, 1.21 mmol) and DIEA (0.44 mL, 2.43 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then poured into water / DCM. The layers were separated and the organic extract washed with water, brine and dried (Na2SO4). The solvent was removed to provide the crude, which was purified by chromatography (silica, MeOH / DCM, 0 to 10%) to provide 4-chloro-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine- 5-carboxamide (100 mg, 44%). LC / MS (M + H) 225.1. Step 2. 3 ((R) -tert-butyl ((5- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a microwave tube containing 4-chloro-N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (100 mg, 0.44 mmol) in dioxane / water (2 mL / 0.5 ml) (R) -tert-butyl 3-aminopiperidine-1-carboxylate (267 mg, 1.34 mmol) and K2CO3 (123 mg, 0.89 mmol) were added. The reaction mixture was heated to 120 ° C overnight and then allowed to cool. The mixture was poured into EtOAc / water and the layers were separated and the organic extract washed with water, brine and dried (Na2SO4). The solvent was removed to provide the crude, which was purified by chromatography (silica, EtOAc / Hep, 90 to 100%) to provide 3 - ((5- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- (R) -tert-butyl 4-yl) amino) piperidine-1-carboxylate (75 mg, 43%). LC / MS (M + H) 389.3. Step 3. (R) -N, N-Dimethyl-4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide. One vial containing (R) -tert-butyl 3 - ((5- (dimethylcarbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -piperidine-1-carboxylate (70 mg, 0 , 18 mmol) in DCM (2 mL) was treated with 4 N HCl in dioxane (0.360 mL, 1.44 mmoL). The reaction was stirred at room temperature for 2 hours and then the solvent was removed to provide (R) -N, N-dimethyl-4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine -5-carboxamide (50 mg, 70%). Step 4. (R) -4 - ((1-acryloylpiperidin-3-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide.
[081] To a vial containing (R) -N, N-dimethyl-4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (40 mg, 0.14 mmol ) in DMF (2 ml) were added acrylic acid (0.01 ml, 0.12 mmol), EDCI (47 mg, 0.23 mmol) and DIEA (0.06 ml, 0.35 mmol). The reaction was stirred at room temperature for 2 hours and then poured into water / ethyl acetate. The layers were separated and the organic extract washed with water, dried (Na2SO4) and the solvent removed to provide (R) -4 - ((1-acryloylpiperidin-3-yl) amino) -N, N-dimethyl-7H-pyrrole [2,3-d] crude pyrimidine-5-carboxamide, which was purified by RP-HPLC to provide pure product (48 mg, 63%). LC / MS (M + H) 343.3.

Example 151: (2E) -1 - [(3R) -3 - {[5- (2-hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] but-2-en-1-one. Step 1. 3 ((R) ((5- ((5- (2 - ((tert-butyldimethylsilyl) oxy) ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate -tert-butyl. To a vial containing 5- (2 - ((tert-butyldimethylsilyl) oxy) ethyl) -4-chloro-7H-pyrrolo [2,3-d] pyrimidine (1.0 g, 3.2 mmol) in dioxane / water (10 ml / 6 ml) (R) -tert-butyl 3-aminopiperidine-1-carboxylate and K2CO3 (1.33 g, 9.6 mmol) were added. The mixture was heated to 100 ° C for 30 hours and cooled to room temperature. The reaction was poured into ethyl acetate / brine and the layers separated. The organic extract was collected, dried (Na2SO4) and the solvent removed to provide an oil, which after chromatography (silica, MeOH / DCM, 0 to 10%) provided 3 - ((5- (2 - ((tert-butyldimethylsily) -oxy) ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) -tert-butyl piperidine-1-carboxylate (914 mg, 60%). LC / MS (M + H) 476.5. Step 2. (R) -2- (4- (Piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethanol. To a vial containing 3 - ((5- (2 - (((tert-butyldimethylsilyl) oxy) ethyl) - 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) piperidine-1-carboxylate ) - tert-butyl (914 mg, 1.92 mmol) dioxane (8 mL) was added followed by 4 M HCl / dioxane (3 mL). The reaction mixture was stirred for 4 hours. Ether was added, and the solid filtered to provide (R) -2- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethanol (750 mg) as the HCl salt. LC / MS (M + H) 262.3. Step 3. (2E) -1 - [(3R) -3 - {[5- (2-Hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] but-2-en-1-one. To a vial containing (R) -2- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethanol (100 mg, 0.38 mmol) in DCM ( 3 mL) were added trans-crotonic acid (27 mg, 0.30 mmol), EDCI (81.5 mg, 0.42 mmol), DIEA (0.67 mL, 3.83 mmol) and DMAP (2.30 mg, 0.02 mmol). The reaction mixture was stirred for 3 hours, and then poured into water / DCM. The layers were separated and the organic extract dried (Na2SO4) and the solvent removed to provide 114 mg of crude material, which was purified by chromatography (silica, MeOH / DCM, 0 to 10%) and then RP-HPLC to provide ( 2E) -1 - [(3R) -3 - {[5- (2-hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] but-2- en-1-one (26 mg, 21%). LC / MS (M + H) 330.3. 1H NMR (400 MHz, DMSO-d6) δ 1.33 - 1.86 (m, 5 H) 2.77 (m, 2 H) 2.86 - 3.20 (m, 2 H) 3.54 - 3.79 (m, 3H) 3.84 - 4.21 (m, 2 H) 5.05 - 5.46 (m, 1 H) 6.21 - 6.63 (m, 2 H) 6.84 (s, 1 H) 6.96 - 7.31 (m, 1 H) 8.04 (br s, 1 H) 11.25 (br s, 1 H). Example 152: 1 - [(3R) -3 - {[5- (2-Hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl] -2-methylprop -2-en-1-one. Prepared as in Example 151, except using methacrylic acid in Step 3. LC / MS (M + H) 330.3. Example 153: 2-Methyl-1 - [(3R) -3- (3-methyl-3,4-dihydro-1,5,6,8-tetraazaacenaftilen-5 (1H) -yl) piperidin-1-yl] prop-2-en-1-one. Step 1. 3 ((((5-Bromo-7 - (((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate R) -tert-butyl. To a solution of 5-bromo-4-chloro-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3- d] pyrimidine (2.0 g, 5.5 mmol) in dioxane / water (10 mL: 5 mL) (R) -tert-butyl 3-aminopiperidine-1-carboxylate (2.21 g, 11.0 mmol) and K2CO3 (1.52 g, 11.0 mmol) were added . The reaction mixture was heated to 100 ° C for 72 hours and then cooled to room temperature. The reaction mixture was diluted with water (10 ml) and the aqueous mixture extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was removed to provide an oil, which after chromatography (silica, EtOAc / Hep, 0 to 50%) provided 3 - ((5-bromo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrole (R) -tert-butyl [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (600 mg, 41%). LC / MS (M + H) 528.3. 1H NMR (400 MHz, CDCl3) δ -0.26 - -0.01 (m, 9 H) 0.69 - 0.91 (m, 2 H) 1.29 (s, 9 H) 1.51 - 1.93 (m, 4 H) 3.12 - 3.31 (m, 1 H) 3.38 - 3.51 (m, 2 H) 3.53 (d, J = 14.05 Hz, 3 H ) 4.29 (br s, 1 H) 5.36 - 5.54 (m, 2 H) 6.11 (d, J = 7.61 Hz, 1 H) 6.87 - 7.03 (m, 1 H) 8.17 - 8.30 (m, 1 H). Step 2. 3- (Allyl (5-bromo-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (R) -tert-butyl. To a vial containing 3 - ((5-bromo-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (R) -tert-butyl (100 mg, 0.19 mmol) in THF (4 mL) NaH (8.4 mg, 0.21 mmol) was added. After 15 min, allyl iodide (64 mg, 0.38 mmol) was added and the reaction stirred at 40 ° C for 2 hours. The mixture was poured into water / EtOAc and the layers separated. The organic layer was collected, dried (Na2SO4) and the solvent removed to provide 3- (allyl (5-bromo-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin -4- yl) amino) (R) -tert-butyl amino) piperidine-1-carboxylate. LC / MS (M + H) 568.3. 1H NMR (400 MHz, CDCl3) δ -0.22 - -0.01 (m, 9 H) 0.72 - 0.96 (m, 3 H) 1.15 - 1.46 (m, 11 H) 2.65 (t, J = 11.81 Hz, 1 H) 2.92 - 3.07 (m, 1 H) 3.30 - 3.60 (m, 2 H) 3.93 - 4.35 ( m, 6 H) 5.04 (d, J = 10.15 Hz, 1 H) 5.21 (d, J = 17.18 Hz, 1 H) 5.44 - 5.59 (m, 2 H) 5.79 - 5.99 (m, 1 H) 7.13 - 7.23 (m, 1 H) 8.36 (s, 1 H). Step 3. 3- (3-Methylene-1 - ((2- (trimethylsilyl) ethoxy) methyl) -3,4-dihydro-1,5,6,8-tetraazaacenaphthilen-5 (1H) -yl) piperidine-1 (R) -tert-butyl carboxylate. To a vial containing 3- (ally (5-bromo-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate of (R) -tert-butyl (400 mg, 0.71 mmol) DMF (5 mL), KOAc (173 mg, 1.76 mmol) and Pd (PPh3) 4 (83.7 mg, 0.07 mmol). The flask was heated to 85 ° C for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water (10 ml) and the aqueous mixture extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (Na2SO4) and the solvent removed to provide the crude product, which after chromatography (silica, EtOAc / Hep, 0 to 25%) provided two main fractions, F1: 3- (3 -methyl-3,4-dihydro-1,5,6,8-tetraazaacenaftilen-5 (1H) -yl) piperidine-1-carboxylate of (R) -tert-butyl and F2: 3- (3-methyl-1 , (R) -tert-butyl, 5,6,8-tetraazaacenaftilen-5 (1H) -yl) piperidine-1-carboxylate. F1: LC / MS (M + H) 486.3. F2: LC / MS (M + H) 486.3. Step 4. 3- (3-Methyl-1 - ((2- (trimethylsilyl) ethoxy) methyl) -3,4-dihydro-1,5,6,8-tetraaza-acenaftilen-5 (1H) -yl) piperidine (3R) -tert-butyl -1-carboxylate. To a Parr flask containing 3- (3-methylene-3,4-dihydro-1,5,6,8-tetraazaacenaftilen-5 (1H) -yl) piperidine-1-carboxylate (420) mg, 0.86 mmol) ethanol (10 mL) and 10% Pd / C (104.8 mg) were added. The reaction was stirred at room temperature at 2.81 kg / cm2 (40 psi) of H2 for 3 hours and then filtered through a pad of Celite®. The pad was washed with methanol and the solvent removed to provide 3- (3-methyl-3,4-dihydro-1,5,6,8-tetrazaza-acenaftilen-5 (1H) -yl) piperidine-1- (3R) -tert-butyl carboxylate (422 mg, 100%), which was used without further purification. LC / MS (M + H) 488.5. Step 5. 3-Methyl-5 - ((R) -piperidin-3-yl) -1,3,4,5-tetrahydro-1,5,6,8-tetra-aza-acenaftylene. To a vial containing 3- (3-methyl-1 - ((2- (trimethylsilyl) ethoxy) methyl) -3,4-dihydro-1,5,6,8-tetra-aza-acenaftilen-5 (1H) - il) (3R) -tert-butyl piperidine-1-carboxylate (422 mg, 0.86 mmol) were added DCM (10 mL) and TFA (5 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in methanol and then NH4OH (10 ml) was added. The mixture was stirred for 3 hours at room temperature and the solvent removed in vacuo and the residue purified by chromatography (silica, MeOH / DCM, 0 to 10%) to provide 3-methyl-5 - ((R) -piperidin -3-yl) -1,3,4,5-tetrahydro-1,5,6,8-tetra-aza-acenaphthene (300 mg, 135% contaminating salt). LC / MS (M + H) 258.3. Step 6. 2-Methyl-1 - ((3R) -3- (3-methyl-3,4-dihydro-1,5,6,8-tetra-aza-acenaftilen-5 (1H) -yl) piperidin- 1-yl) prop-2-en-1-one. To a vial containing 3-methyl-5 - ((R) -piperidin-3-yl) -1,3,4,5-tetrahydro-1,5,6,8-tetra-aza-acenaftylene (75 mg, 0 , 29 mmol) THF (5 mL) and TEA (0.1 mL, 0.58 mmol) were added. The mixture was cooled to 0 ° C and then methacryloyl chloride (30.4 mg, 0.29 mmol) was added. After stirring at room temperature for 5 hours, the reaction was diluted with ethyl acetate / water. The layers were separated and the organic layer collected, dried (Na2SO4) and the solvent removed to provide crude material, which after chromatography (silica, MeOH / DCM, 0 to 15%) provided 2-methyl-1 - ((3R ) -3- (3-methyl-3,4-dihydro-1,5,6,8-tetra-aza-acenaftilen-5 (1H) -yl) piperidin-1-yl) prop-2-en-1- one (5.0 mg, 5%). LC / MS (M + H) = 326.4. 1H NMR (400 MHz, CDCl3) δ 1.11 - 1.34 (m, 3 H) 1.54 - 2.11 (m, 8 H) 2.82 - 3.28 (m, 3 H) 3, 41 - 3.65 (m, 1 H) 3.88 - 4.25 (m, 1 H) 4.54 (br s, 2 H) 4.94 - 5.19 (m, 2 H) 6.66 (s, 1 H) 8.33 (br s, 1 H) 9.47 (br s, 1 H). Example 154: (2E) -1 - [(3R) -3- (3-methyl-3,4-dihydro-1,5,6,8-tetra-aza-acenaftilen-5 (1H) -yl) piper- idin-1-yl] but-2-en-1-one. Prepared as in Example 153, except for Step 6 where transcrotonyl chloride was used instead of methacryloyl chloride. LC / MS (M + H) 326.4. Example 155: 1 - [(3R) -3- (3-Methyl-3,4-dihydro-1,5,6,8-tetra-aza-acenaftilen-5 (1H) -yl) piperidin-1-yl] prop-2-en-1-one. Prepared as in Example 153, except for Step 6 where acryloyl chloride was used instead of methacryloyl chloride. LC / MS (M + H) 312.2. Example 156: 4 - {[(3R) -1-Acryloylpiperidin-3-yl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile. Step 1. (R) -4 - ((1-Benzylpiperidin-3-yl) amino) -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile. To a microwave tube were added 4-chloro-1H-pyrrolo [2,3-b] pyridine-5-carbonitrile (172 mg, 0.97 mmol), (R) -1- benzyl-piperidin-3- amine (553 mg, 2.91 mmol) and NMP (0.5 ml). The mixture was heated to 130 ° C for 2 h and then cooled to room temperature. The mixture was diluted with water / ethyl acetate and the layers separated. The organic extract was washed with water, dried (Na2SO4) and the solvent removed to provide the crude, which after chromatography (silica, EtOAc / Hep, 0 to 100%) provided (R) -4 - ((1- benzylpiperidin-3 -yl) amino) -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile (249 mg, 77%). LC / MS (M + H) 332.3. 1H NMR (400 MHz, DMSO-d6) δ 1.39 - 1.80 (m, 5 H) 2.38 (br s, 2H) 2.56 - 2.73 (m, 1 H) 3.50 ( s, 2 H) 4.23 (br s, 1 H) 6.44 (d, J = 8.59 Hz, 1 H) 6.55 (dd, J = 3.71, 1.95 Hz, 1 H ) 7.10 - 7.40 (m, 6 H) 8.04 (s, 1 H) 11.77 (br s, 1 H). Step 2. (R) -4- (Piperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile. To a flask containing (R) -4 - ((1-benzylpiperidin-3-yl) amino) -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile (155 mg, 0.47 mmol) was added ethanol (3 mL), ammonium formate (296 mg, 4.68 mmol) and Pd (OH) 2 (32.3 mg, 0.02 mmol). The mixture was heated to 100 ° C for 2 hours and then cooled to room temperature. The mixture was filtered through Celite® and the solvent removed to provide the crude, which after chromatography (silica, MeOH / DCM 0 to 40%) gave (R) -4- (piperidin-3-ylamino) -1H-pyrrole [ 2,3-b] pyridine-5-carbonitrile (71 mg, 63%). LC / MS (M + H) 242.3. Step 3. 4 - {[(3R) -1-Acryloylpiperidin-3-yl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile. To a flask containing (R) -4- (piperidin-3-ylamino) -1H-pyrrolo [2,3-b] pyridine-5-carbonitrile (25 mg, 0.1 mmol) were added THF (1 mL) and TEA (30 μL, 0.2 mmol). The mixture was cooled to 0 ° C and then acryloyl chloride (7.5 μL, 0.10 mmol) was added and the reaction stirred for 1 hour. The mixture was diluted with water / ethyl acetate and the layers separated. The organic extract was washed with water, brine and dried (Na2SO4). The solvent was removed in vacuo to provide the crude, which after chromatography (silica, MeOH / DCM, 0 to 15%) provided 4 - {[(3R) -1-acryloylpiperidin-3-yl] amino} - 1H-pyrrole [ 2,3-b] pyridine-5-carbonitrile (17 mg, 55%). LC / MS (M + H) 296.2. 1H NMR (400 MHz, DMSO-d6) δ 1.47 (br s, 1 H) 1.61 - 1.79 (m, 2 H) 1.92 - 2.14 (m, 1 H) 2.64 - 3.21 (m, 2 H) 3.76-4.26 (m, 2 H) 4.43 (d, J = 11.13 Hz, 1 H) 5.45-5.70 (m, 1 H) 5.92 - 6.19 (m, 1 H) 6.44 - 6.89 (m, 3 H) 7.23 (br s, 1 H) 7.90 - 8.10 (m, 1 H ) 11.81 (br s, 1 H). Example 157: 3- [4 - ({(3R) -1 - [(2E) -4- (Dimethylamino) but-2-enoyl] piperidin-3-yl} amino) -7H-pyrrole [2,3-d ] pyrimidin-5-yl] propanonitrile. Step 1. (R) -tert-butyl (- ((5- (2-cyanoethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate. To a vial containing 3 ((5- (2-hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) -tert-butyl piperidine-1-carboxylate (400 mg , 1.11 mmol) in DCM (6.0 mL) at 0 ° C, CH3SO2Cl (0.10 mL, 1.33 mmol) and DIPEA (0.6 mL, 3.32 mmol) were added. The mixture was stirred at 0 ° C for 30 minutes and then poured into water / DCM. The layers were separated and the organic extracts collected and dried (Na2SO4). The solvent was removed to provide 3 - ((5- (2- ((methylsulfonyl) oxy) ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (R) piperidine-1-carboxylate ) crude tert-butyl (540 mg), which was used in the next step without purification. Ao (R) -tert-butyl 3 - ((5- (2 - ((methylsulfonyl) oxy) ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate crude (540 mg, 1.23 mmol) DMF (5 mL) and NaCN (303 mg, 6.1 mmol) were added. The reaction was stirred at 50 ° C for 30 minutes and then poured into water / ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to provide the crude, which after chromatography (silica, 0 to 5% MeOH / DCM) provided 3 - ((5- (2-cyanoethyl) -7H-pyrrolo [2,3-d] pyrimidin-4- il) (R) -tert-butyl amino) piperidine-1-carboxylate (302 mg, 66%). LC / MS (M + H) 371.4. Step 2. (R) -3- (4- (Piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile. To a vial containing (R) -tert-butyl 3 - ((5- (2-cyanoethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate (302 mg , 0.82 mmol) were added DCM (2 mL) and TFA (0.32 mL). The mixture was stirred at room temperature for 4 hours and the solvent removed to provide (R) -3- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile crude, which was used without further purification. LC / MS (M + H) 271.3. Step 3. 3- [4 - ({(3R) -1 - [(2E) -4- (Dimethylamino) but-2-enoyl] piperidin-3-yl} amino) -7H-pyrrole [2,3-d ] pyrimidin-5-yl] propanonitrile. To a vial containing (R) -3- (4- (piperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) propanonitrile (100 mg, 0.37 mmol) were DCM (2 mL), EDCI (78 mg, 0.41 mmol), (E) -4- (dimethylamino) but-2-enoic acid (61 mg, 0.37 mmol), DIPEA (0.6 mL, 3.7 mmol) and DMAP (2.2 mg, 0.018 mmol). The mixture was stirred overnight at room temperature. The reaction was diluted with saturated NaHCO3 and DCM. The layers were separated and organic extract collected and dried (Na2SO4). The solvent was removed to provide 3- [4 - ({(3R) -1 - [(2E) -4- (dimethylamino) but-2-enoyl] piperidin-3-yl} amino) -7H-pyrrole [2, 3- d] crude pyrimidin-5-yl] propanonitrile, which was purified by RP-HPLC to provide pure material (32.8 mg). LC / MS (M + H) 382.1. Example 158: 3- [4 - ({(3R) -1 - [(2E) -4-Hydroxybut-2-enoyl] piperidin-3-yl} amino) -7H-pyrrolo [2,3-d] pyrimidin- 5-yl] propanonitrile. Prepared as in Example 157, except in Step 3 the acid used was (E) - 4-hydroxybut-2-enoic acid. LC / MS (M + H) 355.3. Example 159: (2E) -1 - [(3R) -3 - {[5- (2-Hydroxy-2-methylpropyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amino} piperidin- 1-yl] but-2-en-1-one. Prepared as in Example 53, except (E) -but-2-enoyl chloride used instead of acryloyl chloride in the final step. Example 160: rac- (2E) -1 - [(3S, 4R) -4-Hydroxy-3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] but-2 -en-1-one. Prepared as in Example 64, except in the last step (E) -but-2-enoyl chloride was used instead of acryloyl chloride. LC / MS (M + H) 302.1. Example 161: 1 - [(2R, 5R) -2- (Hydroxymethyl) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl] prop-2-en-1 -one. For preparation, see Example 7. Example 162: 1 - {(3R, 5S) -3 - [(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -5-hydroxypiperidin- 1-il} prop-2-en-1-one. Step 1. 3 - ((tert-butyldimethylsilyl) oxy) -5 - (3S, 5R ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate ) -tert-butyl. A mixture of (3R, 5S) -tert-butyl 3-amino-5 - ((tert-butyldimethylsilyl) -oxy) piperidine-1-carboxylate (200 mg, 0.61 mmol), 4,5-dichloro-7H - pyrrole [2,3-d] pyrimidine (136 mg, 0.73 mmol) and DIPEA (156 mg, 1.21 mmol) in n-BuOH (5 mL) was heated to 80 oC for 20 hours. LC-MS showed that about 60% of 4,5-dichloro-7H-pyrrolo [2,3-d] pyrimidine remained. 200 mg of 3-amino-5 - ((tert-butyldimethylsilyl) oxy) (3R, 5S) -tert-butyl piperidine-1-carboxylate were added, and the reaction mixture was heated to 90 oC for 20 hours. The reaction mixture was evaporated to dryness to provide crude material, which after chromatography (silica, DCM / MeOH, 100: 0 ~ 90: 10) provided 3 - ((tert-butyldimethylsilyl) oxide) -5 - ((5- chlorine-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) (3S, 5R) - tert-butyl piperidine-1-carboxylate (290 mg, 83%) as a yellow solid. LC / MS (M + H) 482.1. Step 2. N - (((3R, 5S) -5 - (((tert-Butyldimethylsilyl) oxy) piperidin-3-yl) -5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine. To a solution stirred at 0 oC of 3 - ((tert-butyldimethylsilyl) oxy) -5 - ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate of (3S, 5R) -tert-butyl (290 mg, 0.60 mmol) in CH2Cl2 (10 mL) was added TFA (3 mL). After the resulting mixture was stirred at room temperature for 2 hours, TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was evaporated to dryness and then purified by chromatography (silica, EtOAc / MeOH, 100: 0 ~ 80: 20) to provide N - ((3R, 5S) -5 - ((tert-butyldimethylsilyl) oxide ) piperidin-3-yl) -5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (120 mg, 52.4%) as a yellow solid. Step 3. 1 - (((3S, 5R) -3 - (((tert-Butyldimethylsilyl) oxy) -5 - ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin -1-yl) prop-2-en-1-one. To a solution stirred at 0 oC of N - ((3R, 5S) -5 - ((tert-butyldimethylsilyl) oxy) piperidin-3-yl) -5-chloro-7H-pyrrolo [2,3-d] pyrimidin- 4-amine (100 mg, 0.26 mmol) and DIPEA (68 mg, 0.52 mmol) in THF-H2O (5 mL, v / v = 1: 1) was added acryloyl chloride (28.5 mg, 0.31 mmol). After the addition, the resulting mixture was stirred at room temperature for 20 min. TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was evaporated to dryness and the crude material used in the next step without purification. Step 4. 1 - (((3R, 5S) -3 - (((5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-hydroxypiperidin-1-yl) prop-2 -en-1-one. To a vial containing 1- ((3S, 5R) -3 - ((tert-butyldimethylsilyl) oxy) -5 - ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) crude piperidin-1-yl) prop-2-en-1-one dissolved in THF (5 ml) at 0 ° C TBAF (0.3 ml, 1 M in THF) was added. After the addition, the resulting mixture was stirred at room temperature for 18 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was evaporated to dryness and the crude material was purified by RP-HPLC (modifying base) to provide 1 - ((3R, 5S) -3 - ((5-chloro-7H-pyrrole [2,3- d] pyrimidin-4-yl) amino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one (31 mg) as a white solid. HNMR showed some TBAF present, so also purification by RP-HPLC (modifying TFA) provided 1 - ((3R, 5S) -3 - ((5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4- il) amino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one (13 mg, 16.7) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 11.82 (br s, 1H), 8.20 (br s, 1H), 8.13 (d, J = 12.3 Hz, 1H), 7.36 (dd, J = 7.9, 18.2 Hz, 1H), 7.23 (d, J = 13.3 Hz, 1H), 6.79 (dd, J = 10.7, 16.7 Hz, 1H), 6.35 (dd, J = 10.4, 16.7 Hz, 1H), 6.01 - 5.83 (m, 1H), 5.61 (d, J = 12.5 Hz, 1H ), 5.51 - 5.29 (m, 1H), 4.45 (br s, 1H), 4.39 - 4.27 (m, 1H), 4.04 - 3.74 (m, 3H) , 3.51 (d, J = 14.3 Hz, 1H), 3.11 (d, J = 11.8 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.83 ( d, J = 13.1 Hz, 1H). Example 163: 4 - {[(3R, 6S) -1-Acryloyl-6-methylpiperidin-3-yl] amino} -7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile. Prepared as in Example 18, except using 4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-carbo-nitrile in Step 1. LC / MS (M + H) 311.4. 1H NMR (400 MHz, CDCl3) δ 1.04-1.27 (m, 3 H) 1.59-2.08 (m, 5 H) 2.76 (br s, 1 H) 4.04-4 , 24 (m, 1 H) 4,444.82 (m, 2 H) 5.45 (d, J = 7.02 Hz, 1 H) 5.56-5.70 (m, 1 H) 6.24 ( dd, J = 16.78, 1.95 Hz, 1 H) 6.60 (dd, J = 16.59, 10.73 Hz, 1 H) 7.19 (s, 1 H) 7.60 (s , 1 H) 8.36 (s, 1 H). Example 164: 4 - {[(3R, 6S) -1-Acryloyl-6-methylpiperidin-3-yl] amino} - 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide. Prepared as in Example 18, except using 4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile in Step 1. Amide is a by-product of Z isomer removal with HBr / AcOH. LC / MS (M + H) 328.4. 1H NMR (400 MHz, CD3OD) δ 1.02 - 1.29 (m, 3 H) 1.54 - 2.06 (m, 5 H) 2.51 - 2.73 (m, 1 H) 2, 91 (br s, 1 H) 3.96 (br s, 2 H) 5.66 (d, J = 1.56 Hz, 1 H) 5.96 - 6.20 (m, 1 H) 6.72 (dd, J = 16.78, 10.54 Hz, 1 H) 8.06 (s, 1 H) 9.65 (d, J = 7.02 Hz, 1 H). Example 165: 4 - {[(3R, 6S) -1-Acryloyl-6-methylpiperidin-3-yl] amino} - 1H-pyrrolo [2,3-b] pyridine-3-carbonitrile. Prepared as in Example 2, except using (2), tert-butyl 5-amino-2-methylpiperidine-1-carboxylate instead of (R) - tert-butyl 3-aminopiperidine-1-carboxylate. LC / MS (M + H) 310.3. 1H NMR (400 MHz, CDCl3) δ 1.15 - 1.36 (m, 3 H) 1.60 - 1.86 (m, 3 H) 1.98 - 2.12 (m, 1 H) 2, 54 - 2.78 (m, 1 H) 3.42 - 3.52 (m, 2 H) 5.12 - 5.29 (m, 1 H) 5.59-5.63 (m, 1 H) 5.64 - 5.73 (m, 1 H) 6.19 - 6.31 (m, 1 H) 6.44 (br s 1 H) 6.45 - 6.62 (m, 1 H) 7, 24 (br s, 1 H) 7.52 - 7.69 (m, 1 H) 7.96 - 8.10 (m, 1 H). Example 166: 1- [1-Methyl-7- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) - 1,4,6,7-tetrahydro-5H-imidazo [4,5-c] pyridin-5-yl] prop-2-en-1-one. Step 1. 3-Bromo-N-methyl-5-nitropyridin-4-amine. To a solution of 3-bromo-4-chloro-5-nitropyridine (10 g, 42 mmol) in THF (100 mL) was added slowly 30% MeNH2 / H2O (20 mL, 210 mmol) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 3 hours. TLC (petroleum ether / EtOAc, 4: 1) showed that the starting material was completely consumed. The reaction mixture was partitioned between EtOAc (300 ml) and water (200 ml) and the organic layer was dried over Na2SO4 and concentrated to dryness to provide 3-bromo-N-methyl-5-nitropyridin-4-amine (8 g, 80%) as a yellow solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.22 (d, J = 5.52 Hz, 3 H) 7.15 (br s, 1 H) 8.47 (s, 1 H) 8.90 (s, 1 H). Step 2. 5-Bromo-N4-methylpyridine-3,4-diamine. To a solution of crude 3-bromo-N-methyl-5-nitropyridin-4-amine (8 g, 34.56 mmol) in AcOH (200 ml) was added Fe (11.6 g, 207.34 mmol) in room temperature. The resulting mixture was heated to 80 ° C for 3 hours. TLC (EtOAc) showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to dryness and then purified by chromatography (silica, MeOH / DCM, 0% to 10%) to provide 8 g of 5-bromo-N4-methyl-pyridine-3, 4-diamine (100% production). Step 3. 7-Bromo-1-methyl-1H-imidazo [4,5-c] pyridine. To a stirred solution of 5-bromo-N4-methylpyridine-3,4-diamine (8 g, 40 mmol) in trimethyl orthoformate (200 mL) was added TsOH ^ H2O (344 mg, 1.8 mmol). The reaction was then stirred at 80 ° C for 4 hours. TLC (EtOAc) showed that the starting material was completely consumed. The reaction mixture was concentrated to dryness and then purified by chromatography (silica, MeOH / EtOAc, 0% to 10%) to provide 6.5 g of 7-bromo-1-methyl-1H-imidazo [4 , 5-c] pyridine (77% production). 1H NMR (400 MHz, DMSO-d6) δ 4.09 (s, 3 H) 8.43 (d, J = 6.27 Hz, 2 H) 8.92 (s, 1 H). Step 4. N- (Diphenylmethylene) -1-methyl-1H-imidazo [4,5-c] pyridin-7-amine. To a stirred solution of 7-bromo-1-methyl-1H-imidazo [4,5-c] pyridine (5.5 g, 26.2 mmol) and NHCPh2 (7.07 g, 39.3 mmol) in toluene anhydrous (200 ml) BINAP (1.7 g, 2.62 mmol) and Cs2CO3 (34 g, 104.8 mmol) were added. After the addition, the reaction was degassed under vacuum and purged with N2 several times. Then, Pd (OAc) 2 (588 mg, 2.62 mmol) was added to the reaction mixture under N2. The suspension was degassed under vacuum and purged with N2 several times. The reaction mixture was stirred at 130 ° C for 12 hours. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to dryness and then purified by chromatography (silica, MeOH / EtOAc, 0% to 10%) to provide N- (diphenylmethylene) -1-methyl-1H-imidazo [4 , 5-c] pyridin-7-amine (6.2 g, 76%) as a yellow solid. LC / MS (M + H) 312.9. Step 5. 1-Methyl-1H-imidazo [4,5-c] pyridin-7-amine. To a stirred solution of N- (diphenylmethylene) -1-methyl-1H-imidazo [4,5-c] pyridin-7-amine (6.2 g, 20 mmol) in MeOH (150 mL) was added NaOAc (4.24 g, 52 mmol) and NH2OH ^ HCl (2.78 g, 40 mmol). After the mixture was stirred at 80 ° C for 12 hours, TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to dryness and then purified by chromatography (silica, MeOH / DCM, 0% to 30%) to provide 1-methyl-1H-imidazo [4,5-c] pyridine -7-amine (5 g, 100% including some inorganic salt) as a white solid. Step 6. N- (1-Methyl-1H-imidazo [4,5-c] pyridin-7-yl) acetamide. A solution of 1-methyl-1H-imidazo [4,5-c] pyridin-7-amine (3.3 g, 22.3 mmol) in acetic anhydride (20 mL) was stirred at 60 ° C for 4 hours. TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was quenched with saturated sodium carbonate (20 ml). The solution was concentrated to dryness and the crude product was purified by chromatography (silica, MeOH / DCM, 0% to 30%) to provide N- (1-methyl-1H-imidazo [4,5-c] pyridin-7 -yl) acetamide (2 g, 47% for 2 steps) as a yellow oil. Step 7. 7-Acetamido-5-benzyl-1-methyl-1H-imidazo [4,5-c] pyridin-5-yl. To a stirred solution of N- (1-methyl-1H-imidazo [4,5-c] pyridin-7-yl) acetamide (2 g, 10.5 mmol) in toluene (20 mL) was added BnBr (1, 8 g, 10.5 mmol). After the mixture was stirred at 110 ° C for 12 hours, TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was filtered to provide 7-acetamido-5-benzyl-1-methyl-1H-imidazo [4,5-c] pyridin-5-ion (2.6 g, 88%) as a white solid . 1H NMR (400 MHz, DMSO-d6) δ 3.91 - 4.18 (m, 3 H) 5.84 (s, 2 H) 7.32 - 7.65 (m, 5 H) 8.69 - 9.01 (m, 2 H) 9.77 (s, 1 H). Step 8. N- (5-Benzyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7-yl) acetamide. To a stirred solution of 7-acetamido-5-benzyl-1-methyl-1H-imidazo [4,5-c] pyridin-5-ion (500 mg, 1.8 mmol) in MeOH (10 mL) was added NaBH4 (140 mg, 3.6 mmol) in portions at -10 ° C. After the mixture was stirred at the same temperature for 30 minutes, TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was concentrated to dryness and the crude product was purified by chromatography (silica, MeOH / DCM, 0% to 10%) to provide N- (5-benzyl-1-methyl-4,5,6,7 - tetrahydro-1H-imidazo [4,5-c] pyridin-7-yl) acetamide (180 mg, 36%) as a yellow oil. Step 9. 5-Benzyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7-amine. A solution of N- (5-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7-yl) acetamide (100 mg, 0.36 mmol) in 6 M HCl solution (5 ml) was stirred at 70 ° C for 12 hours. TLC (DCM / MeOH, 10: 1) showed that the starting material was completely consumed. The reaction mixture was azeotroped with EtOH three times to provide 5-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7-amine (100 mg, 95%) as a yellow solid. 1H NMR (400 MHz, CHCl3) δ 1.86 (br s, 2 H) 2.62 - 2.76 (m, 1 H) 3.23 - 3.33 (m, 1 H) 3.62 - 3 , 73 (m, 2 H) 3.67 - 3.72 (m, 1 H) 3.83 (s, 1 H) 3.74 - 3.81 (m, 1 H) 3.84 - 3.93 (m, 1 H) 7.17 - 7.55 (m, 5 H). Step 10. 5-Benzyl-N- (2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-methyl- 4,5,6,7-tetrahydro-1H-imidazo [4 , 5-c] pyridin-7-amine. A mixture of 5-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7-amine (300 mg, 1.08 mmol), DIPEA (697 mg , 5.4 mmol) and 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (244 mg, 1.3 mmol) in n-BuOH (10 mL) was heated to 135 ° C overnight . LC-MS showed that the reaction was complete. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was diluted with EtOAc (30 ml) and washed with water (20 ml). The aqueous layer was extracted with EtOAc (30 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to provide the crude product, which was purified by chromatography (silica, EtOAc / petroleum ether, 10% to 80%) to provide 5 -benzyl- N- (2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] pyridin-7-amine (250 mg, 60%) as a yellow solid. LC / MS (M + H) 393.9. Step 11. 1-Methyl-N- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7 -the mine. To a bottle of Parr hydrogenation, 10% dry Pd / C (10 mg) was added under Ar atmosphere. Then, a solution of 5-benzyl-N- (2-chloro-7H-pyrrolo [2,3- d] pyrimidin-4-yl) -1-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-7-amine (100 mg, 0.25 mmol) in MeOH ( 10 ml) was added and the resulting mixture was hydrogenated under 3.51 kg / cm2 (50 psi) of H2 at 30 oC for 72 hours. The reaction solution was filtered through a pad of Celite® and the mass was washed with MeOH three times. The combined filtrate was concentrated to provide 1-methyl-N- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] pyridin-7-amine (60 mg, 89.5%) as a yellow oil, which was used for the next step directly without further preparation. Step 12. 1- (7 - ((7H-Pyrrolo [2,3-d] pyrimidin-4-yl) amino) -1-methyl-6,7-dihydro-1H-imidazo [4,5-c] pyridin -5 (4H) -yl) prop-2-en-1-one. To a stirred solution of 1-methyl-N- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin -7-amine (60 mg, 0.22 mmol) in THF (2 mL) and water (2 mL) at 0 ° C were added DIPEA (86 mg, 0.67 mmol) and acryloyl chloride (24 mg, 0 , 27 mmol). After the resulting mixture was stirred at 0 ° C for 2 hours, LCMS showed that the starting material was completely consumed. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (30 ml * 2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to provide the crude product, which was also purified by HPLC to provide 1- (7 - ((7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) -1-methyl-6,7-dihydro-1H-imidazo [4,5-c] pyridin-5 (4H) -yl) prop-2-en-1-one (1.5 mg, 2, 5%) as a white solid. LC / MS (M + H) 324.2. 1H NMR (400 MHz, DMSO-d6) δ 2.02 - 2.14 (m, 1 H) 2.26 - 2.38 (m, 1 H) 2.61 - 2.73 (m, 1 H) 3.44 - 3.52 (m, 3 H) 3.59 (dd, J = 14.43, 2.64 Hz, 1 H) 3.91 - 4.21 (m, 2 H) 4.36 - 4.52 (m, 1 H) 5.04 - 5.63 (m, 1 H) 5.88 - 6.39 (m, 1 H) 6.52 - 6.64 (m, 1 H) 6, 99 - 7.10 (m, 1 H) 7.59 - 7.85 (m, 1 H) 8.17 - 8.27 (m, 1 H) 11.56 (br s, 1 H). Examples 167-196
Figure legend: displacement of N
[082] Starting patterns A (2-bromo-N-isopropyl-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pirazine-7-carboxamide and 2-bromo- 5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine) were prepared as described in WO2010 / 063634 and Journal de Medicinal Chemistry, 56 (4), 1677-1692 (2013 ).
[083] Examples 165-196 were prepared according to the synthetic procedure below. Step 1: (a) Precursor 330 (CONHiPr). A 0.1 M solution of 2-bromo-N-isopropyl-5 - ((2- (trimethylsilyl) eth-oxy) methyl) -5H-pyrrolo [2,3- b] pyrazine-7-carboxamide (330) was prepared in toluene. Amine partners (150 μmol, 2.0 eq.) Were dispensed in 8 ml reaction flasks. Cs2CO3 (48.9 mg, 150 μmol, 2.0 eq.) Was dispensed in each vial. 750 μl (75 μmol, 1.0 eq.) Of 2-bromo- N-isopropyl-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazine-7 solution - carboxamide was added to each vial, followed by Pd2 (dba) 3 (6.9 mg, 7.5 μmol, 0.1 eq.) and then dppf (2.5 mg, 10 μmol, 0.13 eq. ) under N2 atmosphere. The vials were capped and stirred at 100 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. The crude product was washed with H2O (1 ml) and exact with EtOAc (1 ml x 3). The organic layer was collected and concentrated to obtain the intermediates from Step 1. (b) Precursor 329 (H). A 0.1 M solution of 2-bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine (329) was prepared in dioxane. Amine partners (150 μmol, 2.0 eq.) Were dispensed in 8 ml reaction flasks. t-BuONa (14.4 mg, 150 μmol, 2.0 eq.) was added to each vial, followed by 750 μl (75 μmol, 1.0 eq.) of 2-bromo-5 - ((2 - (trimethylsilyl) ethoxy) methyl) -5H- pyrrolo [2,3-b] pyrazine, Pd2 (dba) 3 (6.9 mg, 7.5 μmol, 0.1 eq.) and Ruphos (4.2 mg , 9 μmol, 0.12 eq.) Under N2 atmosphere. The vials were buffered and stirred at 110 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. The crude product was washed with H2O (1 ml) and exact with EtOAc (1 ml x 3). The organic layer was collected and concentrated to obtain the intermediates from Step 1. Step 2: Deprotection (De-Boc & De-SEM). One mL of TFA / DCM (v / v = 1/7) was dispensed in vials containing Step 1 intermediates. The vials were buffered and stirred at 30 oC for 4 hours. The solvents were evaporated under reduced pressure. One and two tenth ml of NH3 ^ O / MeOH (v / v = 1/3) were added to each vial. The vials were buffered and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain the intermediate from Step 2. Step 3: Acylation. Five hundred μl of anhydrous DMF was dispensed in vials containing the Step 2 intermediate. DIEA (29 mg, 225 μmol, 3.0 eq.) Was added to each vial, followed by acryloyl chloride (8.1 mg, 90 μmol, 1.2 eq.) At temperatures under 0 oC. The vials were kept at 0 oC for 15 min, and then stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure, and the residue was purified by preparative HPLC to provide the final product.



[00020] Examples 199-212 were prepared as described in the diagram below.
Step 1: Suzuki coupling. Boronates / boronic acids (200 μmol, 2.0 eq.) Were dispensed in 8 ml reaction flasks, followed by 600 μl (100 μmol, 1.0 eq.) Of 2-bromo-7-iodine solution -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine (0.167 M) in CH3CN, 200 μl of toluene, 400 μl (400 μmol, 4.0 eq.) of NaHCO3 solution (1.0 M in H2O), and then Pd (dppf) Cl2 (7.3 mg, 10 μmol, 0.1 eq.) under N2 atmosphere. The vials were buffered and stirred at 65 oC for 4 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure, and the residue was washed with H2O (1 ml) and extracted with EtOAc (1 ml x 3). The organic layers were concentrated under reduced pressure to obtain Step 1 intermediates. Step 2: N. displacement. A solution of t-BuONa (19.2 mg, 200 μmol, 2.0 eq.) Was dispensed to vials containing intermediates of Step 1, followed by 800 μl (200 μmol, 2.0 eq.) Of tert-butyl 4-aminopiperidine-1-carboxylate solution (0.25 M in dioxane), Pd2 (dba) 3 (9.2 mg , 10 μmol, 0.1 eq.), And RuPhos (5.6 mg, 12 μmol, 0.12 eq.) Under N2 atmosphere. The vials were buffered and stirred at 110 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure, and the residue was washed with H2O (1 ml) and extracted with EtOAc (1 ml x 3). The organic layers were concentrated under reduced pressure to obtain Step 2 intermediates. Step 3 & 4: Deprotection (De-Boc & De-SEM). One mL of TFA / DCM (1: 7, v / v) was dispensed into vials containing Step 2 intermediates. The vials were buffered and stirred at 30 oC for 16 hours. The solvents were evaporated under reduced pressure. One and two tenth ml of NH 3 O / MeOH solution (1: 3, v / v) were added to each vial. The vials were capped and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to provide Step 3/4 intermediates. Step 5: Acylation. Eight hundred (800) μl of DMF were dispensed in vials containing intermediates from steps 3 and 4, followed by DI-EA (38.7 mg, 300 μmol, 3.0 eq.) And acryloyl chloride (18 mg, 200 μmol, 2.0 eq.) At 0 oC. The vials were kept at 0 oC for 15 min, and then stirred at 30 oC for 30 minutes. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. The residue was purified by preparative HPLC to provide final product.

[083] Examples 213-229 were prepared as detailed in the scheme below.
Step 1: Displacement of O. t-BuOK (33.6 mg, 300 μmol, 2.0 eq.) Was dispensed in 8 ml reaction vials, followed by 600 μl (150 μmol, 1.0 eq.) Of solution of 2-bromo-7-iodine-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine (0.25 M in THF), 600 μl (600 μmol, 4.0 eq.) Of tert-butyl 4-hydroxypiperidine-1- solution (1.0 M in THF). The vials were buffered and stirred at 30 oC for 0.5 hr and then stirred at 80 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure, and the residue was washed using H2O (1mL) and extracted using EtOAc (1 mL x 3). The organic layer was concentrated under reduced pressure to obtain Step 1 intermediates. Step 2: Suzuki coupling. The Step 1 intermediates (0.15 M in dioxane) were dispensed in 8 ml reaction flasks, followed by Cs2CO3 (97.7 mg, 300 μmol, 3.0 eq.), 1 ml (150 μmol, 1, 0 eq.) Of boronate / boronic acid solution, and Pd (dppf) Cl2 (11 mg, 15 μmol, 0.1 eq.) Under N2 atmosphere. The vials were buffered and stirred at 100 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure, and the residue was washed using H2O (1 ml) and extracted using EtOAc (1 ml x 3). The organic layer was concentrated under reduced pressure to obtain Step 2 intermediates. Step 3 & 4: Deprotection (De-Boc & De-SEM). 1.5 mL of TFA / DCM solution (1: 4, v / v) was dispensed in vials containing Step 2 intermediates. The vials were buffered and stirred at 30 oC for 8 hours. The solvents were evaporated under reduced pressure. Two mL of NHβ ^ O / MeOH solution (1: 3, v / v) was dispensed into each vial. The vials were buffered and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. The solvents were evaporated to obtain Step 3 intermediates. Step 5: Acylation. 750 μl of DMF was dispensed in vials containing Step 3 intermediates, followed by DIEA (58 mg, 450 μmol, 3.0 eq.) And acyloyl chloride (27 mg, 300 μmol, 2.0 eq.) At 0 oC . The vials were kept at 0 oC for 0.5 hr, and then stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. The residue was purified by preparative HPLC to provide final product.


[084] Examples 230 -291 were prepared as detailed in the scheme below.
FIGURE LEGEND: conditions
[085] For general primary amines (Group 1), Eta pa 1 conditions are DMF / DIEA / HBTU / 30 ° C / 16 hours.
[086] For primary amines with a cyan group (Group 2, Step 1 conditions are DMF / DIEA / HATU / 60 ° C / 16 hours. Step 1: Amide formation. Group 1: Amines (150 μmol, 1, 5 eq.) Were placed in 8 ml reaction vials, followed by 300 μl DMF, 500 μl 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2 - (trimethylsilyl) ethoxy) methyl) - 5H-pyrrolo [2,3-b] pyrazine-7-carboxylic (0.2 M in DMF; 100 μmol, 1.0 eq.), DIEA (70 μl, 400 μmol, 4.0 eq.), And HBTU (170 μmol, 1.7 eq.) In each vial. The vials were buffered and stirred at 30 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. One mL of saturated NaHCO3 solution in each vial. The resulting mixture was extracted with EtOAc (2 mL x 3). The organic layers were combined and dried with anhydrous Na2SO4. Filtration and evaporation under reduced pressure provided crude intermediates that were used directly in the next step. 2: Amines (150 μmol, 1.5 eq.) Were placed in 8 ml reaction flasks, followed by 500 μl of 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino acid) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylic (0.2 M in DMF; 100 μmol, 1.0 eq.), DIEA (70 μl, 400 μmol, 4.0 eq.) And 300 μl of HATU solution (0.67 M in DMF; 200 μmol, 2.0 eq.). The vials were buffered and stirred at 30 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure. One mL of saturated NaHCO3 solution in each fraction. The resulting mixture was extracted with EtOAc (2 ml * 3). The organic layers were combined and dried with anhydrous Na2SO4. Filtration and evaporation under reduced pressure provided crude intermediates that were used directly in the next step. Step 2 & 3: De-Boc & De-SEM. 1.5 mL of TFA / DCM (1: 4, v / v) were dispensed in vials containing Step 1 intermediates. The vials were buffered and stirred at 30 oC for 2 hours. The solvents were evaporated under reduced pressure. One and two tenth ml of NHa2 HaO / MeOH (1: 2, v / v) were then dispensed into each vial. The vials were buffered and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain intermediates from Step 2/3, which were used directly for the next step. Step 4: Acylation: One ml of saturated NaHCO3 solution was dissolved in vials containing Step 2/3 intermediates, followed by 1 ml of EtOAc and acryloyl chloride (200 μmol, 2.0 eq.) In ca -from the jar. The vials were buffered and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain the residues that were purified by preparative HPLC to supply the final product.


[087] Examples 265 - 289 were prepared according to the scheme and procedure for Examples 230-291. (amines of Group 1)


[088] Examples 290-328 were prepared as detailed in the scheme below.
EtOAc / NaHCO3 / DIEA / stir / 30 ° C / 2 hrs legend: condition, stir Group 1: For general amines, conditions for Step 1 are dioxane / Pd2 (dba) 3 / Xphos / Cs2CO3 / N2 / 120 ° C / 16 hours. Group 2: For secondary amines with a sterically demanding group, conditions for Step 1 are toluene / Pd2 (dba) 3 / Ruphos / t-BuONa / N2 / 65 ° C / 2 days. Step 1: Displacement of N. Group 1: Amines (195 μmol, 1.5 eq.) Were placed in 8 ml reaction vials. One thousand μl of 2-bromo-N-isopropyl-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (0.13 M in dioxane; 130 μmol, 1.0 eq.) were dispensed in each vial, followed by Cs2CO3 (81.9 mg, 260 μmol, 2.0 eq.), Pd2 (dba) 3 (11.9 mg, 13 μmol , 0.1 eq.) And Xphos (6.2 mg, 13 μmol, 0.1 eq.) Under N2. The vials were buffered and stirred at 120 oC for 16 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain the residues. The crude product was washed with H2O (1 ml) and extracted with EtOAc (1 ml x 3). The organic layers were combined and dried over Na2SO4. The filtrate was concentrated to provide crude intermediates from Step 1, which were used directly for the next step. Group 2: Amines (195 μmol, 1.5 eq.) Were placed in 8 ml reaction flasks. One thousand μl of 2-bromo-N-isopropyl-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide solution (0.1 M in toluene ; 130 μmol, 1.0 eq.) In each vial, followed by t- BuONa (24.9 mg, 260 μmol, 2.0 eq.) And Pd2 (dba) 3 (11.9 mg, 13 μmol, 0 , 1 eq.) And Ruphos (6.0 mg, 13 μmol, 0.1 eq.) Under N2. The vials were buffered and stirred at 65 oC for 2 days. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain the residues. The crude product was washed with H2O (1 ml) and extracted with EtOAc (1 ml x 3). The organic layers were combined and dried over Na2SO4. The filtrate was concentrated to provide crude intermediates from Step 1, which were used directly for the next step. Step 2 & 3: Deprotection (De-Boc & De-SEM). One mL of TFA / DCM solution (1: 7, v / v) was dispensed in vials containing Step 1 intermediates. The vials were buffered and stirred at 30 oC for 4 hours. The solvents were evaporated under reduced pressure. One and two tenth ml of NHa2 O / MeOH solution (1: 3, v / v) were dispensed into each vial. The vials were capped and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain the intermediates from Step 2. Step 4: Acylation. Five hundred (500) μl of EtOAc were dispensed in each vial containing Step 2 intermediates (130 μmol, 1.0 eq.), Followed by 500 μl of saturated NaHCO3 solution, acryloyl chloride (195 μmol, 1.5 eq. ), and DIEA (390 μmol, 3.0 eq.). The flasks were buffered and stirred at 30 oC for 2 hours. After the reactions were considered complete by LC-MS, the solvents were evaporated under reduced pressure to obtain the residues which were purified by preparative HPLC to obtain final products.


Preparation 329: 2-Bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine.
[089] Prepared as described in WO2010 / 063634. Preparation 330: 2-Bromo-N-isopropyl-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide.
[090] Prepared as described in Journal de Medicinal Chemis try, 56 (4), 1677-1692 (2013). Preparation 331: 2-Bromo-N- (tert-butyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide.
[091] Prepared as described in Journal de Medicinal Chemis try, 56 (4), 1677-1692 (2013). Preparation 332: 2-Bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid.
[092] Prepared as described in Journal de Medicinal Chemis try, 56 (4), 1677-1692 (2013). Preparation 333: 2-Bromo-7-iodo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine. Step 1. 2-Bromo-7-iodo-5H-pyrrolo [2,3-b] pyrazine. To a solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine (8 g, 40.4 mmol) in DMF (160 mL) was added N-iodosuccinimide (11.8 g, 3.6 mmol) at room temperature, and stirred for 1 h. TLC (petroleum ether: EtOAc, 2: 1) indicated that the reaction was complete. The reaction mixture was diluted with water (500 ml), and extracted with EtOAc (300 ml x 3). The combined organic layers were washed with brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to provide 2-bromo-7-iodo-5H-pyrrolo [2,3-b] pyrazine (26.1 g, 100%) as a brown solid (containing some DMF). Step 2. 2-Bromo-7-iodo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine. To a suspension of NaH (4.83 g, 120.83 mmol) in DMF (100 mL) was added a solution of compound 2 (26.1 g, 80.56 mmol) in DMF (200 mL) at 0 oC drop drop, and stirred at this temperature for 20 min. Then, without Cl-16.14 g, 96.67 mmol) it was added dropwise at 0 oC, and warmed to room temperature over 1 hour. TLC (petroleum ether / EtOAc, 2: 1) indicated that the reaction was complete. The reaction mixture was poured into ice water (300 ml) slowly. The mixture was extracted with EtOAc (200 ml x 4), and the combined organic layers were washed with brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and purified with flash column chromatography (petroleum ether / ethyl acetate, 4: 1) to provide product (13 g, 36%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 8.33 (s, 1H), 7.76 (s, 1H), 5.62 (s, 2H), 3.55 - 3.48 (m, 2H), 0.94 - 0.88 (m, 2H), -0.05 (s, 9H). LCMS (M + H) 455.7. Preparation 334: Methyl 2-Bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate.
FIGURE LEGENDS: formaldehyde; Jones reagent; acetone; sulfamic acid; dioxane. Step 1. (2-Bromo-5H-pyrrolo [2,3-b] pyrazine-5,7-diyl) dimethanol. To a stirred solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine (116.5 g, 589 mmol) in dioxane (1.75 L) was added dropwise aqueous NaOH (590 mL, 1175 mmol , 2 M) at room temperature, then formaldehyde (481 mL, 5884 mmol, 37% aqueous solution) was added to the mixture at room temperature. After that, the resulting mixture was stirred at room temperature for 18 hours. TLC (petroleum ether / EtOAc, 2: 1) showed that the starting material was completely consumed. The three batches were combined for preparation together. The reaction mixture was evaporated to remove most of the solvent. The residue was neutralized with 2 M HCl and extracted with EtOAc (1 L x 3), the combined organic layers were washed with water (1 ml) and brine (1 ml), dried over Na2SO4 and concentrated to dryness, which was triturated with MTBE to provide (2-bromo-5H-pyrrolo [2,3-b] pyrazine-5,7-diyl) dimethanol (450 g, 95.5%) as a yellow solid. Step 2. (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) methanol. To a suspension of (2-bromo-5H-pyrrolo [2,3-b] pyrazine-5,7-diyl) dimethanol (150 g, 586 mmol) in THF (1.5 L) was added dropwise a solution of NaOH (70.3 g, 1758 mmol) in H2O (880 mL) at room temperature. After the addition, the resulting mixture was stirred at room temperature for 18 hours. HNMR showed that about 18% of starting material was left. The reaction mixture was stirred at room temperature for 48 hours. HNMR showed that the starting material was completely consumed. The three batches were combined for preparation together. The reaction mixture was evaporated to remove most of the THF. The aqueous residue was acidified to pH = 3 ~ 4 with 2 M HCl and extracted with EtOAc (3 ml x 3), the combined organic layers were washed with water (3 L) and brine (3 L), dried over Na2SO4 and concentrated to provide (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) methanol (381 g, 96%) as a yellow solid, which was used for the next step without purification Step 3. 2 -Bromo-5H-pyrrolo [2,3-b] pyrazine-7-carbaldehyde. To a suspension of (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) methanol (127 g, 562 mmol) in acetone (2.5 L) was added dropwise reagent of Jones (253 mL, 674 mol, 2.67 M) below 10 oC. After the addition, the resulting mixture was stirred at room temperature for 50 min, during which time the suspension became clean and then the brown solid was precipitated. The three batches were combined for preparation together. The reaction mixture was quenched with i-PrOH (60 mL) and filtered, the filter mass was washed with acetone (1 L x 2), the combined filtrate was evaporated to provide 2-bromo-5H-pyrrole [2,3- b] pyrazine-7-carbaldehyde (320 g, 84.4%) as a yellow solid. (A Jones reagent storage (2.67 M) was prepared by carefully adding concentrated H2SO4 (184 mL) to CrO3 (213.6 g), then diluting in 800 mL with H2O.) Step 4. 2-Bromo-acid 5H-pyrrolo [2,3-b] pyrazine-7-carboxylic. To a stirred solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carbaldehyde (75 g, 333 mmol) and sulfamic acid (163 g, 1667 mmol) in dioxane-H2O (1.5 L , 4: 1, v / v) a solution of NaClO2 (36.4 g, 400 mmol) and KH2PO4 (227 g, 1667 mmol) in H2O (0.5 L) was added dropwise over a period of 40 min below 0 oC. After the addition, the resulting mixture was stirred at room temperature for 18 hours. TLC (petroleum ether / EtOAc, 1: 1) showed that the starting material was completely consumed. The two batches were combined for preparation together. The reaction mixture was partitioned between EtOAc (2 L) and water (1 L), also extracted with EtOAc (1.5 L). The combined organic layers were washed with water (1 L) and brine (1 L), dried over Na2SO4 and concentrated to provide 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid (120 g, 75%) as a yellow solid. Step 5. Methyl 2-Bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylate. To a suspension at 0 oC of 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid (145 g, 602 mmol) in MeOH (1.5 L) was added dropwise SOCl2 (93 g, 781 mmol) over a period of 40 min. After the addition, the resulting mixture was heated to reflux for 4 hours, during which time the suspended solution became clear and then a yellow solid was precipitated. TLC (petroleum ether / EtOAc, 1: 1) showed that the starting material was completely consumed. The reaction mixture was evaporated to dryness, which was triturated with MTBE to provide methyl 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylate (109 g, 71%) like a yellow solid. Step 6. Methyl 2-Bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate. To a suspension at 0 oC of NaH (11.9 g, 297 mmol, 60% in oil) in DMF (500 mL) was added 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylate methyl (55 g, 228 mmol) in portions. After the addition, the reaction mixture was stirred at 0 ° C for 10 min. Then, SEMCl (49.3 g, 251 mmol) was added dropwise to the mixture below 0 oC. After that, the resulting mixture was stirred at room temperature for 3 hours. TLC (petroleum ether / EtOAc, 1: 1) showed that the starting material was completely consumed. The two batches were combined for preparation together. The reaction mixture was poured into cold water (1.5 L), then extracted with EtOAc (1.5 L x 3). The combined organic layers were washed with water (2 L) and brine (1.5 L3), dried over Na2SO4 and concentrated to dryness. The residue was triturated with MTBE to provide methyl 2-bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate (105 g, 59.7 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.85 (m, 1H), 8.61 (s, 1H), 5.70 (s, 2H), 3.87 (s, 3H) , 3.57 (t, J = 8.0 Hz, 2H), 0.83 (t, J = 7.8 Hz, 2H), -0.05 -0.14 (m, 9H). Example 335: (R) -1- (3 - ((5H-Pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one.
LEGENDS TO THE FIGURE: sodium tert-butoxide; dioxane; 2.0 M HCl / ether; 2-bromo-5H-pyrrolo [2,3-b] pyrazine. Step 1. 2-Bromo-5-trityl-5H-pyrrolo [2,3-b] pyrazine. At 40 ° C, a solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine (725 mg, 3.66 mmol) and cesium carbonate (3250 mg, 9.95 mmol) in DMF (20.0 ml) was treated with trityl chloride (925 mg, 3.32 mmol). After 2 hours, the reaction mixture was cooled to room temperature and poured into water (150 ml). The mixture was filtered and the filter mass was triturated with water (250 ml) for 1 hour. The solid was isolated and recrystallized from hot ethanol to provide 2-bromo-5-trityl-5H-pyrrolo [2,3-b] pyrazine (750 mg, 52%) as a colorless crystalline solid. LC / MS (M + H) 440.16. Step 2. (R) -tert-butyl ((5-Trityl-5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidine-1-carboxylate. Under nitrogen, a solution of (R) -tert-butyl 3-aminopyrrolidine-1-carboxylate (850 mg, 4.5 mmol), 2-bromo-5-trityl-5H-pyrrolo [2,3-b] pyrazine (1000 mg, 2.3 mmol), degassed dioxane (9.0 mL), sodium tert-butoxide (500 mg, 5.2 mmol), Pd2 (dba) 3 (35 mg, 0.23 mmol), and MePhos (85 mg, 0.23 mmol) was heated to 125 ° C. After 90 minutes, the reaction mixture was filtered through a thin pad of Celite ™ and the solvent was removed in vacuo. The resulting crude oil was dissolved in 100 ml of 1: 1 EtOAc: water and the organic layer was extracted. The aqueous layer was extracted again with EtOAc (2 x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by column chromatography to provide 3 - ((5-trityl-5H-pyrrolo [2,3-b] pyrazin- (R) -tert-butyl 2-yl) amino) pyrrolidine-1-carboxylate (520 mg, 42%) as a colorless solid. LC / MS (M + H) 546.39. Step 3. (R) -N- (Pyrrolidin-3-yl) -5-trityl-5H-pyrrolo [2,3-b] pyrazin-2-amine. A solution of (R) -tert-butyl 3 - ((5-trityl-5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidine-1-carboxylate (250 mg, 0.46 mmol ) was treated with 2.0 M HCl / ether (10 mL) and sonicated for 15 minutes. The reaction mixture was then stirred for 3 hours at room temperature and the solvent was removed in vacuo to provide (R) -N- (pyrrolidin-3-yl) -5-trityl-5H-pyrrole [2,3 -b] pyrazin-2-amine (221 mg, 100%) as the HCl salt. LC / MS (M - H) 446.33. Step 4. (R) -1- (3 - ((5-Trityl-5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop -2-en-1- ona. A solution of (R) -N- (pyrrolidin-3-yl) -5-trityl-5H-pyrrolo [2,3-b] pyrazin-2-amine (220 mg, 0.47 mmol) in anhydrous chloroform (10.0 mL) was treated with Hunig's base (0.4 mL, 3.0 mmol), cooled to 2 ° C, and treated, dropwise, with an acrylic chloride solution (0.38 mL, 0 , 47 mmol) in anhydrous chloroform (2.0 mL). After 30 minutes, the reaction mixture was warmed to room temperature and allowed to stir for 1 hour before being cooled to 2 ° C and quenched with 10% sodium bicarbonate (15 mL). The organic layer was extracted and the aqueous layer was extracted again with chloroform (2 x 10 ml). The organic layers were combined, dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography to provide (R) -1- (3 - (((5-trityl-5H-pyrrole [2, 3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one (221 mg, 97%) as a colorless solid. LC / MS (M + H) 500.35. Step 5. (R) -1- (3 - ((5H-Pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one. A solution of (R) -1- (3 - ((5-trityl-5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1- one (221 mg, 0.5 mmol) in TFA (4.9 ml) was allowed to stir at room temperature for 22 hours. Concentrated in vacuo and purified by column chromatography to provide (R) -1- (3 - (((5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one (107 mg, 84%) as a colorless solid. LC / MS (M + H) 258.3. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 6.77-6.71 (m, 1H) , 6.59-5.54 (m, 1H), 6.26 (s, 1H), 6.15-6.09 (m, 1H), 5.65-5.59 (m, 1H), 4 , 45-4.01 (m, 1H), 3.99-3.88 (m, 1H), 3.70-3.44 (m, 3H), 2.22 - 1.86 (m, 1H) , 1.19-1.14 (m, 1H). Example 336: (S) -1- (3 - ((5H-Pyrrolo [2,3-b] pyrazin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one.
[093] Prepared as in Example 173, except using (S) -tert-butyl 3-aminopyrrolidine-1-carboxylate in Step 2. LC / MS (M + H) 258.3. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 6.77-6.71 (m, 1H) , 6.59-5.54 (m, 1H), 6.26 (s, 1H), 6.15-6.09 (m, 1H), 5.65-5.59 (m, 1H), 4 , 45-4.01 (m, 1H), 3.99-3.88 (m, 1H), 3.70-3.44 (m, 3H), 2.22 - 1.86 (m, 1H) , 1.19-1.14 (m, 1H). Example 337: 1- (3 - ((5H-Pyrrolo [2,3-b] pyrazin-2-yl) amino) azetidin-1-yl) prop-2-en-1-one.
[094] Prepared as in Example 173, except using tert-butyl 3-aminoazetidine-1-carboxylate in Step 2. LC / MS (M + H) 244.3. 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.17 (bs, 1H), 6.36 -6.29 (m, 1H), 6.24 (s, 1H), 6.11-6.06 (m, 1H), 5.65-5.62 (m, 1H), 4.56 -4 , 54 (m, 2H), 4.68-3.75 (m, 3H). Example 338: 2 - ((1-Acryloylpiperidin-4-yl) oxy) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide.
Step 1. 4 - (((7- (tert-butylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl) oxy) piperidine-1 tert-butyl carboxylate. To a solution of 2-bromo-N- (tert-butyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (200 mg, 0.468 mmol) in 10 mL of toluene tert-butyl 4-hydroxypiperidine-1-carboxylate (188 mg, 0.935 mmol) and Cs2CO3 (305 mg, 0.935 mmol) were added at room temperature. The mixture was degassed and purged with N2 several times. Pd2 (dba) 3 (43 mg, 0.0468 mmol) and dppf (34 mg, 0.06 mmol) were added repeatedly and the flasks degassed and purged with N2 several times as before. After the addition, the mixture was heated to 100 ° C overnight. TLC (petroleum ether: EtO-Ac, 4: 1) showed that 2-bromo-N- (tert-butyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3- b] pyrazine-7-carboxamide was completely consumed. The resulting mixture was cooled to room temperature and the mixture was diluted with H2O (30 ml). The aqueous mixture was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by chromatography (silica, petroleum ether: EtOAc 10: 1 to 1: 2) to provide 4 - ((7- (tert-butylcarbamoyl) - 5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl) oxy) piperidine-1-carboxylate (160 mg, 62.7%) like an oil. Step 2. N- (tert-Butyl) -5- (hydroxymethyl) -2- (piperidin-4-yloxy) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. 4 - ((7- (tert-Butylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl) oxy) piperidine-1-carboxylate tert-butyl (160 mg, 0.29 mmol) was dissolved in a mixed solution of TFA / DCM (1 mL / 7 mL, 1: 7, v / v) at room temperature. The mixture was stirred at room temperature overnight. LC-MS showed that most of 4 - ((7- (tert-butylcarbamoyl) - 5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl ) oxy) tert-butyl piperidine-1-carboxylate was consumed. The resulting mixture was concentrated in vacuo, and chased with DCM several times to provide the crude TFA salt of N- (tert-butyl) -5- (hydroxymethyl) -2- (piperidin-4-yloxy) -5H-pyrrole [ 2,3-b] pyrazine-7-carboxamide (200 mg, ~ 0.29 mmol) as an oil that was used for the next step without further preparation. LC / MS (M + H) 348.2. Step 3. N- (tert-Butyl) -2- (piperidin-4-yloxy) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. The TFA salt of N- (tert-butyl) -5- (hydroxymethyl) -2- (piperidin-4-yloxy) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (200 mg, ~ 0 , 29 mmol) was dissolved in a mixed NH3 ^ H2O / MeOH solution (1.8 mL / 5.4 mL, 1: 3, v / v) at room temperature. The mixture was stirred at room temperature for 2 h. TLC (DCM / MeOH, 10: 1) showed that the starting material was consumed. The resulting mixture was evaporated in vacuo, and chased with DCM several times to provide an N- (tert-butyl) -2- (piperidin-4-yloxy) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide crude (160 mg, ~ 0.29 mmol) as an oil that was used for the next step without further preparation. LC / MS (M + H) 318.2. Step 4. 2 - (((1-Acryloylpiperidin-4-yl) oxy) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. To a solution of N- (tert-butyl) -2- (piperidin-4-yloxy) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (80 mg, ~ 0.145 mmol) in a mixed solution of THF / H2O (2 mL / 2 mL, 1: 1, v / v) at room temperature DIPEA (56 mg, 0.435 mmol) was added dropwise. The mixture was then cooled to 0 ° C and acryloyl chloride (26 mg, 0.29 mmol) was added dropwise. After the addition, the mixture was stirred at 0 ° C for 2 h. TLC (DCM / MeOH, 10: 1) showed that the reaction was complete. To the mixture, 10 ml of H2O were added, and the aqueous mixture extracted with ethyl acetate (10 ml x 2). The combined organic fractions were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by means of preparative HPLC to provide 2 - ((1-acryloylpiperidin-4-yl) oxy) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (30 mg total, 30% 3-step) as a white solid. LC / MS (M + H) 372.2. 1H NMR (400 MHz, DMSO-d6) δ 8,114 (s, 1H), 7,981 (s, 1H), 7,790 (s, 1H), 6,870-6,802 (m, 1H), 6,126-6,078 (m, 1H), 5.688-5.656 (m, 1H), 5.236-5.217 (m, 1H), 3.946 (s, 2H), 3.461 (m, 3H), 2.080 (m, 2H), 1.838-1.722 (m, 2H), 1.428 ( s, 9H). Example 339: 2 - ((1-Acryloylpiperidin-4-yl) oxy) -N-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxamide.
[095] Prepared as in Example 176: (((1-acryloylpiperidin-4-yl) oxy) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide, except using 2- bromo-N-isopropyl-5 - ((2- (trimethyl-silyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide in the first step. LC / MS (M + H) 358.2. 1H NMR (400 MHz, DMSO-d6) δ 1.15 - 1.38 (m, 6 H) 1.74 (br. S., 2 H) 2.13 (br. S., 2 H) 3, 41 - 3.60 (m, 2 H) 3.84 - 4.28 (m, 3 H) 5.25 (dt, J = 8.09, 4.11 Hz, 1 H) 5.59 - 5, 80 (m, 1 H) 6.13 (dd, J = 16.69, 2.38 Hz, 1 H) 6.87 (dd, J = 16.69, 10.42 Hz, 1 H) 7.78 (d, J = 7.53 Hz, 1 H) 7.95 - 8.07 (m, 1 H) 8.13 - 8.32 (m, 1 H) 11.76 - 12.61 (m, 1 H). Example 341: 2 - ((((2S, 4S) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7- carboxamide. Example 342: 2 - ((((2R, 4R) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7- carboxamide. Step 1. 4 - (((7- (tert-butylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) -2- (2S, 4S) -tert-butyl methylpiperidine-1-carboxylate. To a solution of 2-bromo-N- (tert-butyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (250 mg, 0 , 58 mmol) in 15 mL of toluene (2S, 4S) -tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (250 mg, 1.17 mmol) and Cs2CO3 (381 mg, 1.17 mmol) at room temperature. The mixture was degassed and purged with N2 several times. Pd2 (dba) 3 (55 mg, 0.058 mmol) and dppf (40 mg, 0.075 mmol) were added and the flask degassed and purged with N2 several times as before. The mixture was heated to 100 ° C overnight. TLC (petroleum ether / EtOAc, 2: 1) showed that the starting material was completely consumed. The resulting mixture was cooled to room temperature and the mixture was diluted with H2O (30 ml). The aqueous mixture was extracted with ethyl acetate (30 ml x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated and purified by chromatography (silica, petroleum ether / EtOAc 10: 1 to 1: 2) to provide 4 - ((7- (tert-butylcarbamoyl) - (2S, 4S) -tert-butyl 5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) -2-methylpiperidine-1-carboxylate (308 mg, 95%) as an oil. Step 2. N- (tert-Butyl) -2 - ((((2S, 4S) -2-methylpiperidin-4-yl) amino) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. 4 - ((7- (tert-Butylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl) amino) -2-methylpiperidine-1 (2S, 4S) -tert-butyl carboxylate (345 mg, 0.616 mmol) was dissolved in a mixed solution of TFA / DCM (1 mL / 7 mL, 1: 7, v / v) at room temperature. The mixture was stirred at room temperature overnight. LC-MS indicated the starting material consumed. The resulting mixture was evaporated in vacuo, and chased with DCM several times to provide the crude TFA salt of N- (tert-butyl) -5- (hydroxymethyl) -2 - (((2S, 4S) -2-methylpiperidin- 4-yl) amino) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (500 mg, ~ 0.616 mmol) as an oil that was used for the next step without further preparation. LC / MS (M + H) 361.2.
[096] The TFA salt of N- (tert-butyl) -5- (hydroxymethyl) -2 - (((2S, 4S) -2- methylpiperidin-4-yl) amino) -5H-pyrrole [2,3 -b] pyrazine-7-carboxamide (500 mg, ~ 0.616 mmol) was dissolved in a mixed solution of NH3 ^ H2O / MeOH (3 mL / 9 mL, 1: 3, v / v) at room temperature. The mixture was stirred at room temperature for 2 h. LC-MS showed that the starting material was consumed. The resulting mixture was evaporated in vacuo, and chased with DCM several times to provide an N- (tert-butyl) -2 - (((2S, 4S) -2-methylpiperidin-4-yl) amino) -5H- crude pyrrole [2,3-b] pyrazine-7-carboxamide (500 mg, ~ 0.616 mmol) as an oil, which was used for the next step without further preparation. LC / MS (M + H) 331.2. Step 3. rac-2 - ((((2S, 4S) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine- 7-carboxamide. To a solution of N- (tert-butyl) -2 - (((2S, 4S) -2-methylpiperidin-4-yl) amino) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (500 mg, ~ 0.616 mmol) in a mixed THF / H2O solution (8 mL, 1: 1, v / v) at room temperature DIPEA (232 mg, 1.8 mmol) was added dropwise. The mixture was then cooled to 0 oC and acryloyl chloride (108.6 mg, 1.2 mmol) was added dropwise at 0 oC. After the addition, the mixture was warmed to room temperature and stirred for 2 h. TLC (DCM / MeOH, 10: 1) showed that the reaction was complete. The mixture was diluted with 10 ml of H2O, and extracted with ethyl acetate (10 ml x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by means of preparative HPLC to provide rac-2 - (((2S, 4S) -1-acryloyl-2-methyl-piperidin-4-yl) amino) -N- (tert-butyl) -5H - pyrrole [2,3-b] pyrazine-7-carboxamide (32 mg total, 14% from 3 steps) as a white solid. LC / MS (M + H) 385.2. 1H NMR (400 MHz, DMSO-d6) δ 8.776 (s, 1H), 8.107 (s, 1H), 7.999-7.991 (d, 1H), 7.673 (s, 1H), 6.622-6.554 (m, 1H), 6,352-6,306 (m, 1H), 5,729-5,698 (m, 1H), 4,596-4,582 (d, 2H), 4,240-4,191 (m, 2H), 3,333-3,273 (m, 1H), 2,176-2,090 (m , 2H), 1.970-1.925 (m, 2H), 1.503 (s, 9H) 1.407-1.390 (d, 3H). Step 4. 2 - ((((2S, 4S) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) - 5H-pyrrolo [2,3-b] pyrazine-7- carboxamide and 2 - (((2R, 4R) -1-acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide . rac-2 - ((((2S, 4S) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide was purified by chiral SFC (21 x 250 ChiralPak IA, CO2 / EtOH) to provide two peaks, arbitrarily assigned absolute stereochemistry. Peak 1: 2 - ((((2S, 4S) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) - 5H-pyrrolo [2,3-b] pyrazine-7- carboxamide. LC / MS (M + H) 385.2. Peak 2: 2 - ((((2R, 4R) -1-Acryloyl-2-methylpiperidin-4-yl) amino) -N- (tert-butyl) - 5H-pyrrolo [2,3-b] pyrazine-7- carboxamide. LC / MS (M + H) 385.2. Example 343: 2 - ((1-Acryloylpiperidin-4-yl) amino) -N- (prop-2-in-1-yl) - 5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. Step 1. 4 - ((7- (Prop-2-in-1-ylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl ) tert-butyl amino) piperidine-1-carboxylate. To a stirred solution of 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b ] pyrazine-7-carboxylic (3 g, 6.1 mmol) in 50 mL of DMF was added HATU (2.78 g, 7.32 mmol) at 0 ° C. After the addition, the mixture was stirred at room temperature for 20 min. Then, prop-2-in-1-amine compound (0.67 g, 12.2 mmol) and Et3N (1.23 g, 12.2 mmol) were added separately. After the addition, the mixture was stirred at room temperature for 3 hours. LC-MS indicated that the acid was completely consumed. To the mixture was added H2O (70 ml) and the aqueous mixture extracted with ethyl acetate (50 ml x 4). The organic extracts were dried over anhydrous Na2SO4 and the solvent removed in vacuo. The crude product was purified by column chromatography (silica, EtOAc / Hep) to provide 4 - ((7- (prop-2-in-1-ylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl ) -5H- pyrrolo [2,3-b] pyrazin-2-yl) amino) tert-butyl piperidine-1-carboxylate (2.7 g, 83%) as a yellow solid. 1H NMR (400 MHz, CHCl3-d) δ -0.07 - -0.05 (m, 7 H) 0.85 - 0.95 (m, 2 H) 1.48 (s, 9 H) 1, 66 (br s, 6 H) 2.16 (d, J = 9.54 Hz, 2 H) 2.29 (t, J = 2.51 Hz, 1 H) 2.94 - 3.06 (m, 2 H) 3.47 - 3.56 (m, 3 H) 4.01 (br s, 1 H) 4.12 (d, J = 7.28 Hz, 2 H) 4.32 (d, J = 2.01 Hz, 2 H) 4.50 - 4.62 (m, 1 H) 5.55 (s, 2 H) 7.66 (s, 1 H) 8.04 (s, 1 H) 8, 39 (t, J = 4.89 Hz, 1 H). Step 2. 5- (Hydroxymethyl) -2- (piperidin-4-ylamino) -N- (prop-2-in-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. A solution of 4 - ((7- (prop-2-in-1-ylcarbamoyl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl ) tert-butyl amino) piperidine-1-carboxylate (2.2 g, 4.16 mmol) in anhydrous DCM (10 mL) was cooled to -5 oC in an ice-methanol bath. Then, TFA (20 ml) was added dropwise. After the addition, the cooled bath was removed and the resulting solution was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was completed. The reaction solution was concentrated to remove most of the DCM and TFA. Then, MeOH (10 mL) was added and the resulting solution was concentrated again and dried under high vacuum to provide the TFA salt of 5- (hydroxymethyl) -2- (piperidin-4-ylamino) -N- ( prop-2-in-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (3.57 g,> 100%) as a yellow solid / oil. LC / MS (M + H) = 329.0. Step 3. 2- (Piperidin-4-ylamino) -N- (prop-2-in-1-yl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxamide. To a stirred solution of TFA salt of 5- (hydroxymethyl) -2- (piperidin-4-ylamino) -N- (prop-2-in-1-yl) -5H-pyrrolo [2,3-b] pyrazine -7-carboxamide (3.57 g, crude) in anhydrous MeOH (20 ml) K2CO3 (5.7 g, 41.6 mmol) was added in portions at room temperature. After the addition, the resulting mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was completed. The reaction suspension was filtered, and the filtrate was concentrated to provide 2- (piperidin-4-ylamino) -N- (prop-2-in-1-yl) -5H-pyrrolo [2,3-b] pyrazine- Crude 7-carboxamide (4.47 g,> 100%). LC / MS (M + H) = 299.2 Step 4. 2 - ((1-acryloylpiperidin-4-yl) amino) -N- (prop-2-in-1-yl) -5H-pyrrole [2, 3-b] pyrazine-7-carboxamide.
[097] To a solution of 2- (piperidin-4-ylamino) -N- (prop-2-in-1-yl) - 5H-pyrrolo [2,3-b] pyrazine-7-carboxamide (4.49 g, crude, 4.16 mmol) in THF / H2O (20 mL / 20 mL, V / V = 1: 1) DIPEA (2.7 mL, 20.8 mmol) was added dropwise. The resulting mixture was cooled to 0 ° C and acryloyl chloride (376 mg, 4.16 mmol) was added dropwise at 0 ° C. After the addition, the mixture was stirred at 0 ° C for 1 h. LC-MS indicated that ~ 20% of starting material was left. More acryloyl chloride (376 mg) was added at 0-5 oC and then stirred at temperature for 0.5 h. LC-MS indicated that most of the starting material was consumed. The reaction mixture was extracted with ethyl acetate (20 ml x 3). The organic phases were combined and washed with brine, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by means of preparative HPLC to provide 2- ((1-acryloylpiperidin-4-yl) amino) -N- (prop-2-in-1-yl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide (9 mg) as an off-white solid. LC / MS (M + H) = 353.0 1H NMR (400 MHz, MeOH-d4) δ 1.48 - 1.62 (m, 2 H) 2.24 (t, J = 14.18 Hz, 2 H) 2.87 (t, J = 2.51 Hz, 1 H) 3.07 - 3.22 (m, 1 H) 3.45 (br. S., 1 H) 4.08 - 4.23 (m, 2 H) 4.30 (d, J = 2.26 Hz, 2 H) 4.50 (d, J = 13.55 Hz, 1 H) 5.77 (dd, J = 10.54, 2.01 Hz, 1 H) 6.23 (dd, J = 16.81, 2.01 Hz, 1 H) 6.84 (dd, J = 16.81, 10.79 Hz, 1 H) 7, 72 (s, 1 H) 7.94 (s, 1 H). Preparation 344: 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine- 7- carboxylic. Step 1. Methyl 2-Bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate. A mixture of 2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid (50 g, 134.8 mmol), K2CO3 (28 g, 202.2 mmol) and iodomethane (34.5 g, 242.9 mmol) in DMF (1200 mL) was heated to 35 ° C for 2 h. The mixture was cooled to room temperature, diluted with water (500 ml) and the mixture extracted with ethyl acetate (800 ml x 3). The combined organic phases were washed with water (2000 ml x 1) and brine (1000 ml x 1), dried over anhydrous Na2SO4 and concentrated to provide 2-bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H -methyl pyrrolo [2,3-b] pyrazine-7-carboxylate (49 g, 94.4%) as a yellow solid. LC / MS (M + H) = 387.9. Step 2. 2 - ((1- (tert-Butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7 -methyl carboxylate. To a solution of methyl 2-bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate (39 g, 101.3 mmol) ml of toluene were added tert-butyl 4-aminopiperidine-1-carboxylate (30.4 g, 151.9 mmol) and Cs2CO3 (66 g, 202.6 mmol) at room temperature. The mixture was degassed and purged with N2 several times, followed by the addition of Pd2 (dba) 3 (9.3 g, 10.13 mmol) and dppf (7.3 g, 13.17 mmol). The mixture was subsequently degassed and purged with N2 several times as before. The resulting mixture was heated to 80 ° C and stirred at this temperature overnight under N2. TLC (petroleum ether: EtOAc = 4: 1) indicated that methyl 2-bromo-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate consumed completely. The resulting mixture was cooled to room temperature and H2O (400 ml) added. The aqueous mixture was extracted with EtOAc (300 ml x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated and purified by column chromatography (silica, petroleum ether: EtOAc 10: 0 to 10: 3) to provide 2 - ((1- ( tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine-7-carboxylate (50 g, 78% ) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm -0.09 (s, 9 H) 0.81 (t, J = 7.91 Hz, 2 H) 1.42 (s, 9 H) 1.94 - 2.01 (m, 3 H) 2.96 (br. S., 2 H) 3.52 (t, J = 8.03 Hz, 2 H) 3.77 (s, 3 H) 3.84 - 3.96 (m, 3 H) 5.54 (s, 2 H) 6.86 (d, J = 7.28 Hz, 1 H) 7.73 (s, 1 H) 8.29 (s, 1 H) Step 3. Acid 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b ] pyrazine-7-carboxylic. To a solution of 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b] pyrazine- Methyl 7-carboxylate (50 g, 99 mmol) in THF (1000 mL) 1 M aqueous NaOH (396 mL) was added. The reaction mixture was stirred at room temperature overnight. TLC (PE / EA = 2: 1) showed that most of the 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl) ethoxy) methyl) - Methyl 5H-pyrrolo [2,3-b] pyrazine-7-carboxylate remained. The reaction mixture was heated to 45 oC for 3 h. TLC (PE / EA = 2: 1) still showed remaining ester. The reaction mixture was heated to 60 ° C overnight. LC-MS indicated about 15% of remaining ester. A solution of NaOH (7.9 g, 198 mmol) in H2O (200 mL) was added to the reaction mixture. The reaction mixture was heated to reflux. LC-MS indicated about 8% of remaining ester. After cooling to room temperature, a majority of the THF was removed and during this time a green solid formed. The mixture was filtered and 45 g of light green solid were obtained. This solid was acidified to pH = 4 ~ 5 with HCl (2 M in H2O) and extracted with ethyl acetate (400 ml x 3). The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 2 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -5 - ((2- (trimethylsilyl ) ethoxy) methyl) - 5H-pyrrolo [2,3-b] pyrazine-7-carboxylic (total 29.1 g, 44% 3-step) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm -0.04 (s, 8 H) 0.89 - 0.95 (m, 2 H) 1.48 (s, 9 H) 2.11 (d, J = 11.29 Hz, 2 H) 2.94 - 3.05 (m, 3 H) 3.53 - 3.60 (m, 2 H) 3.97 (br., 1 H) 4.08 ( br., 2 H) 4.71 (br., 1 H) 5.58 (s, 2 H) 7.72 (s, 1 H) 8.05 (s, 1 H) Biological Evaluation Assay Enzyme Per JAK Caliper at 4 μM or 1mM ATP
[098] Test article was solubilized in dimethyl sulfoxide (DMSO) at a stock concentration of 30 mM. A 11-point half-dilution series was created in DMSO with a higher concentration of 600 μM. The test compound plate also contained positive control wells containing a known inhibitor to define 100% inhibition and negative control wells containing DMSO to define no inhibition. The compound plates were diluted 1 to 60 resulting in a final test compound concentration greater than 10 μM and a 2% concentration of DMSO.
[099] The test article and test controls were added to a 384 well plate. Reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01% bovine serum albumin (BSA), 0.0005% Tween 20, 4 μM or 1 mM ATP and 1 μM of peptide substrate. The JAK3 assays contained 1 μM of the JAKtide peptide (FITC-KGGEEEEYFELVKK). The assays were started by adding the enzyme JAK3 at 1 nM and were incubated at room temperature 75 minutes for JAK3. Enzyme concentrations and incubation times have been optimized for each new enzyme preps and have been modified slightly over time to ensure 20% to 30% phosphorylation. The tests were interrupted with a final concentration of 10 mM EDTA, 0.1% Coating Reagent and 100 mM HEPES, pH = 7.4. The assay plates were placed on a Caliper Life Science Lab Chip 3000 (LC3000) instrument, and each well was sampled using appropriate separation conditions to measure the non-phosphorylated and phosphorylated peptide. Stability of JAK3 Covalent Inhibitors in Rats and Whole Human Blood
[0100] Rat blood was collected from 3 male Sprague-Dawley rats (200-250g, Charles River Laboratories) and pooled for each study. Human blood was collected from a male and a female from healthy individuals at the Occupational Health & Wellness Center at Pfizer, Groton, CT and pooled for each study. Rat and human blood was recently collected in K2-EDTA tubes and kept on ice. An aliquot of the blood was transferred to microtubes and preheated for 10 minutes at 37 ° C using a heating block. The test compound was then added (final concentration of 1 μM) and the incubation was continued for 180 minutes at 37 ° C in duplicates. An aliquot of the incubation mixture was removed at designated time points during the course of the incubation, mixed with an aliquot of acetonitrile containing an internal pattern, vortexed and centrifuged. The resulting supernatants were removed and subjected to LC-MS / MS analyzes to determine concentrations of parent compound. Peak area relationships of the parent compound versus the internal standard were used to determine the% of compound left versus incubation time. IL-15 DE HWB-induced STAT5 phosphorylation assay
[0101] After serially diluting the test compounds 1: 2 in DMSO in the desired concentration (500X of the final), the compounds were also diluted in PBS (adding 4 μL of compound / DMSO in 96 μL of PBS, [DMSO] = 4% , 20X final). To the 96-well polypropylene plates were added 90 μl of HWB (heparin-treated human whole blood) / well, followed by 5 μl / well 4% DMSO in D-PBS or various concentrations of 20X inhibitor in 4% DMSO in D-PBS (w / o Ca + 2 or Mg + 2) to provide 1X in 0.2% DMSO. After mixing and incubating for 45 minutes at 37 ° C, 5 μl of D-PBS (unstimulated control) or 20X 5 μl stocks of human IL-15 (final concentration is 50 ng / ml) were added, and three were mixed times. After incubating 15 minutes at 37 ° C, 1X Lyse / Fix Buffer (BD Phosflow 5x Lyse / Fix Buffer) was added to all wells at 1000 μl / well, then incubated for 20 minutes at 37 ° C and spun 5 minutes at 1200 rpm. After washing in 1000 μl of FACS 1X buffer and rotating for 5 minutes at 1200 rpm, 400 μl of ice-cold Perm Buffer III was added to each well. After mixing gently (1-2X) and incubating on ice for 30 minutes, rotating for 5 minutes at 1200 rpm without interruption, and washing 1X in 1000 ml of cold FACS buffer (D-PBS containing 0.1% BSA and 0, 1% sodium azide) 250 μl / well of the anti-phosphorus STAT5 antibody conjugated to the desired AlexaFluor647 at a 1: 125 dilution in FACS buffer was added. After incubation at 4 ° C overnight, all samples were transferred to a 96-well polypropylene U-base plate and checked by closed flow cytometry on total lymphocytes. IC50 values obtained are listed in the Table. IL-15-induced P-STAT5 from PBMC
[0102] Test compounds were serially diluted in DMSO, with another dilution of the compounds in RPMI 1640 medium (Invitrogen # 72400) supplemented with 10 mM HEPES, pH 7.4, 1 mM sodium pyruvate, and Penicillin / Streptomycin (adding 5 μL of compound / DMSO in 120 μL of Dulbecco's Phosphate Buffered Saline (D-PBS, 1X), [DMSO] = 4%, and mixing the solution by repeated piercing, 6X). IL-15 was diluted to a concentration at 820 ng / mL in RPMI 1640 medium.
[0103] Frozen human PBMC (200 to 250 million cells / flask) was thawed at 37 oC. The cells were transferred to 10 mL of hot medium in a 50 mL conical tube, and centrifuged at 1,200 RPM at room temperature for 5 minutes. The supernatant was aspirated. The cells were suspended in 3 mL of warm human plasma and incubated at 37 oC in a tissue culture incubator for 1.5 to 2 hours. After adding 47 ml of D-PBS (37 oC) to the PBMC / FBS suspension, centrifuging at 1,200 RPM at room temperature for 5 minutes, and aspirating the supernatant, the cells were resuspended in 20 ml of hot RPMI medium. Ninety μL of cell suspension was pipetted per well into a 96-well deep V-shaped base plate and the plate was incubated at 37 oC for 30 min. Five μL of compound were transferred to each well (final 0.2% DMSO), submitted to a gentle vortex and incubated at 37oC for 15 minutes; 5 μL of 4% DMSO / PBS was added to the control wells. After adding 5 μL of 820 ng / mL of human IL-15 (final 41 ng / mL) to each well (5 μL of PBS to the control wells), gently vortex and incubate at 37 oC for 15 minutes, followed by 0.3 mL of 1% paraformaldehyde / PBS (37oC) in each well, and incubating the plate at room temperature for 15 minutes, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) in at room temperature for 5 minutes, and the supernatant was aspirated using an 8-channel or 12-channel collector. After adding 0.8 mL of spotting buffer per well, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room temperature for 5 minutes, and again the supernatant was aspirated using an 8-channel collector. or 12 channels. The plate was vortexed, and 0.35 mL of 90% methanol / 10% H2O (-20oC) was added per well, and the plate incubated on ice for 20 min. After again adding 0.8 mL of staining buffer per well, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room temperature for 5 min, and again the supernatant was aspirated using an 8-channel collector or 12 channels, and then 0.8 ml of staining buffer was added per well. After again adding 0.8 mL of staining buffer per well, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room temperature for 5 min, and again the supernatant was aspirated using an 8-liter collector. channels or 12 channels. Then the plate was vortexed, and 250 μL / well of anti-STAT5 antibody conjugated to Alexa Fluor® 647 (1 to 125 dilution; 1 μL of antibody per 250 μL of staining buffer) was added, and plate was incubated at 4oC overnight in the dark. The 250 μL / well samples were transferred to a 96-well U base plate, and the FACS analysis was performed by closing in total lymphocytes. The samples were analyzed using a BD CaliburTM or BD FACSCantoTM flow cytometer equipped with the BD High Productivity Sampler.

权利要求:
Claims (9)
[0001]
1. Compound, characterized by the fact that it presents the structure:
[0002]
2. Composed according to claim 1, characterized by the fact that it has the structure:
[0003]
3. Compound according to claim 1, characterized by the fact that it is selected from the group consisting of: (R) -1- (3- (5-chloro-7H-pyrrolo [2,3-d] pyrimidine- 4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-hydroxypiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1- (5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - ((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3S, 4R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-fluoropiperidin-1-yl) prop-2-en-1-one; 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-ethylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((2R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2- (hydroxymethyl) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5R) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-fluoropiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((2S, 5R) -5- (5- (2-methoxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en -1-one; 1 - (((3R, 5S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -5-methylpiperidin-1-yl) prop-2-en-1-one; 1 - (((3R, 4S) -3- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -4-methylpiperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; (R) -1- (3- (5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) prop-2-en-1-one; (R) -4- (1-acryloylpiperidin-3-ylamino) -7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile; and, (3R, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -1- acryloylpiperidine-3-carbonitrile; or, a pharmaceutically acceptable salt thereof.
[0004]
4. Compound according to claim 1, characterized by the fact that the compound is selected from the group consisting of: 1 - ((3R, 4S) -3 - ((7H-pyrrole [2,3-d] pyrimidin-4-yl) amino) -4-methylpiperidin-1-yl) prop-2-en-1-one; and 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin-1-yl) prop-2-en-1-one; or a pharmaceutically acceptable salt thereof.
[0005]
5. Compound according to claim 1, characterized by the fact that it is 1 - ((2S, 5R) -5- (7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) -2-methylpiperidin -1-yl) prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.
[0006]
6. Composed according to claim 5, characterized by the fact that it is:
[0007]
7. Pharmaceutical or veterinary composition, characterized in that it comprises a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0008]
8. Composition according to claim 7, characterized by the fact that it is for use in the treatment or prevention of a selected disorder or condition of rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis, Alzheimer's disease, lupus, nephritis, systemic lupus erythematosus, psoriasis, eczema dermatitis, pruritus or other pruritic conditions, vitiligo, alopecia, disorders of autoimmune thyroid, multiple sclerosis, major depression disorder, allergy, asthma, Sjogren's disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune brain myelitis, autoimmune orchitis, Goodpasture disease, autoimmune thrombo-cytopenia, sympathetic ophthalmia, myasthenia severe, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, membranous glomerulopathy, organ transplant rejection, graft versus host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, disc intervertebral, islet, kidneys, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xenotransplant, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type 1 diabetes youth-onset, and complications of diabetes, or thyroiditis, chronic obstructive pulmonary disorder, acute respiratory disease, cachexia, cancer, including alimentary / gastrointestinal cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and breast cancer, ovarian cancer, prostate cancer, leukemia, adult T cell leukemia, large diffuse B cell lymphoma a, activated B cell type, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma septic shock, cardiopulmonary dysfunction, acute myeloid leukemia, leukemia acute T-cell lymphoblastic, multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, or angiogenic-associated disorders including solid tumors, pancreatic cancer, brain tumors, gliomas including astrocytoma, oligodendroglioma, and glioblastoma, traumatic CNS trauma , encephalitis, stroke, and spinal cord injury, epilepsy, chronic neuroinflammation associated with neurodegeneration, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, cerebral ischemia, fronto-temporal lobe dementia, and with neuropsychiatric disorders, including schizophrenia, bipolar disorder, treatment-resistant depression, Post Traumatic Stress Disorder, anxiety, and autoantibody-mediated encephalopathies, ophthalmic diseases, disorders or conditions, including autoimmune diseases of the eye, kerato-conjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleucoma, ocular pemphigus, Mooren's ulcer, scleritis, Grave ophthalmopathy, Vogt-Koyanagi-Harada syndrome, dry keratoconjunctivitis (dry eye), phytidytopathitis, iridescent, iris endocrine, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization.
[0009]
9. Composition according to claim 7, characterized by the fact that it is for use in the treatment or prevention of inflammatory bowel disease.

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法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2020-01-28| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-02-11| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-08-04| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-12-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-02| B09X| Republication of the decision to grant [chapter 9.1.3 patent gazette]|

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2021-04-13| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/11/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201361912074P| true| 2013-12-05|2013-12-05|

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US61/912,074|2013-12-05|

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PCT/IB2014/066202|WO2015083028A1|2013-12-05|2014-11-20|Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides|

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