OA17901A - Pyrrolo[2,3-D]Pyrimidinyl, Pyrrolo[2,3B]Pyrazinyl and Pyrrolo[2,3-D]Pyridinyl Acrylamides. - Google Patents

Pyrrolo[2,3-D]Pyrimidinyl, Pyrrolo[2,3B]Pyrazinyl and Pyrrolo[2,3-D]Pyridinyl Acrylamides. Download PDF

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OA17901A
OA17901A OA1201600205 OA17901A OA 17901 A OA17901 A OA 17901A OA 1201600205 OA1201600205 OA 1201600205 OA 17901 A OA17901 A OA 17901A
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linear
branched chain
chain alkyl
aryl
heteroaryl
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OA1201600205
Inventor
Matthew Frank Brown
Agustin Casimiro-Garcia
Ye Che
Jotham Wadsworth Coe
Mark Edward Flanagan
Adam Matthew Gilbert
Matthew Merrill Hayward
Jonathan David LANGILLE
Justin lan MONTGOMERY
Jean-Baptiste Telliez
Atli Thorarensen
Rayomand Jal Unwalla
John I. Trujillo
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Pfizer Inc.
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Abstract

The present invention provides pharmaceutically active pyrrolo[2,3-d]pyrimidinyl and pyrrolo[2,3-d]pyridinyl acrylamides and analogues thereof. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention also is directed to compositions comprising methods for making such compounds, and methods for treating and preventing conditions mediated by JAK.

Description

The présent invention provides pharmaceutically active heterocyclic acryla5 mides, inter alia, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3djpyridinyl acrylamides and analogues thereof. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention also is directed to compositions comprising methods for making such compounds, and methods for treating and preventing conditions mediated by JAK.
BACKGROUND OF THE INVENTION
Protein kinases are families of enzymes that catalyze the phosphorylation of spécifie residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or in15 appropriate régulation, dys-regulation or de-regulation, 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 cel. lular responses relating to cell growth, cell différentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases.
Thus, protein kinases hâve 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) play a central rôle in cytokine signaling (Kisseleva, et al., Gene, 2002, 285, 1; Yamaoka, et al. Genome Biology, 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molécules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines 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), gamma-common chain family (IL-2, IL-4,IL-7, IL-9, IL-15, IL-21, ), and 1L-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).
There remains a need for new compounds that effectively and selectively inhibit spécifie 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 to various levels in ail 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 hâve 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 can prove useful in the treatment of various immune disorders (Murray, P.J. J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285, 1-24 (2002); O'Shea, J. J., et al., Cell, 109, (suppl.) S121-S131 (2002)) while avoiding JAK2 dépendent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer, H., et al., Cell, 93(3), 397-409 (1998); Parganas, E., et al., Cell, 93(3), 385-95 (1998)).
SUMMARY OF THE INVENTION
The présent invention provides a c a compound having the structure:
or a pharmaceutically acceptable sait or soivate thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, Ο^Οθ linear or branched chain alkyl, Ο3-Ο6 cycloalkyl, C6-C-io aryl, monocyclic or bicyclic •
heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C-|-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, (Ci-C6 linear or branched chain alkyl)heterocyclic, 5 C1-C6 linear or branched chain perfluoroalkyl, C1-C6 linear or branched chain alkoxy,
CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR13SO2R12, -SO2NR13R14, and -NR13SO2NR14R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C-|-C6 linear or branched chain alkyl)aminocarbonyl, and Ο3-Ο6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
A is —(CRaRb)q-(CRcRd)r-> wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, Ο6-Ο10 aryl, monocyclic or bicyclic heteroaryl, comprising 520 and/or 6-membered rings, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-(-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (C-i-C6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain al25 kyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R5, Re, R7, Rs, R9 and R1o are independently selected from hydrogen, CrC6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or
branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrCe linear or branched chain alkyl, (C-|-C6 linear or branched chain alkyl)aryl, (Ci-Οθ linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or Ri, and/or R6 or R7j respectively together with either of R4, R5, Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternatively, R4 or R5, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-
6-membered ring optionally containing one or two O or N atoms;
R11 is hydrogen or deuterium;
R12, R13, Ru and R15 are independently selected from hydrogen, C-|-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, 15 alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
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 CRw or N when the dotted bond to Z’ is a single bond, 20 and Z’ is C; where R16 is C1-C4 alkyl, C6-C-io aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, (heterocyclic)C-i-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, or (C1-C6 linear or branched chain al25 kyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, Y is N, and X is O or —(CReRf)s--, where Re and Rf are independently hy30 drogen, deuterium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)C-i-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and —(CH2)n-- is absent, and when X is —(CReRf)s—, and X is bonded 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 substituted by H, (ii) Z is C, Z’ is C or N, the dotted bond to Z is a single bond, the dotted bond to Z’ being absent, or (iii) Z is C or N, Z’ is C, the dotted bond to Z’ is a single bond, the dotted bond to Z being absent, where said Y being an N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by Ci-C6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
In other aspects, the présent invention also provides: pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a compound of the invention;
methods for treating or preventing a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigoid, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, celiac diseases, proctitis, éosinophilie 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 dépréssion disorder, allergy, asthma, Sjogren’s disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anémia, autoimmune atrophie gastritis of pernicious anémia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves1 disease, primary biliary cirrhosis, chronic aggressive hepatitis, membranous glomerulopathy ,organ transplant rejection, graftversus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertébral dise, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancréas, skin, small intestine, ortrachea, orxeno transplantation, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, auto17901
immune alopecia, Type I or juvénile onset diabètes, and complications from diabètes, orthyroiditis, chronic pulmonary obstructive disorder, acute respiratory disease, cachexia, cancer, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, leukemia, adult T cell leukemia activated B-cell like, diffuse large B cell lymphoma, 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, T cell acute lymphoblastic leukemia, mul10 tiple myeloma, myeloproliferative disorders, proliférative 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 injury, encephalitis, stroke, and spinal cord injury, epilepsy, seizures, chronic neuroinflammation associated with neurodegeneration including Alzheimer’s disease, Parkinson’s disease, Amyotropic Latéral Sclerosis, Huntington's disease, cérébral ischemia, fronto-temporal lobe dementia, and with neuropsychiatrie disorders including schizophrenia, bipolar disorder, treatment résistant dépréssion, Post Traumatic Stress Disorder, anxiety, and auto-antibodies mediated encéphalopathies, Eye diseases, disorders or 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 épithélial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergie conjunctivitis, and ocular neovascularization, comprising the step of administering to a subject an effective amount of a composition comprising a compound or a pharmaceutically acceptable sait thereof set forth herein;
methods for treating conditions or disorders including atopie dermatitis, ecze30 ma, psoriasis, scleroderma, lupus, pruritus, other pruritic conditions, allergie reactions including allergie dermatitis in mammal, horse allergie diseases including bite hypersensitivity, summer eczema, sweet itch in horses, heaves, inflammatory airway
disease, récurrent airway obstruction, airway hyper-responsiveness, and chronic obstruction pulmonary disease by administering to a mammal in need a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable sait thereof; and, methods for the préparation of compounds of the présent invention. The présent invention will be further understood from the following description given by way of example only. The présent invention is directed to a class of pyrrolo[2,3djpyrimidinyl and pyrrolo[2,3-d]pyridinyl acrylamides and analogues thereof. In particular, the présent invention is directed to compounds including pyrrolo[2,310 d]pyrimidinyl and pyrrolo[2,3-d]pyridinyl acrylamides which are useful as inhibitors of JAK, and particularly JAK3. While the présent invention is not so limited, an appréciation of various aspects of the invention will be gained through the following discussion and the examples.
The term “alkyl, alone or in combination, means an acyclic, saturated hydro15 carbon group of the formula CnH2n+i which may 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 from 1 to 6 carbon atoms. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix Cj-Cj indicates a moiety of the integer i to the integer j carbon atoms, inclusive. Thus, for example, C-|-C6 alkyl refers to alkyl of one to six carbon atoms, inclusive.
The term “hydroxy,” as used herein, means an OH radical. The term “heterocyclic” refers to a saturated or partially saturated (i.e. non aromatic) heterocycle which may be attached via a ring nitrogen atom (when the heterocycle is attached to a carbon atom) or a ring carbon atom (in ail cases). Equally, when substituted, the substituent may be located on a ring nitrogen atom (if the substituent is joined through a carbon atom) or a ring carbon atom (in ail cases). Spécifie examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl and diazepinyl.
The term “aryl” refers to an aromatic monocyclic or bicyclic hydrocarbon which may be attached via a ring carbon atom. Equally, when substituted, the substituent may be located on a ring carbon atom. Spécifie examples include phenyl, toluyl, xylyl, trimethylphenyl, and naphthyl. Examples of aryl substituents include alkyl, hy5 droxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO2Me, benzyl, and substituted benzyl.
The term “heteroaryl” refers to an aromatic heterocycle which may be attached via a ring carbon atom (in ail cases) or a ring nitrogen atom with an appropriate valency (when the heterocycle is attached to a carbon atom). Equally, when sub10 stituted, the substituent may be located on a ring carbon atom (in ail cases) or a ring nitrogen atom with an appropriate valency (if the substituent is joined through a carbon atom). Spécifie examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. The term ‘'cycloalkyl means 15 a monocyclic, saturated hydrocarbon group of the formula CnH2n-i· Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, a cycloalkyl group comprises from 3 to 8 carbon atoms.
The terms “halo” and “halogen” refer to fluoride (F), chloride (Cl), bromide (Br) oriodide(l).
The term mammal refers to human, livestock or companion animais.
The term “companion animal” or “companion animais” refers to animais kept as pets or household animal. Examples of companion animais include dogs, cats, and rodents including hamsters, guinea pigs, gerbils and the like, rabbits, ferrets and birds.
The term “livestock” refers to animais reared or raised in an agricultural setting to make products such as food or fiber, or for its labor. In some embodiments, livestock are suitable for consumption by mammals, for example humans. Examples of livestock animais include cattle, goats, horses, pigs, sheep, including lambs, and rabbits, as well as birds, such as chickens, ducks and turkeys.
The term “treating” or “treatment” means an alleviation of symptoms associated with a disease, disorder or condition, or hait of further progression or worsening of those symptoms. Depending on the disease and condition of the patient, the term “treatment” as used herein may include one or more of curative, palliative and prophylactic treatment. Treatment can also include administering a pharmaceutical formulation of the présent invention in combination with other thérapies.
The term therapeutically-effective indicates the capability of an agent to prevent, or improve the severity of, the disorder, while avoiding adverse side effects typically associated with alternative thérapies. The phrase therapeutically-effective is to be understood to be équivalent to the phrase effective for the treatment, prévention, or amelioration, and both are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of cancer, cardiovascular disease, or pain and inflammation and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative thérapies.
“Pharmaceutically acceptable” means suitable for use in mammals, companion animais or livestock animais.
If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
DETAILED DESCRIPTION OFTHE INVENTION
The présent invention is related to novel compounds which are sélective JAK3 modulators useful for the treatment of diseases and conditions associated with dysrégulation of the JAK3. The présent invention further provides pharmaceutical compositions comprising such JAK3 modulators as well as methods of treating and preventing such diseases and conditions. Accordingly, the présent invention provides a compound having the structure:
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or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (C-i-Ce linear or branched chain alkyl)heteroaryl, (Ci-C6 linear or branched chain alkyl)heterocyclic, Ci-C6 linear or branched chain perfluoroalkyl, Ci-C6 linear or branched chain alkoxy, Cj-Ce linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR13SO2R12, -SO2NR13R14, and -NR13SO2NR14R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, C-|-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
A is --(CRaRb)c?-(CRcRd)/'-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5 and/or 6-membered rings, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (Οι-Ο6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R5, R6, R7, Rs, R9 and Rw are independently selected from hydrogen, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C-i-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (C-|-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1: and/or R6 or R7, respectively together with either of R4, R5, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R4 or R5, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R3 and Rg may together form a 3-
6-membered ring optionally containing one or two O or N atoms;
R11 is hydrogen or deuterium;
R12, R13, Ru and R-|5 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Ci0 aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
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 CRw or N when the dotted bond to Z’ is a single bond, and Z’ is C; where Ri6 is CrC4 alkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-Ce linear or branched chain alkyl, (heterocyclic)CrC6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, or (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, 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, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)Ci-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and — (CH2)n— is absent, and when X is --(CReRf)s--, and X is bonded 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 substituted by H, (ii) Z is C, Z’ is C or N, the dotted bond to Z is a single bond, the dotted bond to Z’ being absent, or (iii) Z is C or N, Z’ is C, the dotted bond to Z’ is a single bond, the dotted bond to Z being absent, where said Y being an N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by Ci-C6 linear or branched chain alkyl or Ο3-Οβ cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
In one embodiment, the invention provides a compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)C-i-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, (C-|-C6 linear or branched chain alkyl)heterocyclic, Ci-C6 linear or branched chain perfluoroalkyl, C-i-C6 linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, -SORi2, -SO2R12, NR13SO2R12, -SO2NR13R14, and -NR13SO2NR14R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Οι-Οβ linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, Ο-ι-Οβ linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
A is -(CRaRbjq-iCRcRd)/--, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, C-|-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)CrCe linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclicjCrCe linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl) heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R6, Rs, R9 and R1o are independently selected from hydrogen, C1C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrCe linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ο-ι-Οθ linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1( and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
R11 is hydrogen or deuterium;
R12, R13, Ru and R15 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Ci0 aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
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, • 15 and Z’ is N or CR16; or, Z is CRw or N when the dotted bond to Z’ is a single bond, and Z’ is C; where R-t6 is C1-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, (heterocyclic)CrC6 linear or branched chain alkyl, (C-i-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, or (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, 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, C-i-C6 linear or branched chain alkyl, Ο3-Οβ cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (C-|-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)C-i-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and —(CH2)n— is absent, and when X is —(CReRf)s--, and X is bonded 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 substituted by H, (ii) Z is C, Z’ is C or N, the dotted bond to Z is a single bond, the dotted bond to Z’ being absent, or (iii) Z is C or N, Z’ is C, the dotted bond to Z’ is a single bond, the dotted bond to Z being absent, where said Y being an N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring op25 tionally substituted by CrC6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, r and s are independently 0, 1 or 2.
In another embodiment, the invention provides a compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclicJCrCe linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, (C1-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, Ci-C6 linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (CrC6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SORi2, -SO2Ri2, NR13SO2R12, -SO2NR13Ri4, and -NR-i3SO2NRuRi5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C-i-Ce linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
A is — (CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, C-|-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)C-f-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyQheteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, R-i, R4, R6, Rs, R9 and R10 are independently selected from hydrogen, C1C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C-|-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternative^, Ro or R-i, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ο^Οβ linear alkyl chain; and/or, alternatively, R4) respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C-i-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
R11 is hydrogen ordeuterium;
R12, R13, Ru and R15 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Ci0 aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
Z is CRi6 or N, where R-i6 is C1-C4 alkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-Ce linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, (heterocyclic)C1-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, or (Ο-ι-Οβ linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, X is O or —(CReRf)s—, where Re and Rf are independently hydrogen, deutérium, halo, hydroxy, C1-C4 alkoxy, amino, CF3, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (CfC6 linear or branched chain alkyl)heteroaryl, (heteroaryl)CrCe linear or branched chain alkyl, or (heterocyclic)Ci-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded 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 (i) the adjacent N atom is substituted by H, or (ii) said N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by CrC6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-C6 linear or branched chain alkyl, (heteroaryl)C-i-C6 linear or branched chain alkyl, (heterocyclic)C-i-C6 line • 19 ar or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-Cô linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, C1-C6 linear or branched chain alkoxy, C-rC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12j NRi3SO2Ri2, -SO2NRi3Ri4, and -NRi3SO2NR14Ri5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (CrC6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
A is — (CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)Ci-Ce linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, Re, Re, Rg and R1o are independently selected from hydrogen, C1C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6C-io aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-C6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain 30 alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain al17901 • 20 kyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or Ri, and/or R6, respectively together 5 with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
Z is CR16 or N, where R-|6 is CrC4 alkyl, Οθ-Ο-ιο aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C-|-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, or (C1-C6 linear or branched chain al15 kyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
Ru is hydrogen or deuterium;
R12, R13, Ru and R15 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, Οβ-Ο-ιο aryl, alkylaryl, and (aryl)Ci-Ce linear or branched chain alkyl; and, p, q, and rare independently 0, 1 or 2.
In another embodiment, the invention provides the compound having the structure:
Φ 21
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-|-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)C-i-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic,
Ci-C6 linear or branched chain perfluoroalkyl, Ο-ι-Οβ linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR-|2, -SO2R12, NRi3SO2R12, -SO2NR13Ri4, and -NRi3SO2NRuRi5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
Ra, Rb, Rc and Rd are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Οι-Οθ linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4j R6, Re, R9 and R10 are independently selected from hydrogen, Cr C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrCe linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (C-|-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and Ο3-Ο6 cycloalkyl; where, alternative^, Ro or R1( and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternative^, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
Z is CR16 or N, where R-|6 is C1-C4 alkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, or (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
Rn is hydrogen or deuterium; and,
Ri2, Ri3, Ru and R15 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6-Cw aryl, alkylaryl, and (aryl)C-|-C6 linear or branched chain alkyl.
In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (C-i-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, CrC6 linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (CrC6 linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2Ri2, NRi3SO2Ri2, -SO2NR13Ri4, and -NRi3SO2NRuRi5,· where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C-i-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, Ci-Οθ linear or branched chain alkyl, Οι-Ce linear or branched chain perfluoroalkyl, halogen, and cyano;
Ra, Rb, Rc and Rd are independently selected from hydrogen, C-|-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-Ce linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R6, Rs, R9 and R1o are independently selected from hydrogen, Cr C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, ΟβCw aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-Ce linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C-|-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl,. (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ο-ι-Οβ linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R-i, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C-|-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
Ru is hydrogen or deuterium; and,
Ri2, R13, Ru and R-i5 are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, Οι-Οθ linear or branched chain perfluoroalkyl, C6-C10 aryl, alkylaryl, and (aryl)C-|-C6 linear or branched chain alkyl.
In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, C-i-C6 linear or branched chain alkyl, Ο3-Οβ cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ο-ι-Οθ linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, Ο-ι-Οθ linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, -SOR-|2, -SO2R12, NR-i3SO2Ri2, -SO2NR13Ri4, and -NR13SO2NRuRi5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C-i-Ce linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
Ra, Rb> Rc and Rd are independently selected from hydrogen, CrC6 linear or branched chain alkyl, C-|-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C-|-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocycIic)C-|-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R6, Rs, R9 and R10 are independently selected from hydrogen, C1C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternative^, Ro or Ri, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternative^, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
R11 is hydrogen or deuterium; and,
R-I2, Ri3, Ru and R15 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Cio aryl, alkylaryl, and (aryl)C-i-C6 linear or branched chain alkyl.
In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, Οι-Όβ linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, (C1-C6 linear or branched chain alkyl)heterocyclic, C-i-C6 linear or branched chain perfluoroalkyl, C-|-C6 linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C-i-C6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR-i2, -SO2R12, NRi3SO2Ri2, -SO2NRi3Ri4, and -NR13SO2NR14Ri5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C-i-Ce linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, C-|-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
A is --(CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, haiogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-i-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkyiamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ra, Rb, Rc and Rd are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain 15 alkyl, heteroaryl, haiogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, wherein said alkyl is further optionally substituted with one or.more substituents selected from the 20 group consisting of halo, hydroxy, methoxy, amino, alkyiamino, dialkylamino, CF3, and C3-C6 cycloalkyl, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkyiamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R6, Rb, R9 and R10 are independently selected from hydrogen, Cr 25 C6 linear or branched chain alkyl, Οι-Οθ linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, haiogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-i-Ce linear or branched chain alkyl, 30 (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R^ and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ο-ι-Οβ linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C-|-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-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, Ru and R15 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, Y is N, and X is O or --(CReRf)s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, Ci-C4 alkoxy, amino, CF3, C-|-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (ary))Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)C-|-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and — (CH2)n—· is absent, and when X is — (CReRf)s--> and X is bonded 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 substituted by H, or (ii) said N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by C-|-C6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
In another embodiment, the invention provides the compound having the structure:
• 30
or a pharmaceutically acceptable sait thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, Ο-ι-Οβ linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, C1-C6 linear or branched chain perfluoroalkyl, C-|-C6 linear or branched chain alkoxy,
C1-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Οι-Οθ linear or branched chain alkyl)aminocarbonylamino, (C1-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR13SO2Ri2, -SO2NR13R14, and -NR-13SO2NR14R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents se15 lected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C-|-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and 20 cyano;
Ro, R-i, Re, Rs, Rg and R1o are independently selected from hydrogen, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain 25 alkyl, heteroaryl, halogen, cyano, hydroxyl, C-i-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain al kyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or Ri, and/or R6, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Cf-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
Ru is hydrogen ordeuterium; and,
R12, R13, Ru and Ri5 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-C-io aryl, alkylaryl, and (aryl)Ci~C6 linear or branched chain alkyl.
In another embodiment, the invention provides the compound having the structure:
or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
R2 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)C-i-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, Ci-C6 linear or branched chain perfluoroalkyl, Ci-C6 linear or branched chain alkoxy, C1-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-Ce linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NRi3SO2R12, -SO2NR13R14, and -NR13SO2NRi4R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents se5 lected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, halogen, and 10 cyano;
A is —(CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)Ci-Ce linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with 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, C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-Ce linear or branched chain 25 alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (Ο-ι-Οθ linear or branched chain alkyl)heterocyclic, wherein said alkyl is further optionally substituted with one or more substituents selected from the 30 group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl, where said alkyl is further optionally substituted with one or
more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
Ro, Ri, R4, R6, Rs> R9 and Rw are independently selected from hydrogen, C1C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C65 C™ aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (C-i-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain al10 kyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1? and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Ro or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R8 and R9 may together form a 3-6-membered ring optionally containing one or two O or N atoms; and, . Ru is hydrogen or deuterium;
Y is O or N, where when Y is O, n is 0;
R12, R13, Ru and R15 are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, 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, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)C-|-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and --(CH2)n-- is absent, and when X is —(CReRf)s--, and X is bonded 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 substituted by H, or (ii) said N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by Ci-C6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
Specifically, the invention provides compounds selected from the group consisting of:
2-(1-acryloylpiperidin-4-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
N-isopropyl-2-(3-(N-methylacrylamido)azetidin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
2-((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-ylamino)-N-isopropyl-5H-pyrrolo[2,3-
b]pyrazine-7-carboxamide;
(S)-2-(1-acryloyIpyrrolidin-3-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
(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-7carboxamide; and, (S)-2-((1-acryloyIpyrrolidin-3-yl)methylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-
7-carboxamide; or, a pharmaceutically acceptable sait thereof.
The invention further 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-2en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-hydroxypiperidin-1-yl)prop-2en-1-one;
» 35 (R)-1-(3-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1yl)prop-2-en-1-one;
1-(5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(hydroxymethyl)piperidin-1-yl)prop-2en-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-2en-1-one;
1-((3S,4R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-fluoropiperidin-1-yl)prop-2-en10 1-one;
1-((2S,5R)-5-(7H-pyrrolo[2J3-d]pyrimidin-4-y[amino)-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;
-((3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydro-1 H-pyrrolo[2,3-c]pyridin15 6(2H,7H,7aH)-yl)prop-2-en-1 -one;
(R)-1 -(3-(3-chloro-1 H-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-8yl)prop-2-en-1-one;
1-((2R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(hydroxymethyl)piperidin-120 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 -((3RJ5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1 -yl)prop-2en-1-one;
1-((2S,5R)-5-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2methylpiperidin-1 -yl)prop-2-en-1 -one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1-yl)prop-230 en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1-yl)prop-2en-1-one;
• 36 (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-2en-1-one;
(R)-1 -(3-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1 -yl)prop-2-en-1 5 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 sait thereof.
In particular, the invention provides 2-(1-acryloylpiperidin-4-ylamino)-N10 isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide; or, a pharmaceutically acceptable sait thereof; N-isopropyl-2-(3-(N-methylacrylamido)azetidin-1-yl)-5H-pyrrolo[2,3-
b]pyrazine-7-carboxamide; or, a pharmaceutically acceptable sait thereof; 2((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-yIamino)-N-isopropyl-5H-pyrrolo[2,3-
b]pyrazine-7-carboxamide; or, a pharmaceutically acceptable sait thereof; (S)-2-(1- acryloylpyrrolidin-3-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide; or, a pharmaceutically acceptable sait thereof; (S)-2-((1-acryloylpyrrolidin-2yl)methylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide; or a pharmaceutically acceptable sait thereof; 1-((3aS,7aS)-1-(7H-pyrrolo[2,3-d]pyrimidin-4yl)tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)prop-2-en-1-one; or, a phar20 maceutically acceptable sait thereof; 1 -((1 R,2R,5R)-2-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one, or a pharmaceutically acceptable sait thereof; 1-((3R,4S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4methylpiperidin-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable sait thereof; 1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1-yl)prop-225 en-1 -one; or, a pharmaceutically acceptable sait thereof; (R)-4-(1 -acryloylpiperidin-3ylamino)-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile; or, a pharmaceutically acceptable sait thereof.
The présent invention also provides a pharmaceutical or a veterinary composition comprising a compound described above, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.
The présent invention also provides a method for treating or preventing a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus,
bullous pemphigoid, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, celiac diseases, proctitis, éosinophilie 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 dépréssion disorder, allergy, asthma, Sjogren’s disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anémia, autoimmune atrophie gastritis of pernicious anémia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, auto10 immune thrombocytopenia, 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, intervertébral dise, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancréas, skin, small intestine, or trachea, or xeno transplantation, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvénile onset diabètes, and complications from diabètes, or thyroiditis, chronic pulmonary obstructive disorder, acute respiratory disease, cachexia, cancer, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer in20 cluding mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, leukemia, adult T cell Ieukemia activated B-cell like, diffuse large B cell lymphoma, 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, T cell acute lymphoblastic leukemia, multiple myeloma, myeloproliferative disorders, proliférative 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 injury, encephalitis, stroke, and spinal cord injury, epilepsy, seizures, chronic neuroinflammation associated with neurodegeneration including Alzheimer’s disease, Parkinson’s disease, Amyotropic Latéral Sclerosis, Huntington's disease, cérébral ischemia, fronto-temporal lobe dementia, and with neuropsychiatrie disorders » 38 including schizophrenia, bipolar disorder, treatment résistant dépréssion, Post Traumatic Stress Disorder, anxiety, and auto-antibodies mediated encéphalopathies, Eye diseases, disorders or 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 épithélial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergie conjunctivitis, and ocular neovas10 cularization, comprising the step of administering to a subject an effective amount of a composition comprising a compound set forth hereinabove.
In spécifie embodiments, the invention provides the method of treatment or prévention noted above, wherein the compound is selected from the group consisting of:
2-(1-acryloylpiperidin-4-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
N-isopropyl-2-(3-(N-methylacrylamido)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-7carboxamide;
(S)-2-((1-acryloyIpyrrolidin-2-yl)methylamino)-N-isopropyl-5H-pyrrolo[2,3-
b]pyrazine-7-carboxamide;
2-((1 R,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; 30 (R)-4-(1 -acryloylpiperidin-3-ylamino)-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile;
(R)-1-(3-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-hydroxypiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1yl)prop-2-en-1-one;
1-(5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(hydroxymethyl)piperidin-1yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1yl)prop-2-en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1yl)prop-2-en-1-one;
1-((3S,4R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-yIamino)-4-fluoropiperidin-1yl)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-ylannino)piperidin-1 -yl)prop-2-en-1 -one;
-((3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydro-1 H-pyrrolo[2,3-
c]pyridin-6(2H,7H,7aH)-yl)prop-2-en-1-one;
(R)-1 -(3-(3-chloro-1 H-pyrrolo[2,3-b]pyridin-4-ylamino)piperidin-1 -yl)prop-2-en1-one;
-((1 R,2R,5R)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-8azabicyclo[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-l -yl)prop-2-en-1 -one;
1-((3R,5R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1yl)prop-2-en-1-one;
1-((2S,5R)-5-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2methylpiperidin-1 -yl)prop-2-en-1 -one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1yl)prop-2-en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
1- ((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
(R) -4-(1-acryloylpiperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5carbonitrile; and, (3R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-acryloylpiperidine-3carbonitrile; or, a pharmaceutically acceptable sait thereof.
The présent 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 sait thereof.
In spécifie embodiments, the invention provides the method for treating or preventing inflammatory bowel disease, wherein the compound is selected from the group consisting of:
2- (1-acryloylpiperidin-4-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
N-isopropyl-2-(3-(N-methylacrylamido)azetidin-1-yl)-5H-pyrrolo[2,3-
b]pyrazine-7-carboxamide;
2-((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-ylamino)-N-isopropyl-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide;
(S) -2-(1-acryloylpyrrolidin-3-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
(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-2en-1-one;
1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-hydroxypiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1yl)prop-2-en-1-one;
1-(5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(hydroxymethyl)piperidin-1yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1yl)prop-2-en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-meÎhylpiperidin-1yl)prop-2-en-1-one;
1-((3S,4R)-3-(7H-pyrrolo[2J3-d]pyrimidin-4-ylamino)-4-fluoropipendin-1yl)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;
-((3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydro-1 H-pyrrolo[2,3-
c] pyridin-6(2H,7H,7aH)-yl)prop-2-en-1-one;
(R)-1 -(3-(3-chloro-1 H-pyrrolo[2,3-b]pyridin-4-ylamino)piperidin-1 -yl)prop-2-en1-one;
-((1 R,2R,5R)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-8azabicyclo[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-l -yl)prop-2-en-1 -one;
1-((3R,5R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1yl)prop-2-en-1-one;
1-((2S,5R)-5-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2methylpiperidin-1 -yl)prop-2-en-1 -one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1yl)prop-2-en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1yl)prop-2-en-1-one;
(R)-1-(3-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
(R)-4-(1-acryloylpiperidin-3-ylamino)-7H-pyrroIo[2,3-d]pyrimidine-5carbonitrile; and, (3R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-acryloylpiperidine-3carbonitrile; or, a pharmaceutically acceptable sait thereof.
More generally, the présent invention provides a method of treating a disorder or condition related to dysrégulation of JAK, and particularly of JAK3, in a subject, comprising administering to the subject a therapeutically effective amount of the compound described above, or a pharmaceutically acceptable sait thereof.
In certain embodiments, the therapeutically effective amount used in accord with the method is from 0.01 mg/kg of body weight/day to 100 mg/kg of body weight/day. In certain other embodiments, the therapeutically effective amount used in accord with the method is the therapeutically effective amount is from 0.1 mg/kg of body weight/day to 10 mg/kg of body weight/day. In the practice of the method, the compound is preferably selected from those specified above.
In certain embodiments, the therapeutically effective amount used in accord with the method is from 0.01 mg/kg of body weight/day to 100 mg/kg of body weight/day. In certain other embodiments, the therapeutically effective amount used in accord with the method is wherein the therapeutically effective amount is from 0.1 mg/kg of body weight/day to 10 mg/kg of body weight/day. In accord with the method, the mammal treated with the compound of the invention is selected from companion animais, dogs, and Iivestock. In certain embodiments, the compound of the invention, or a pharmaceutically acceptable sait thereof, may be administered in accord with the method orally, parenterally, or topically.
Compounds that hâve the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed isomers. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. It will be appreciated by those skilled in the art that the compound of the invention can exist as cis- and trans- achiral diastereomers.
Included within the scope of the described compounds are ail isomers (e.g. cis-, trans-, or diastereomers) of the compounds described herein alone as well as any mixtures. Ail of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvatés (including hydrates), tautomers, and mixtures thereof, are included in the described compounds. Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable séparation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This séparation may take place either at the level of one of the starting compounds or in a compound of the invention itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by sait formation with an enantiomerpure chiral acid, or by means of chromatography, for example by HPLC, using chromatographie substrates with chiral ligands.
In therapeutic use for treating disorders in a mammal, a compound of the présent invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parentéral 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 readily accessible by local application, for example, eyes or ears. It also includes transdermal delivery to generate a systemic effect. The rectal administration includes the form of suppositories. The preferred routes of administration are oral and parentéral.
Pharmaceutically acceptable salts of the compounds of the invention include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
Pharmaceutically acceptable salts of compounds of the invention, may be prepared, respectively, by one or more of three methods: (i) by reacting the compound with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ringopening a suitable cyclic precursor, for example, a lactone or lactam, using the de-
sired acid or base; or (iii) by converting one sait 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. Ail three reactions are typically carried out in solution. The resulting sait may precipitate out and be collected by filtration or may be recovered by 5 évaporation of the solvent. The degree of ionization in the resulting sait may vary from completely ionized to almost non-ionized.
Pharmaceutical compositions ofthe présent invention may be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, ly10 ophilizing processes or spray drying.
Pharmaceutical compositions for use in accordance with the présent invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into préparations, which can be used pharmaceutically. Proper 15 formulation is dépendent upon the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers 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 short20 acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations can also be formulated for controlled release or for slow release.
Pharmaceutical compositions suitable for use in the présent invention include compositions wherein the active ingrédients are contained in an amount sufficient to achieve the intended purpose, i.e., control or the treatment of disorders or diseases. 25 More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms/signs of disease or prolong the survival of the subject being treated.
The quantity of active component, which is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof, may be varied or ad30 justed widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Détermination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the
quantity of active component will range between 0.01 % to 99% by weight of the composition.
Generally, a therapeutically effective amount of dosage of 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 of body weight/day, even more preferably about 0.3 to 1.5 mg/kg of body weight/day It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the disorders or diseases being treated.
The desired dose may 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 sub-dose itself may be further divided, e.g., into a number of discrète loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in orderto rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
There are substantial needs for safe and efficacious agents to control disorders related to JAK, such as atopie dermatitis, both in human and animais. The market fortreating atopie dermatitis in animais is currently dominated by corticosteroids, which cause distressing and undesirable side effects in animais, specifically in 25 companion animais such as dogs. APOQUEL™ is a pan-JAK inhibitor recently approved for atopie dermatitis in canines. Antihistamines are also used, but are poorly effective. A canine formulation of cyclosporine (ATOPICA™) is currently being marketed for atopie dermatitis, but is expensive and has a slow onset of efficacy. In addition, there are Gl toleration issues with ATOPICA™. Compounds of the présent 30 invention are JAK inhibitors with sélective efficacy against JAK3. These compounds are expected to provide an alternative to steroid usage and provide resolution of chronic pruritus and inflammation that would either persist in atopie dermatitis or slowly regress following removal of allergen or causative agent, such as fleas in fleaallergic dermatitis.
Compounds of the présent invention may be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional 5 agents which modulate a mammalian immune System or with anti-inflammatory agents. These agents may include but are not limited to cyclosporin A (e.g., Sandimmune™ or Neoral™, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g., Cellcept™, azathioprine (e.g., Imuran™), daclizumab (e.g., Zenapax™), OKT3 (e.g., Orthocolone™), AtGam™, aspirin, acet10 aminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone), IFN-beta, teriflunomide, Laquinimod, glatiramer acetate, dimethyl fumerate, rituximab, fingolimod, natalizumab, alemtuzumab, mitoxantrone. Sulfasalazine (Azulfidine), Mesalamine (Apriso, Asacol, Lialda, others), balsalazide (Colazal) and olsalazine (Dipentum), and mercaptopurine (Purinethol), antibiotics (antimycobacterial drugs, e.g., Metronidazole, ciprofloxacin), Ustekinumab and vedolizumab These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.
Accordingly, the invention provides methods of treating or preventing a disease, condition or disorder associated with JAK in a subject, such as a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject. Suitable subjects that can be treated include domestic or wild animais, companion animais, such as dogs, cats, horses and the like; livestock including, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhésus monkeys and cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the compound is administered in a pharmaceuti30 cally acceptable form, optionally in a pharmaceutically acceptable carrier.
Another embodiment 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 presently taught compounds. Such methods can occur in vivo or in vitro. In vitro contact can involve a screening assay to détermine the efficacy of the one or more compounds against a selected enzyme at various amounts or concentrations. In vivo contact with a thera5 peutically effective amount of the one or more compounds can involve treatment of a described disease, disorder or condition or prophylaxis of organ transplant rejection in the animal in which the contact occurs. The effect of the 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 10 those disclosed in WO99/65908, WO 99/65909, WO01 /42246, W002/00661, W002/096909, W02004/046112 and W02007/012953.
Chemical Synthesis
The following schemes and written descriptions provide general details regarding the préparation of the compounds of the invention. It will be apparent to 15 those skilled in the art that sensitive functional groups (PG) may need to be protected and deprotected during the synthesis of a compound of the invention. Protection and deprotection may 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 therein.
Several methods exist for the préparation of such compounds, which are well known to those skilled in the art and hâve been described in texts such as Advanced Organic Chemistry by J. March, John Wiley & Sons (1985). It is noted that certain compounds of the invention can be obtained by functional group transformations at a Iate stage of the synthesis. Such functional group transformations may include one step or multiple steps, for example, réduction of an ester to an alcohol, reoxidation to an aldéhyde, addition of an organomagesium reagent to form a secondary alcohol, reoxidation to a ketone and, finally, addition of an organomagesium reagent to yield a tertiary alcohol. The intermediates and compounds were named using ChemDrawl 1 (CambridgeSoft™) structure to name converter or ACD Labs Name
Software v12. The inclusion of rac- (or racemic) modifier indicates material is racémie. When rac- (or racemic) is included with R,S indications this is intended to convey relative stereochemistry, however in the absence of the rac- (or racemic) nota
tion the compounds absolute stereochemistry is known. In some instances the rac(or racemic) notation conveys the stereochemistry of a fragment of the compound, while the R,S désignation conveys absolute stereochemistry of another portion. For cases where racemates are separated into their constituent enantiomers the abso5 lute stereochemistry is arbitrarily assigned, unless otherwise noted.
In executing the synthesis of the compounds of the invention, one skilled in the art will recognize the need to sample and assay reaction mixtures prior to work up in order to monitor the progress of reactions and décidé whether the reaction should be continued or whether it is ready to be worked up to obtain the desired product. Common methods for assaying reaction mixtures include thin-layer chromatography (TLC), liquid chromatography/mass spectroscopy (LCMS), and nuclear magnetic résonance (NMR).
One skilled in the art will also recognize that the compounds of the invention may be prepared as mixtures of diastereomers or géométrie isomers (e.g., cis and 15 trans substitution on a cycloalkane ring). These isomers can be separated by standard chromatographie techniques, such as normal phase chromatography on silica gel, reverse phase préparative high pressure liquid chromatography or supercritical fluid chromatography. One skilled in the art will also recognize that some compounds of the invention are chiral and thus may be prepared as racemic or scalemic mix20 tures of enantiomers. Several methods are available and are well known to those skilled in the art for the séparation of enantiomers. A preferred method for the routine séparation enantiomers is supercritical fluid chromatography employing a chiral stationary phase.
EXPERIMENTAL SECTION
Except where otherwise noted, reactions were run under an atmosphère of nitrogen. Chromatography on silica gel was carried out using 250-400 mesh silica gel using pressurized nitrogen (-10-15 psi) to drive solvent through the column (“flash chromatography”). Where indicated, solutions and reaction mixtures were concentrated by rotary évaporation under vacuum.
Example 1 : (R)-1 -(3-((3-chloro-1 H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidïn-1 yl)prop-2-en-1 -one.
Example 2: (R)-4-((1-acryloylpiperidin-3-yl)amino)-1 H-pyrrolo[2,3-b]pyridine-3carbonitrile.
Example 3: (R)-1 -(3-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin1 -yl)prop-2-en-1 -one.
\
Step 1. Halide monomers (300 pmol) were dissolved anhydrous DMF (10 ml/mmol, 3 ml) under argon atmosphère. NaH (60% suspension in minerai oil, 2 equiv, 600 pmol, ~30 mg) was added at 0 °C to each reaction vial. Each reaction vial was stirred at 0 °C for 30 min. SEM chloride (2 equiv, 600 pmol, 106 pL) was added dropwise to the reaction mixture and stirring was continued at 25 °C for 16 hrs. Completion of reaction was monitored by LCMS/TLC and solvents were stripped off using thermo explorer (1 hr, 5 torr, and 45 °C). The residue was purified by column chromatography using 5-10% ethyl acetate-hexane as eluent. For each monomer yield was around 75-80%.
Step 2. The amine template (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 pmol) was added followed by 1 ml of solution B (1.5 equiv, 300 pmol) to each reaction vial under argon purging condition. Anhydrous t-BuONa (3 equiv, 600 pmol, ~60 mg) was added to each reaction vial. Pd2(dba)3 (0.03 equiv, 6 pmol, ~6 mg) was dispensed under argon flow followed by BINAP ( 0.06 equiv, 12 pmol, ~7.5 mg). Each reaction vial was stirred at 90°C for 16 hrs. The reaction was checked by LCMS. The reaction mix
ture was filtered and the solvent was evaporated in thermo explorer (1 hr, 5 torr, and 45°C)
Step 2. (Set 2 monomers) The amine template (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 pmol) was added followed by 1 ml of solution B (1.5 equiv, 300 pmol) to each reaction vial. 103 pl_ (3 equiv, 600 pmol) of DIPEA was dispensed to each vial. Reaction vials were stirred for 16 h at 80°C. The reaction was checked by LC-MS. Solvent was evaporated in thermo explorer (1 hr, 5 torr, and 45°C)
Step 3 and 4 (Boc deprotection and Sem deprotection) Each step 2 residue was treated with 2 ml of TFA at 25 °C for 4 hrs. LCMS monitoring was done to check complété conversion to intermediate hydroxyl methyl dérivative. After completion of reaction, solvents were evaporated using thermo explorer (1 hr, 5 torr, and 45°C) and azeotroped with toluene to remove traces of TFA (1 hr, 5 torr, and 45°C). Each residue was dissolved in 2 ml of MeOH and ~70 pl_ of ethylenediamine was added to each reaction vial and again stirred for 16 hrs at 25°C. Reactions were checked by LC-MS. After completion of reaction, the solvent was evaporated and 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 con20 centrated under reduced pressure.
Step 5 (Rxn with acryloyl chloride) Ail the calculations were done in 100 pmol scale at the final step. Each step 4 residue was dissolved in anhydrous THF (1 ml) under argon atmosphère. 200 pmol (2 equiv, 28 pL) of TEA was added to each reaction mixture. Reaction mixtures were cooled to 0°C and a solution of 0.5 equiv of acryloyl 25 chloride in THF (4 pL in 500 pL THF) was added slowly maintaining ice cold condition during the addition. After stirring for 10 min at 0°C, the solvent was evaporated and the residue was dissolved in 1 ml DMSO. 10 pL of the DMSO solution was diluted to 200 pL with DMSO for QC analysis and remaining amount was submitted for prep-HPLC purification. Purification on Xterra® RP18 (19 x 250 mm, 10 μ, H2O (10mM NH4OAc): CH3CN).
Example LC/MS
1 305.7
2 296.3
3 306.7
Example 4:1 -((3S,4S)-3-((7H-pyrrolo[2,3-d]pyrimîdîn-4-yl)amino)-4fluoropiperidin-1 -yl)prop-2-en-1 -one.
Step 1. (3S,4S)-Benzyl 4-fluoro-3-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-45 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 césium fluoride (430 mg, 2.83 mmol) in DMSO (2.0 mL) was added (3S,4S)-benzyl 3-amino-4-fluoropiperidine-1-carboxylate (prepared as described in WO2010016005) (100 mg, 0.346 mmol). 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 with a 1:1 mixture of DCM/water (200 mL). The organic layer was extracted and the aqueous layer was back extracted 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 yield crude product which was dry loaded with Celite® onto a Silicycle 25g HP column and purified via normal phase column chromatography (075% EtOAc/heptanes over 15 column volumes) to afford (3S,4S)-benzyl 4-fluoro-3((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (149.6 mg, 69%) as a colorless solid. 1H NMR (400MHz, DMSO-d6) 7.74 (s, 1 H), 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, 1 H), 5.05 (s, 2H), 4.84-4.64 (m, 2H), 4.35 -4.24 (m, 1 H), 4.15 - 4.05 (m,
H), 3.95 - 3.85 (m, 1 H), 2.25 - 2.13 (m, 1 H), 1.70-1.58 (m, 1 H).
Step 2. N-((3S,4S)-4-Fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-amine . To a dry hydrogénation bottle, 10% Pd/C (65 mg) was added under nitrogen atmosphère. Then a solution of (3S,4S)-benzyl 4-fluoro-3-((7-trityl-7H-pyrrolo[2,325 d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (150 mg, 0.245 mmol) in anhydrous éthanol (5.0 mL) was added and the resulting mixture was hydrogenated under 50 psi of H2 at ambient température for 3 hours. LCMS showed the starting material was consumed completely. The reaction mixture was filtered through a thin pad of Celite® and the filter cake was washed with éthanol. The combined filtrate was evaporated, azeotroped with toluene (5 x) at 75°C to afford compound N-((3S,4S)-4fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (104 mg, 89%) as a 5 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-4yl)amino)piperidin-1-yl)prop-2-en-1-one. To a solution of N-((3S,4S)-4fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (102 mg, 0.214 mmol) in anhydrous d-CHCI3 (5.0 mL) is added Hunig’s base (0.2 mL, 1.0 mmol). The reac10 tion mixture was cooled to 2° C then treated, dropwise, with a solution of acrylic chloride (0.017 mL, 0.214 mmol) in anhydrous d-CHCI3 (1.0 mL). The reaction mixture was allowed to warm to ambient température and after 30 minutes, LCMS showed compound N-((3S,4S)-4-fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4amine was consumed completely. 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 back extracted with chloroform (2x2 mL). The organic extracts were combined, dried over magnésium sulfate, filtered, and concentrated in vacuo to yield crude product which was dry loaded with Celite® onto a Silicycle 12 g HP column and purified via normal phase column chromatography (5020 80% EtOAc/heptanes over 10 column volumes) to afford 1-((3S,4S)-4-fluoro-3-((7trityl-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. Préparation of 1-((3S,4S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4fluoropiperidin-1 -yl)prop-2-en-1 -one. A solution of 1 -((3S,4S)-4-fluoro-3-((7-trityl-7H25 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 ambient température for hours. The reaction mixture was concentrated in vacuo and dry loaded with Celite® onto a Silicycle® 12 g HP column and purified via normal phase column chromatography (0-20% MeOH/DCM over 10 column volumes) to afford 1-((3S,4S)30 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, 1 H), 4.93 - 4.71 (m, 1 H), 4.62 - 4.03 (m, 3H), 3.44 - 3.04 (m, 2H), 2.36 -2.24 (m, 1 H), 1.89-1.74 (m, 1 H).
Example 5:1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperidin-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 température overnight. TLC (petroleum ether/EtOAc, 2:1) showed 6-methylpyridin-3amine was consumed completely. The reaction mixture was filtered and the filter cake was washed with EtOH (30 mLx3). The combined filtrate was concentrated in vacuo to afford a yellow residual, which was purified by chromatography (petroleum ether/EtOAc, 4:1 to 1:1) to give tert-butyl (6-methylpyridin-3-yl)carbamate (32.5 g, 67.4%) as a white solid. 1H NMR (400MHz, CDCI3) 8.30 (d, J=2.0 Hz, 1H), 7.86 (br s, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.57 (brs, 1H), 2.49 (s, 3H), 1.51 (s, 9H)
Step 2. rac-cis/trans- tert-Butyl (6-methylpiperidin-3-yl)carbamate. To a dry hydrogénation bottle, PtO2 (2.5 g) was added under Ar atmosphère. 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 55 psi of H2 at 50 °C for 30 hours. TLC (petroleum ether/EtOAc, 2:1) showed the starting material was con20 sumed completely. The reaction mixture was filtered and the filter cake was washed with MeOH (50 mLx2). The combined filtrate was evaporated to give tert-butyl (6methylpiperidin-3-yl)carbamate (34 g, 100%) as a yellow oil (~2:1 cis/trans), which was used directly to next step without further purification. LC/MS (M+H) 215.2.
Step 3. rac-cis/trans-Benzyl 5-((tert-butoxycarbonyl)amino)-2-methylpiperidine-125 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) was added CbzCI (32.17 g, 189 mmol) dropwise at room température. After the addition, the resulting mixture was stirred at room température for 2 hours. TLC (CH2CI2/MeOH, 10:1) showed the starting material was consumed completely. The reaction mixture was extracted with EtOAc (300 mLx2). The combined organic layer was washed with brine, dried over Na2SO4i filtered and concentrated to give crude product. The crude product was further purified by chromatography (PE/EA, 30:117901
10:1) to give rac-cis/trans benzyl 5-((tert-butoxycarbonyl)amino)-2-methylpiperidine1-carboxylate (44.0 g, 100%) as a colorless oil. (1H NMR showed ~ 1mol of BnOH.) 1H NMR (400MHz, CDCI3) 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=13.8Hz, 1H), 3.73 (brs, 1H), 3.39 (brs, 1H), 3.02 (d, J=14.1 Hz, 1H), 2.49 (t,
J=12.0 Hz, 1 H), 1.89 - 1.59 (m, 3H), 1.48 (dd, J=1.5, 13.8 Hz, 1 H), 1.39 -1.32 (m, 8H), 1.11-1.01 (m, 3H).
Step 4. rac-(2S,5R)-Benzyl 5-((tert-butoxycarbonyl)amino)-2-methylpiperidine-1carboxylate and rac- (2S,5S)-benzyl 5-((tert-butoxycarbonyl)amino)-210 methylpiperidine-1-carboxylate. The rac-cis/trans benzyl 5-((tertbutoxycarbonyl)amino)-2-methylpiperidine-1-carboxylate (44 g) was separated by chiral SFC to give rac-cis - (2S,5R)-benzyl 5-((tert-butoxycarbonyl)amino)-2methylpiperidine-1-carboxylate (Peak 2, 24.5 g, 55.68%) and rac-trans - (2S,5S)benzyl 5-((tert-butoxycarbonyl)amino)-2-methylpiperidine-1-carboxylate_(Peak 1,
12.3 g, 27.95%). Peak 2, cis material was carried on to Boc removal. Prep SFC
Column : ChiralCel OD 300mmx50mm, 10 μιτι; Mobile phase: A: Supercritical CO2 , B: IPA (0.1%NH3H2O), A:B =85:15 at 180ml/min; Column Temp: 38 °C; Nozzle Pressure: 100Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; TrimmerTemp: 25 °C; Wavelength: 220nm
Peak 1 (trans): 1H NMR (400MHz, CDCI3) 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, 1 H), 3.58 - 3.25 (m, 1 H), 2.58 (t, J=12.0 Hz, 1 H), 1.87 (d, J=11.0 Hz, 1 H), 1.82 -1.69 (m, 2H), 1.56 (d, J=13.8 Hz, 1 H), 1.50 -
1.36 (m, 9H), 1.21 (d, J=6.3 Hz, 3H).
Peak 2 (cis): 1H NMR (400MHz, CDCI3) δ 7.42 - 7.29 (m, 5H), 5.20 - 5.08 (m, 2H),
4.89 (brs, 1H), 4.47 (brs, 1H), 4.05 (d, J=14.1 Hz, 1 H), 3.81 (brs, 1H), 3.11 (d,
J=13.8 Hz, 1 H), 1.93 - 1.68 (m, 4H), 1.43 (s, 9H), 1.20 -1.13 (m, 3H).
Step 5. Racemic (2S,5R)-benzyl 5-amino-2-methylpiperidine-1 -carboxylate. To a solution of rac-cis - [2S,5R)-benzyl 5-((tert-butoxycarbonyl)amino)-2methylpiperidine-1-carboxylate (pk 2, 40.0 g, 115.6 mmol) in CH2CI2 (60 mL) at 0 °C was added (4M HCl (g)/dioxane (200 mL) dropwise. After the addition, the solution was stirred at room température for4hrs. TLC (petroleum ether/EtOAc, 2:1) showed the starting material was consumed completely. The reaction mixture was concen trated to give racemic (2S,5R)-benzyl 5-amino-2-methylpiperidine-1-carboxylate (31.0 g, 94.8%) as a white solid (HCl sait). 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. Racemic (2S,5R)-benzyl 5-((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 (21.8 g, 0.116 mol), DIPEA (67.7 g, 0.525 mol) and racemic (2S,5R)benzyl 5-amino-2-methylpiperidine-1-carboxylate (30 g, 0.105 mol) in n-BuOH (300 mL) was heated to 140 °C overnight. LC-MS indicated the reaction was completed. The reaction mixture was cooled to room température 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 give crude product, which was triturated with MTBE to give racemic (2S,5R)-benzyl 5-((2-chloro7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (36 g, 86 %) as a yellow solid. 1H NMR (400MHz, DMSO-de) δ 11.70 (br s, 1 H), 7.71 (d, J=7.8 Hz, 1 H), 7.46 - 7.25 (m, 5H), 7.10 (br s, 1 H), 6.56 (br s, 1 H), 5.18 - 5.00 (m, 2H), 4.38 (d, J=6.8 Hz, 1 H), 4.16 (br s, 1 H), 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 hydrogénation bottle, 10% dry Pd/C (7 g) was added under Ar atmosphère. Subsequently, a solution of racemic (2S,5R)-benzyl 5-((2-chloro-7H-pyrrolo[2,3d]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 shaken on a Parr apparatus (45 psi of H2 at 25 °C for 48 hours). LC-MS indicated the Cbz was removed completely, but -30% of chloride remained. The reaction mixture was filtered and the filtrate was subjected to the reaction conditions again with 5 g of 10% dry Pd/C under 50 psi of H2 at 45 °C for 12 h. LC-MS showed the reaction was completed. The reaction mixture was filtered through a pad of Celite® and the cake was washed with MeOH three times. The combined filtrâtes were concentrated to give rac -N-((3RJ6S)-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 (brs, 1H), 8.11 (d, J=12.5 Hz, 1H), 7.30 (dd, J=6.5, 18.6 Hz, 1 H), 7.10 (brs, 1 H), 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, 1 H), 4.86-
4.51 (m, 1 H), 4.41 - 3.97 (m, 2H), 3.02 - 2.55 (m, 1 H), 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-methylpiperidin5 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 sait (5.00 g, 18.5 mmol) in THF (250 mL) and saturated aq. NaHCO3 solution (250 mL) was added acryloyl chloride (2.02 g,
22.2 mmol) dropwise at 0 °C carefully. After addition, the resulting mixture was stirred at 0 °C for 4 hours. TLC (DCM/MeOH/NH4OH, 10:1:1) showed 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 mLx3); the combined organic layer was washed with brine, and dried over Na2SO4. The most volatile components were removed in vacuum. The crude product was purified by column chromatography on silica gel (DCM/MeOH, 10:1) to give pure product. The product was triturated with EtOAc (150 mL) and filtered to give 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, 1 H), 8.12 (d, J=12.8 Hz, 1 H), 7.30 (dd, J=6.8, 18.8 Hz, 1 H), 7.10 (br s, 1 H), 6.89-6.71 (m, 1 H), 6.56 (d, J=1.8 Hz, 1 H), 6.10 (dd, J=2.1, 16.7 Hz, 1 H), 5.7220 5.61 (m, 1 H), 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. Préparation of (+)-1-((2R,5S)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperidin-125 yl)prop-2-en-1-one (pk 1) and (-) 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2-methylpiperidin1-yl)prop-2-en-1-one (pk2). The racemic compound : rac-1 -((2S,5R)-5-((7Hpyrrolo[2,3-d]pyrimidin-4yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (from Step 8) was purified by chiral 30 SFC to give pure enantiomers. Peak 1 (4.63 g, +) and peak 2 (4.42 g, -) SFC conditions: Column: ChiralPak IC (300 mm*50 mm, 10 pm); Mobile phase: 40% éthanol (0.05% NH3in H2O) in CO2; Flow rate: 200 mL/min; wavelength: 220nm.
The absolute stereochemistry was assigned based on X-ray crystallographic analysis.
Peak 1: (+) 1-((2R,5S)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yI)amino)-2-methylpiperidin15 yl)prop-2-en-1-one 1H NMR (400MHz, DMSO-d6) δ 11.53 (brs, 1H), 8.12 (d, J=12.8 Hz, 1H), 7.30 (dd, J=6.8, 18.8Hz, 1H), 7.10 (brs, 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, 1 H), 4.81 (brs, 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]D 20 =+0.34 (c = 0.6, MeOH).
Peak 2: (-) 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin1-yl)prop-2-en-1-one 1H NMR (400MHz, DMSO-d6) δ 11.53 (brs, 1H), 8.12 (d,
J=12.8 Hz, 1H), 7.30 (dd, J=6.8,18.8 Hz, 1H), 7.10 (brs, 1H), 6.89 - 6.71 (m, 1H),
6.56 (d, J=1.8 Hz, 1H), 6.10 (dd, J=2.1, 16.7 Hz, 1 H), 5.72-5.61 (m, 1 H), 4.81 (brs,
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]D 20 = -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. Préparation of N-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-
3-yl)-7-trityl-7H-pyrroIo[2,3-d]pyrimidin-4-amine. To a mixture of 4-chloro-7-trityl-7Hpyrrolo[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 rt was added
DIPEA (14.5 g, 112.32 mmol). The reaction mixture was heated to 110 °C for 3 days. TLC (DCM/MeOH, 10:1) showed most of amine was consumed. The reaction mixture was cooled to room température and evaporated to dryness via oil pump at 45°C; 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 give crude product, which was purified by chromatography (EtOAc/PE from 0% to 30%) to give N-((3R,5R)-1 -benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-7-trityl-7Hpyrrolo[2,3-d]pyrimidin-4-amine (15 g, 65%) as a yellow solid. LC/MS (M+H) 679.4.
1H NMR (400 MHz, CDCI3) 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)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a dry hydrogénation bottle, 10% dry Pd/C (1.5 g) was added. Then a solution of N-((3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)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 10 the resulting mixture was hydrogenated under 50 psi of H2 at 40 °C for 12 hours.
TLC (PE/EtOAc 4:1) showed the reaction was complété. 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 give (3R,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidine-115 carboxylate (14.8 g, -100%) as a yellow solid, which was used directly to next step without further purification. 1H NMR (400 MHz, CDCI3) δ 0.06 (br s, 6 H) 0.72 - 0.94 (m, 9 H) 1.16-1.43 (m, 4 H) 1.49 (brs,9H) 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. (3R,5R)-tert-Butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a solution of (3R,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (15 g, 21.74 mmol) in anhydrous THF (300 mL) was added n-Bu4NF (11.38 g, 43.47 mmol). The reaction mixture was then heated to 40 °C overnight.
TLC (PE/EtOAc 4:1) indicated the reaction was complété. 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)-tert-butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (14.6 g, -100%), which was used directly in the next step without further purification. 1H NMR (400MHz, CDCI3) δ
8.01 (s, 1H), 7.37-7.08 (m, 17H), 6.91 (d, J=3.5 Hz, 1H), 6.30 (brs, 1H), 4.48 (d,
J=3.5 Hz, 1 H), 4.05 (br s, 1 H), 3.83 - 3.51 (m, 4H), 3.23 (br s, 1 H), 1.58 - 1.29 (m, 10H).
Step 4. (R)-tert-Butyl 3-oxo-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a solution of compound (3R,5R)-tert-butyl 35 hydroxy-5-((7-trityl-7H-pyrroIo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (5.0 g, 8.68 mmol) in DCM (100 mL) was added Dess-Martin periodinane (4.0 g,
9.55 mmol). The mixture was stirred at room température for 18 hours. TLC (DCM/MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was concentrated to give crude product (7.8g) as yellow solid, which was purified by prep-HPLC to give (R)-tert-butyl 3-oxo-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (3.7 g, 74 %) as a white solid. LC/MS (M+H) = 574.3.1H NMR (400 MHz, DMSO-ofe) 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. (5R)-tert-Butyl 3-cyano-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (mixture of isomers). To a mixture of (R)-tert-butyl
3-oxo-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate_(1.0 g, 1.74 mmol) and TOSMIC (693.7 mg, 3.83 mmol) in DME (30 ml) at 0 °C 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 température and stirred for 2 hours. TLC (DCM/MeOH, 10:1) showed the reaction was complété. The reaction solution was filtered, and the filtrate was concentrated to dryness and purified by préparative TLC (petroleum ether/EtOAC, 2:1) to afford (5R)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidine-325 carbonitrile (mixture of isomers, 200 mg, 20%) as a yellow solid. LC/MS (M+H)
585.3.
Step 6. Préparation of (5R)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-3-carbonitrile (mixture of isomers). To a solution of (5R)-tertbutyl 3-cyano-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-130 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 mixture was then stirred at room température for 12 hours. TLC (petroleum ether/EtOAC, 1:1) showed the reaction was complété. The reaction mixture was concentrated in vacuo to give (5R)-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-3-carbonitrile (mixture of isomers) (235 mg, 100%) as a yellow solid. LC/MS (M+H) 485.0.
Step 7. Préparation of (5R)-1-acryloyl-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-45 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) :aq. NaHCO3 solution (2.5 mL) at 0 °C was added acryloyl chloride (22.4 mg, 0.247 mmol) dropwise. After addition, the resulting mixture was stirred at 0 °C for 2 hours. TLC (DCM/MeOH, 20:1) showed the reaction was completely. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mLx2), the combined organic layer were washed with brine, dried over Na2SO4 and concentrated to give crude product, which was further purified by préparative TLC (petroleum ether/EtOAC, 1:1) to give (5R)-1-acryloyl-5-((7-trityl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-3-carbonitrile and trans isomer (80 mg,
72 %) as yellow solid. LC/MS (M+H) 539.1.
Step 8. Préparation of (3S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1acryloylpiperidine-3-carbonitrile and (3R,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-1-acryloylpiperidine-3-carbonitrile.
To a round bottom flask containing (5R)-1 -acryloyl-5-((7-trityl-7H-pyrrolo[2,320 d]pyrimidin-4-yl)amino) piperidine-3-carbonitrile_and compound 5-1 (80 mg, 0.272 mmol) was added TFA (1 mL). The mixture was stirred at room température for 12 hours. TLC (petroleum ether/EtOAC, 1:1) showed 20% starting material remained. The reaction was heated to 30 °C for another 5h. LCMS indicated completion. The reaction mixture was concentrated to give crude product, which was further purified by prep. TLC (Petroleum ether/EtOAC, 1:1) to give a mixture of (3S,5R)-5-((7Hpyrrolo[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, % for 3 steps) as a white solid. Chiral HPLC showed it was a mixture of trans/cis, which was purified further by chiral SFC. After chiral SFC, 1.4 mg of peak 1 and 3.3 30 mg of peak 2 was obtained. Peak 1 : (3S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-1-acryloyl piperidine-3-carbonitrile and Peak 2: (3R,5R)-5-((7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)-1-acryloylpiperidine-3-carbonitrile. SFC séparation condi17901 ~ 62 tions: Column: ChiralPak AD (250mmx30mm, 20 μιτι); Mobile phase: 50% Et’OH+NH3/H2O 80mL/min; Column: Chiralpak AD-H 250x4.6mm I.D., 5 μιτι; Mobile phase: éthanol (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 (brs, 1H), 7.10 (d, J=3.5
Hz, 1 H), 6.85 (dd, J=10.4, 16.7 Hz, 1 H), 6.57 (d, J=3.5 Hz, 1 H), 6.27 (dd, J=1.8, 16.8 Hz, 1 H), 5.80 (d, J=9.5 Hz, 1 H), 4.85 - 4.77 (m, 1 H), 4.63 (s, 1 H), 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). Peak2:1H NMR (400MHz, CD3OD) δ 8.20 (brs, 1H), 7.09 (d, J=3.5 Hz, 1 H), 6.90 - 6.54 (m, 2H), 6.32 - 6.07 (m, 1 H), 5.90 - 5.57 (m, 1 H), 4.71 - 4.41 (m,
2H), 4.40 - 4.01 (m, 2H), 3.71 - 3.40 (m, 2H), 2.39 (br s, 1 H), 2.17 (d, J=9.0 Hz, 1 H).
Example 7:1 -((2R,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2(hydroxymethyl)piperidin-l -yl)prop-2-en-1 -one.
Step 1. Methyl 5-aminopicolinate. To a stirred solution of 5-aminopicolinic acid (170g, 1.23mol) in MeOH (1700 ml) was added SOCI2 (178.6 ml, 2.47mol) at 0°C.
The reaction mixture was then refluxed for 72 h. The mixture was then cooled to 0°C and additional SOCI2 was added (40 ml, 0.55mol). The mixture was then refluxed for 24h. The excess SOCI2 was removed under reduced pressure and the crude material was neutralized with aq. NaHCO3. The mixture was filtered and the filter cake dried at 40-50°C overnight. The solid was collected to give methyl 5-aminopicolinate (350g). The filtrate was further extracted with DCM (3x2 L). The organic extract was washed with brine, dried (Na2SO4) and concentrated to dryness to afford crude compound (200g). Ail of solids were collected to give methyl 5-aminopicolinate (550g from 680 g of compound 1, 73%) as a white solid. 1H NMR (400MHz, CDCI3) 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 (brs,
2H), 3.93 (s, 3H).
Step 2. Methyl 5-((tert-butoxycarbonyl)amino)picolinate. Methyl 5-aminopicolinate (110g, 0.723mol) was dissolved in DCM (2000 ml) at 20°C under N2. To the reaction mixture, Boc-anhydride (173.6g, 0.80mol) and DMAP (8.8 g, 0.0723 mol) were added. The reaction mixture was stirred at 20°C for 20 h. TLC (PE/EA, 2:1) showed that the starting material was consumed completely. The reaction mixture was filtered and washed with DCM (4x3000ml). H2O (2000 ml) was added and layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SC>4 and evaporated under reduced pressure to give crude product. The crude compound was washed with petroleum ether (4000mL) and stirred for 1.0 hour. Filtration and évaporation in vacuo afforded methyl 5-((tert-butoxycarbonyl)amino) picolinate (750g from 550 g of methyl 5-aminopicolinate, 82.3%) as a white solid for 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, 0.96mol) was suspended in dry THF (1000 ml) under N2 atmosphère and cooled to 0°C. To the mixture was added compound 3 (150g, 0.60mol) in dry THF (1000 ml) slowly at 0°C. The reaction mixture was gradually warmed to room température and 10 stirred for 12h. TLC(PE/EA, 1:1) showed that the reaction was complété, and the reaction was quenched with dropwise addition of THF-Water (9:1,400 mL) followed by 90 ml 15% NaOH aqueous and 50 ml of water at 0°C, stirred for 0.5h at room température, and filtered through a pad of Celite®, and then washed with THF (4 x 1000ml). The filtrate was concentrated under reduced pressure to give the crude which was purified by column chromatography over silica gel eluting with PE/EA (2:1-1:2). The desired fraction was concentrated to afford tert-butyl (6(hydroxymethyl)pyridin-3-yl)carbamate (450g, 67%) as a white solid. 1H NMR (400MHz, DMSO-de) 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 tertbutyl (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/55 psi of 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 con25 centrated under reduced pressure to remove EtOH and HOAc. Saturated aqueous NaHCO3 was added to adjust pH to 6-7 and the aqueous layer was extracted with EtOAc (3x2000ml). The combined organic layer were washed with brine, dried over Na2SO4 and concentrated to dryness to give the crude product, which was triturated with PE/EA (1:1) for 2 hours and filtered to give recovered tert-butyl (630 (hydroxymethyl)pyridin-3-yl)carbamate (90g, 50%) as a white solid. The aqueous layer was evaporated to remove most of the water to give a mixture of tert-butyl (6 (hydroxymethyl)piperidin-3-yl)carbamate (90g, 50%) in aq.NaHCO3, which was directly used for next step without further purification. LC/MS (M+H) = 231.2.
Step 5. Benzyl 5-((tert-butoxycarbonyI)amino)-2-(hydroxymethyl)piperidine-1carboxylate. To a stirred solution of tert-Butyl (6-(hydroxymethyl)piperidin-3yl)carbamate (45g, 0.20mol) in THF (600 ml) and H2O (300 ml) was added NaHCO3 (33.6 g, 0.40mol). To this mixture was added Cbz-CI (41g, 0.24mol) dropwise at 0°C and the résultant mixture was allowed to corne to room température and stirred for 12 h. TLC (5% MeOH in DCM) was checked to show starting material was consumed completely. 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 afford the crude product, which was purified by column chromatography (silica gel eluted with DCM/EA (4:1 ~2:1 ) to give benzyl 5-((tertbutoxycarbonyl)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)-Benzyl 5-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2(hydroxymethyl) piperidine-1-carboxylate. To a round bottom flask was added 2,4dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.03 g, 17.6 mmol), DIPEA (6.8 mL, 2.2 eq), benzyl 5-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)piperidine-1 carboxylate (5.6 g, 1.0 eq) and n-butanol (50 mL). The reaction mixture was heated to 50 °C overnight. 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 give an oil, which after chromatography (silica, ethyl acetate/heptanes) gave two major peaks with équivalent mass. Pk 1 = 2.5 g (trans material); Pk 2 = 3.3 g (cis material): Peak 1 (trans): (2S,5R)-benzyl 2-(hydroxymethyl)-5-((7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. LC/MS (M+H) 570.1 1H NMR (400 MHz, MeOH-c/4) 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)
Peak2 (cis): (2R,5R)-benzyl 5-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)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)-Benzyl 5-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2(hydroxymethyl) piperidine-1-carboxylate and (2S,5S)-benzyl 5-((2-chloro-7-tosyl-7H10 pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)piperidine-1 -carboxylate. Racémie -cis-(2R,5R)-benzyl 5-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2-(hydroxymethyl)piperidine-1-carboxylate (3.31 g) wasseparated by chiral SFC-Chiral (Lux Cellulose-3 250 mm x 21.2 mm, 5 pm, CO2/MeOH, 80 mL/min) to give two peaks, absolute stereochemistry arbitrarily assigned: pk1 (1.5 g) (2R,5R)-benzyl 5-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2(hydroxymethyl)piperidine-l-carboxylate. OR a^j20 = -0.10 (c = 0.5, MeOH). Pk2 (1.5 g) (2S,5S)-benzyl 5-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2(hydroxymethyl)piperidine-l-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-yI)amino)piperidin20 2-yl)methanol. To a Parr hydrogénation bottle was added (2R,5R)-benzyl 5-((2chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-(hydroxymethyl)piperidine-1carboxylate (in 100 mL of EtOH) and Pd(OH)2 (1.2 g). The reaction was shaken on a Parr shaker apparatus at 20 psi H2 for 4 hr at room température. The reaction mixture was then filtered through a pad of Celite® and the solvent removed in vacuo to 25 give ((2R,5R)-5-((2-chloro-7-tosyl-7H-pyrroIo[2,3-d]pyrimidin-4-yl)amino)piperidin-2yl)methanol (1.73 g, 91%). LC/MS (M+H) =436.1. 1H NMR (400 MHz, MeOH-d4) δ 1.33- 1.65 (m, 2H) 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 30 (d, J=8.20 Hz, 2 H).
Step 9. ((2R,5R)-5-((2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-2yl)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) was added MeOH (10 mL) and K2CO3 (767 mg, 2.2 eq). The reaction was stirred at room température 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 give the crude product, which was purified by chromatography (silica, DCM/MeOH (10:1, MeOH:NH4OH) to give 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-yl)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 éthanol (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-4yl)amino)piperidin-2-yl)methanol (110 mg, 62%). LC/MS (M+H) 248.1. 1H NMR (400 MHz, MeOH-c/4) 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-((7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-2-yl)methanol (172 mg, 0.69 mmol) in DCM/CHCI3/CF3CH2OH (3:1:0.5 mL) was added TEA (0.19 mL, 2.0 eq). The reaction mixture was cooled to 0 °C. After 30 min, acryloyl chloride (in DCM, 1 mL) was added dropwise. After 2 hrs, the reaction mixture was poured into water/DCM and the layers separated. The organic layer was collected, dried (Na2SO4) and the solvent removed to give the crude product (224 mg). A portion of the crude product (50 mg) was purified by RP-HPLC to give 1-((2R,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4yl)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-1 Hpyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1-one.
Step 1. tert-Butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate. To a solution of 1Hpyrrolo[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 min, (Boc)2O (508.7 g, 2.33 mol) was added over a period of 40 min. After the addition, the resulting mixture was stirred at room température for 3 hour. TLC (petroleum ether: ethyl acetate, 1:1) indi10 cated starting material was consumed completely. 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 give tert-butyl 1 H-pyrrolo[2,3-c]pyridine-1-carboxylate (830 g, 90%) as a white solid. 1H NMR (400 MHz, CDCI3) δ 9.3 (bs, 1 H) 8.32 (d, 1 H), 7.65 (bs, 1 15 H), 7.41-7.39 (m, 1 H), 6.50 (d, 1 H), 1.62 (s, 9 H).
Step 2. (3aS,7aR)-tert-Butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate. To a dry hydrogénation bottle, PtO2 (13 g) was added under Ar atmosphère. A solution of tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (135 g, 0.62 mol) in EtOH (3 L) was added and the resulting mixture was hydrogenated at 50 psi H2 at 80 °C for 48 hours. TLC (petroleum ether/EtOAc, 1:1) showed starting material was consumed completely. The reaction mixture was filtered, and the filtrate was concentrated to give (3aS,7aR)-tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (810 g, 96.4%) as a colorless oil. 1H NMR (400 MHz, MeOH-c/4) 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 25 3.42 (m, 2 H) 3.62 (br s, 1 H).
Step 3. (3aR,7aR)-Benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate. To a stirred solution of (3aS,7aR)-tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1carboxylate (200 g, 0.885 mol) and DIPEA (251 g, 1.95 mol) in DCM (2L) at 0 °C was added dropwise Cbz-Cl (181 g, 1.06 mol) over a period of 45 min. After the addi30 tion, the resulting mixture was stirred at room température for 16 hours. TLC (DCM/MeOH, 10:1) showed the starting material was consumed completely. The reaction mixture was evaporated to dryness, and then partitioned between EtOAc (8L) and water (3 L); the organic layer was washed with water (3 L) and brine (3 L), dried over anhydrous Na2SO4 and concentrated to give (3aS,7aR)-tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1147 g, 90%) as a colorless oil. 1H NMR (400 MHz, CDCI3) 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).
Step 4, 5 and 6. (3aR,7aR)-Benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate and (3aS,7aS)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate. To a 0 °C stirred solution of (3aS,7aR)-tert-butyl octahydro-1 H10 pyrrolo[2,3-c]pyridine-1-carboxylate (280 g, 0.68 mol) in DCM (600 mL) was added dropwise 4M HCl in dioxane (2.5 L) over a period of 1 hour. The reaction mixture was stirred at room température for 15 hours. TLC (petroleum ether/EtOAc, 2:1) showed the starting material was consumed completely. The reaction mixture was evaporated to dryness, and then partitioned between MTBE (6L) and water H2O (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 give rac-(3aR,7aR)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate (687 g, 85%), which was separated by SFC to give (3aS,7aS)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine6(2H)-carboxylate (280 g, 42.2%) and (3aR,7aR)-benzyl hexahydro-1 H-pyrrolo[2,320 c]pyridine-6(2H)-carboxylate (270, 39.3%) as yellow oil. (Peak 1 was(3aR,7aR)benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate, RT = 9.81 ; peak 2 was (3aS,7aS)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate, RT = 10.63). 1H NMR (400 MHz, CDCI3) δ 1.28 -1.63 (m, 3 H) 1.68 - 1.90 (m, 2 H) 1.972.09 (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). Séparation conditions: Instrument: SFC 350; Column:
AS 250mmx50mm,10 pm; Mobile phase: A: Supercritical CO2 , B: EtOH (0.05%DEA) , A:B =65:35 at 240ml/min; Column Temp: 38 °C; Nozzle Pressure: 100Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; TrimmerTemp: 25 °C; Wavelength: 220nm. Step 7. (3aS,7aS)-Benzyl 1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1H30 pyrrolo[2,3-c]pyridine-6(2H)-carboxylate. A mixture of (3aS,7aS)-benzyl hexahydro1H-pyrrolo[2,3-c]pyridine-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 C for 3 hours, TLC (Petroleum ether/ether, 2:1) showed 2,4dichloro-7H-pyrrolo[2,3-d]pyrimidine was consumed completely. The reaction mixture was cooled to room température and evaporated to dryness via oil pump at 45 °C. 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 give (3aS,7aS)-benzyl 1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4yl)hexahydro-1H-pyrrolo[2,3-c]pyridine-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)-Octahydro-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3djpyrimidine. To a dry Parr hydrogénation bottle, Pd/C (12 g) was added under Ar atmosphère. Then a solution of (3aS,7aS)-benzyl 1-(2-chloro-7H-pyrrolo[2,3d]pyrimidin-4-yl)hexahydro-1H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate (62 g, 0.15 mol) in EtOH (1.2 L) was added and the resulting mixture was hydrogenated under 50 psi of H2 at 65 °C for 48 hours, TLC (Petroleum ether/EtOAc, 1:1) showed the starting material was consumed completely; the reaction mixture was filtered and the filter cake was washed with warm MeOH and water (v/v 1:1, 500 mLx2); the combined filtrate was evaporated to give 4-((3aR,7aS)-octahydro-1 H-pyrrolo[2,3-
c]pyridin-1-yl)-7H-pyrroIo[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-1 H-pyrrolo[2,3-
c]pyridin-6(2H)-yl)prop-2-en-1 -one. To a solution of 4-((3aR,7aS)-octahydro-1 Hpyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (150 g, 0.54 mol) in aq NaHCO3 (150 g, 1.79 mol) in H2O (1.5 L) at 0 °C was added dropwise 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 température for 2 hours. TLC (DCM/MeOH, 5:1) showed 4-((3aR,7aS)-octahydro-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3djpyrimidine was consumed completely. The reaction mixture was extracted with DCM (500 mL*4) and the combined organic layers were concentrated to give the crude product, which was purified by column chromatography to give 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, 1 H), 6.51 (m, 1H), 6.056.01 (m, 1 H), 5.69-5.85 (m, 1 H), 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)-25 ethylpiperidin-1-yl)prop-2-en-1-one. The racemic 5-((tert-butoxycarbonyl)amino)-
2-ethylpiperidine-1-carboxylate was prepared using a process similarto the methyl intermediate. The racemic intermediate contained the cis-isomers as the major component as was the case for the methyl intermediate. The racemic mixture was separated into four optically pure isomers via chiral SFC, and the two cis-isomers were obtained as peak 3 and 4. SFC préparative séparation conditions: Column: Chiralcel OJ-H 30x250mm; Mobile phase: 95/5 CO2/methanol; Flow rate: 120mL/min; Wavelength: 210nm; SFC analytical condition: Column: Chiralcel OJ-H 4.6x25mm; Mobile phase: 5-60% CO2/methanol; Flow rate: 3mL/min; Wavelength: 210nm.
Préparation of final analogs using the enantiomerically pure benzyl 5-((tertbutoxycarbonyl)amino)-2-ethylpiperidine-1-carboxylatefollowed protocols similarto other analogs (see Example 5). Thus 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2-ethylpiperidin-1-yl)prop-2-en-1-one was prepared from peak 3 of the chiral séparation of the racemic 5-((tert-butoxycarbonyl)amino)-2-ethylpiperidine-120 carboxylate. 1H NMR (400MHz, DMSO-d6) δ 11.51 (br s, 1 H), 8.11 (d, J=13.6 Hz,
H), 7.26 (dd, J=6.6, 21.4 Hz, 1 H), 7.08 (br s, 1 H), 6.9 - 6.7 (m, 1 H), 6.53 (s, 1 H),
6.10 (d, J=16.8 Hz, 1 H), 5.7 - 5.6 (m, 1 H), 4.57 (br s, 1 H), 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 min run): 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)-5fluoropiperidin-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-7Hpyrrolo[2,3-d]pyrimidine (495 mg, 2.64 mmol) in n-BuOH (35 mL) was heated to 130140 °C overnight. LC-MS showed the reaction was completed. TLC (PE/EtOAc, 1:1) showed the starting material was consumed completely and the desired product was formed. The reaction mixture was cooled to room température and evaporated to dryness in vacuo at 45 °C. The residue was treated with water (20 mL) and extracted with EtOAc (30 mLx2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified via chromatography to give N-((3R,5R)-1-benzyl-5-fluoropiperidin-3-yl)-2-chloro-7Hpyrrolo[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 hydrogénation bottle, 10% dry Pd/C (160 mg) was added under Ar atmosphère followed by a solution of N-((3R,5R)-1-benzyl-5-fluoropiperidin-3-yl)-2-chloro7H-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 50 psi of H2 at 35 °C for 72 hours. LC-MS showed most 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 give 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, 1 H), 9.50 (br s, 1 H), 8.22 - 8.11 (m, 1 H), 7.60 (d, J=7.8 Hz, 1 H), 7.23 7.03 (m, 1 H), 6.61 (d, J=1.8 Hz, 1 H), 5.32 - 5.13 (m, 1 H), 4.80 - 4.64 (m, 1 H), 3.32 -
3.24 (m, 1 H), 3.22 - 3.12 (m, 1 H), 2.84 (t, J=11.5 Hz, 1 H), 2.32 (br s, 1 H), 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 aq. NaHCO3 solution (12 mL) at 0 °C was added acryl-CI (85 mg, 0.93 mmol) dropwise. The resulting mixture was stirred at 0 °C for 2 hours. TLC (DCM/MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mLx2); the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was further purified by column chromatography on silica gel (MeOH: DCM, 0-8%) to give 1((3R,5R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en ~ 72
1-one (130 mg, 53.0%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.55 (br s, 1 H), 8.13 (d, J=18.8 Hz, 1 H), 7.41 - 7.27 (m, 1 H), 7.10 (br s, 1 H), 6.80 (dd, J=10.5, 16.8 Hz, 1H), 6.55 (brs, 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,
1 H), 2.61 (t, J=11.5 Hz, 0.5H), 2.29 (d, J=6.0 Hz, 1 H), 2.05 -1.74 (m, 1 H).
Example 11:1 -((3R,4S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4methylpïperidin-1 -yl)prop-2-en-1 -one
Step 1. rac-(3R,4S)-tert-Butyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4methylpiperidine-1-carboxylate. To a solution of rac-(3R,4S)-tert-butyl 3-amino-410 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) was added DIPEA (903 mg, 6.999 mmol, 3.0 eq.) at room température, and heated to 140 °C overnight. After LCMS indicated the reaction was complété, the reaction mixture was concentrated to dryness in vacuo. The resi15 due 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 mLx1), 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 give rac-(3R,4S)-tert-butyl 3-((2-chloro20 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-methylpiperidine-1 -carboxylate (rac-trans,
563 mg, 66 %) as a yellowsolid. 1H NMR (400MHz, CDCI3) δ 11.92 (brs, 1H), 7.14 (br s, 1 H), 6.46 (br s, 1 H), 4.40 (d, J=9.3 Hz, 1 H), 4.08-3.65 (m, 2H), 2.98 - 2.63 (m, 2H), 1.90 - 1.60 (m, 3H), 1.52-1.38 (m, 1 H), 1.48 (s, 9H), 1.11 -1.05 (m, 3H). Step 2. Rac-(3R,4S)-tert-Butyl 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-425 methylpiperidine-1-carboxylate. To a dry Parr hydrogénation bottle, dry Pd/C (100 mg) was added under N2 atmosphère. A solution of rac-(3R,4S)-tert-butyl 3-((2chloro-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 50 psi of H2 for 2 days. After LCMS showed the reac30 tion to be complété, the reaction mixture was filtered, and the filter cake was washed with MeOH. The combined filtrate was evaporated to give rac-(3R,4S)-tert-butyl 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 rac-(3R,4S)-tert-butyl 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4methylpiperidine-1-carboxylate (520 mg, 1.531 mmol) in DCM (15 mL) at 0 °C was added 4.0 M HCl/ dioxane (15 mL). The reaction mixture was allowed to warm to room température and stirred for 3 hours. After LCMS showed the reaction to be complété, the reaction mixture was concentrated to give rac-N-((3R,4S)-4methylpiperidin-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-methylpiperidin1 -yl)prop-2-en-1 -one.
To a solution of rac- N-((3R,4S)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4amine (410 mg, 1.530 mmol) in THF (20 mL) and saturated.NaHCOs (15 mL) at 0 °C 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 (EtOAc/MeOH, 10:1 ) showed the reaction to be complété, the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (MeOH/EtOAc, 2%~10%) and lyophilized to give rac-1-((3R,4S)-3-((7Hpyrrolo[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, 1 H), 8.08 (d,J=15.1 Hz, 1 H), 7.32 - 7.20 (m, 1 H), 7.08 (br s, 1 H), 6.81 (dt, J=10.5, 17.3 Hz, 1H), 6.59 (brs, 1H), 6.12 (d, J=14.8 Hz, 1H), 5.69 (d, J=10.3 Hz, 1 H), 4.65 - 4.39 (m, 1 H), 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 (pk 1) and 1-((3S,4R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-
4-methylpiperidin-1 -yl)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 SFC (Chiral Pak-AD (250 x 30 mm, 5um), 30% EtOH (0.05% NH3 in H2O) in CO2) to give the pair of enantiomers, (peak 1, 47.8 mg) and (peak 2, 48.2 mg) as white solids, absolute stereochemistry arbitrarily assigned.
Peak 1 data: 1H NMR (400MHz, DMSO-d6) δ 11.53 (brs, 1H), 8.08 (d, J=15.1 Hz,
H), 7.32 - 7.20 (m, 1 H), 7.08 (br s, 1 H), 6.81 (dt, J=10.5, 17.3 Hz, 1 H), 6.59 (br s,
H), 6.12 (d, J=14.8 Hz, 1 H), 5.69 (d, J=10.3 Hz, 1 H), 4.65 - 4.39 (m, 1 H), 4.27 4.04 (m, 1 H), 3.94 - 3.71 (m, 1 H), 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 2 data: 1H NMR (400MHz, DMSO-de) δ 11.53 (br s, 1 H), 8.08 (d, J=15.1 Hz, 1H), 7.32-7.20 (m, 1H), 7.08 (brs, 1H), 6.81 (dt, J=10.5, 17.3 Hz, 1H), 6.59 (brs, 1H), 6.12 (d, J=14.8 Hz, 1H), 5.69 (d, J=10.3 Hz, 1H), 4.65 - 4.39 (m, 1 H), 4.27 - 4.04 (m, 1 H), 3.94 - 3.71 (m, 1 H), 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, 1 H), 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-1yl)prop-2-en-1 -one
Step 1. (R)-tert-Butyl 3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-120 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 at 70°C for overnight. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography (10025 200 mesh silica, 0-3% MeOH in DCM) to obtain (R)-tert-butyl 3-((7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (5.6 g, 42%). LC/MS (M+H) = 472.2. 1H NMR (400 MHz, CDCI3) 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 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate. To a stirred solution of (R)-tert-butyl 3-((7-tosyl-7H-pyrrolo[2,3
d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (29.4g, 62mmol) in MeOH (96 mL), THF (96 mL) and water (96mL) was added LiOH-H2O (2.99g, 125 mmol, 2 eq). The mixture was heated at 60°C for 1 hour. After the reaction mixture was cooled to room température, the organic solvent evaporated in vacuo. The aqueous mixture was made 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 mesh silica, 0-2% MeOH in DCM) to provide 8.5g (70%) of (R)-tert-butyl 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as an off white solid. LC/MS(M+H) 318.2. 1H NMR (400 MHz, CDCI3) δ 1.45 (brs, 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 (brs, 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-1carboxylate in dioxane (40 mL) was added 4M HCl in dioxane (60 mL) dropwise. The reaction was stirred for ~1hr and then diluted with diethyl etherto form a solid, which was filtered and collected. The solid was dried on high vacuum to give (R)-N(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl sait (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[2,3d]pyrimidin-4-amine HCl sait (1.0 g, 3.44 mmol) was added DCM (30 mL), EtOH (3 mL) and TEA (2.11 mL, 4.4 eq). After 30 min, acrylolyl chloride in 20 ml of DCM was added dropwise and the reaction stirred at rt for 2 hrs. The mixture was poured into water and the layers separated. The organic layer was dried (Na2SO4) and the solvent removed to give crude product (-900 mg). The material was purified by chromatography (silica, DCM/MEOH) to give (R)-1-(3-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yl)prop-2-en-1-one (310 mg, 33%). LC/MS (M+H) = 272.1. 1H NMR (400 MHz, DMSO-ofe) δ 1.40 - 2.12 (m, 3 H) 2.61 -2.76 (m, 1 H) 2.89-3.18 (m, ~ 76
H) 3.92 - 4.22 (m, 2 H) 4.55 (d, 7=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, 7=6.63 Hz, 1 H) 8.12 (d, 7=14.44 Hz, 1 H) 11.50 (brs, 1 H).
Example 13: 1-((2S,5R)-5-((5-(2-Methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-45 yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one
Step 1. (+)-(2S,5R)-Benzyl 5-amino-2-methylpiperidine-1-carboxylate and (-)(2R,5S)-benzyl 5-amino-2-methylpiperidine-1-carboxylate. 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% NHs/EtOH) to give pk 1 : (2R,5S)-benzyl 5- amino-2-methylpiperidine-1-carboxylate, [a]d20 = -7.09 (c = 1.1, MeOH). 1H NMR (400MHz, DMSO-de) δ 8.37 (br s, 3H), 7.24 - 7.49 (m, 5H), 5.09 (s, 2H), 4.32 (m,
H), 4.16 (d, J=8.28Hz, 1 H), 3.00 (br s, 2H), 1.83 (m, 2H), 1.59 (m, 2H), 1.11 (d, J=7.03Hz, 3H). pk2 : (2S,5R)-benzyl 5-amino-2-methylpiperidine-1-carboxylate, [a]d20 = +7.09 (c = 1.1, MeOH). 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 2. (2S,5R)-Benzyl 5-((5-(2-methoxyethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2-methylpiperidine-1-carboxylate. A mixture of 4-chloro-5-(2methoxyethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, (+)-(2S,5R)-benzyl 5-amino-220 methylpiperidine-1-carboxylate and Hunig’s base in n-BuOH were combined and heated to 90 °C overnight.. The mixture was removed from heat and concentrated.
The residue was purified by CombiFlash® (24g gold column, 0 to 50% EA in Hept) to give 264 mg of (2S,5R)-benzyl 5-((5-(2-methoxyethyl)-7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate. LC/MS (M+H) 578.5.
Step 3. 5-(2-Methoxyethyl)-N-((3R,6S)-6-methyIpiperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-amine. To a Parr reactor bottle was added (2S,5R)-benzyl 5-((5-(2methoxyethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1carboxylate (in 10 mL of EtOH) and Pd(OH)2 (126 mg). The reaction was stirred at psi H2 overnight at rt. The mixture was filtered through Celite® and the solvent removed to give 190 mg 5-(2-methoxyethyl)-N-((3R,6S)-6-methylpiperidin-3-yl)-7tosyl-7H-pyrrolo[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-4yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one. To a solution of 5-(2methoxyethyl)-N-((3R,6S)-6-methylpiperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-
4-amine chloroform(5 mL) ) was added Hunig’s base. The solution was cooled to 0 °C and acryloyl chloride was added. After 30 min, the reaction was determined to be complété by LC/MS, and NaHCO3 was added. The reaction was stirred for 30min. The organic layer was separated and concentrated. The residue was purified by CombiFlash® (20 to 100 EA in heptane) to give 210 mg 1-((2S,5R)-5-((5-(2methoxyethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-110 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)-2methylpiperidin-1 -yl)prop-2-en-1 -one. 1 -((2S,5R)-5-((5-(2-Methoxyethyl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)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 15 added. The reaction mixture was heated to 60°C and stirred overnight. The reaction was cooled to rt and diluted with 10mL of EtOAc. The solution was washed with NH4C] (10%), brine and dried (Na2SO4). The mixture was filtered and concentrated.
The residue was purified by CombiFlash® (12g gold column, 0 to 10% MeOH in DCM) to give 100 mg of 1-((2S,5R)-5-((5-(2-methoxyethyl)-7H-pyrrolo[2,320 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 (brs, 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)-525 methylpiperidin-1 -yl)prop-2-en-1 -one (chiral and rac-cis)
Stepl : tert-Butyl (5-methylpyridin-3-yl)carbamate. A solution of 5-methylpyridin-3amine (20 g, 185 mmol) and (Boc)2O (44.4 g, 203.5 mmol) in THF (360 mL) was stirred at room température for 5 h. TLC (PE/ EtOAc, 1:1) showed the reaction was completed. The reaction mixture was concentrated, and triturated with MTBE to give 30 tert-butyl (5-methylpyridin-3-yl)carbamate (26.4 g, 69%) as a white solid. 1H NMR (400MHz, CDCI3) δ 8.21 (d, J=2.3 Hz, 1H), 8.15 - 8.10 (m, 1H), 7.88 (brs, 1H), 6.66 (brs, 1H), 2.33 (s, 3H), 1.53 (s, 9H),
Step 2. rac-cis/trans- tert-Butyl (5-methylpiperidin-3-yl)carbamate. To a dry hydrogénation bottle, PtO2 (3.0 g) was added under N2 atmosphère. 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 55 psi of H2 for 5 days. 1H NMR showed most of 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 give rac-cis/trans- tert-butyl (5-methylpiperidin-3-yl)carbamate (27.3 g, 100%) as a yellowoil. LC/MS (M+H) 214.2
Step 3. rac-cis/trans-Benzyl 3-((tert-butoxycarbonyl)amino)-5-methylpiperidine-110 carboxylate. To a solution of rac-cis/trans- tert-butyl (5-methylpiperidin-3yl)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 température, and stirred at room température for 1 h. CbzCI (26 g, 152 mmol, 1.2 eq.) was added dropwise, and stirred at room température for 8 h. TLC (PE/EtOAc, 2:1) showed the reaction to be com15 plete. 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 give rac-cis/trans - benzyl 3-((tert-butoxycarbonyl)amino)-5-methylpiperidine-1carboxylate (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-1carboxylate (20 g, 57.4 mmol) in DCM (40 mL) was added HCl (g)/dioxane (50 mL, 4M) dropwise at room température, and stirred at room température for 6 hrs. LCMS showed the reaction to be complété. The reaction mixture was concentrated, and filtered, and then triturated with MTBE to give rac-cis/trans-benzyl 3-amino-5methylpiperidine-1 -carboxylate (5.8 g, 43%, 0.817 mol HCl) as a gray solid. 1H NMR (400MHz, 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, 1 H), 4.04 - 3.90 (m, 1 H), 3.74 - 3.43 (m, 1 H), 3.23 - 3.10 (m, 1 H), 2.82 30 2.59 (m, 1 H), 2.40 (s, 1 H), 2.26 - 2.05 (m, 1 H), 1.92 (d, J=11.3 Hz, 1 H), 1.78 -1.58 (m, 1 H), 1.30 (s, 1 H), 1.25 - 1.05 (m, 2H), 1.01 - 0.93 (m, 3H). LCMS (M+H) = 248.9.
Step 5. rac-cis-(3R,5S)-Benzyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-
5-methylpiperidine-1-carboxylate and rac-trans-(3R,5R)-benzyl 3-((2-chloro-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-methylpiperidine-1-carboxylate. 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 nBuOH (70 mL) at room température was added DIPEA (7.248 g, 56.184 mmol, 4.0 eq.). The reaction mixture was heated to 140 °C for 30 h. After LCMS showed the reaction to be complété, 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 the organic layer was separated. The aqueous layer was extracted with EtOAc (150 mLx2), 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 give rac-cis-(3R,5S)15 benzyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-methylpiperidine-1 carboxylate (rac-cis, spot 2 on the TLC plate -high polarity, 1.934 g, 34 %) and ractrans-(3R,5R)-benzyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidine-1-carboxylate (rac-trans, spot 1 on the TLC plate-low polarity, 559 mg, 10 %) as a yellow solid.Pk2:.rac-cis-(3R,5S)-benzyl 3-((2-chloro-7H-pyrrolo[2,320 d]pyrimidin-4-yl)amino)-5-methylpiperidine-1-carboxylate (rac-cis): 1H NMR (400MHz, DMSO-de) δ 11.70 (br s, 1 H), 7.70 (d, J=7.5 Hz, 1 H), 7.45 - 7.24 (m, 5H), 7.09 (br s, 1 H), 6.58 (br s, 1 H), 5.21 - 5.01 (m, 2H), 4.33 (br s, 1 H), 4.07 - 3.96 (m, 2H), 3.17 (d, J=5.3 Hz, 1H), 2.61 -2.53 (m, 1H), 2.33 (brs, 1H), 2.06-1.94 (m, 1H),
1.67 (br s, 1 H), 1.29 -1.13 (m, 1 H), 0.91 (d, J=6.5 Hz, 3H).
Pk1: rac-trans-(3R,5R)-benzyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidine-1-carboxylate (rac-trans): 1H NMR (400MHz, DMSO-d6) δ 11.69 (br s, 1 H), 7.63 - 6.59 (m, 8H), 5.05 (d, J=16.8 Hz, 1 H), 4.87 (br s, 1 H), 4.35 - 3.95 (m, 2H), 3.86 - 3.51 (m, 2H), 3.11 - 2.64 (m, 1H), 2.19 (brs, 1H), 1.90 -1.72 (m, 2H),
1.56 (brs, 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-4amine
To a dry Parr hydrogénation bottle, dry Pd/C (500 mg) was added under N2 atmosphère. Then, a solution of rac-cis-(3R,5S)-benzyl 3-((2-chloro-7H-pyrroIo[2,3d]pyrimidin-4-yl)amino)-5-methylpiperidine-1-carboxylate (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 50 psi of H2 for 3 days. After LCMS showed the reaction to be complété and Cl atom was removed, the reaction mixture was filtered, and the filter cake was washed with MeOH. The combined filtrate was evaporated to give 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)-5methylpiperidin-1-yl)prop-2-en-1-one. To a solution of rac-cis-N-((3R,5S)-5methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 1.494 mmol) in THF (20 mL) was added saturated aq.NaHCOa (15 mL) at 0 °C was added acryloyl chloride (149 mg, 1.643 mmol, 1.1 eq.) slowly. The reaction was stirred at 0 °C for 2 hours. After TLC (EtOAc/ MeOH, 10:1) showed the reaction to be complété, the reaction mixture was diluted with water (80 mL), and extracted with EtOAc (80 mLx2). 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 give rac-cis- 1-((3R,5S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidin-1-yl)prop-2-en-1-one (300 mg, 71 %) as a white solid. 1H NMR (400MHz, DMSO-de) δ 11.52 (brs, 1H), 8.10 (d, J=14.3 Hz, 1 H), 7.39 - 7.22 (m, 1H), 7.07 (brs, 1H), 6.94-6.78 (m, 1H), 6.56 (brs, 1H), 6.12 (dd, J=8.9, 16.2 Hz, 1H), 5.69 (t, J=10.4 Hz, 1 H), 4.71 (d, J=10.0 Hz, 1 H), 4.47 - 4.29 (m, 1 H), 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, 1 H), 2.05 (d, J=11.8 Hz, 1H), 1.36-1.17 (m, 1 H), 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)-5methylpiperidin-1 -yl)prop-2-en-1 -one. rac-cis-1 -((3R,5S)-3-((7H-Pyrrolo[2,3d]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 pm, 35% MeOH/NH4OH, 80 ml/min) to give 1((3R,5S)-3-((7H-pyrrolo[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)-5methylpiperidin-1-yl)prop-2-en-1-one (pk 2).
Peak 1: 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1 H), 8.10 (d, J=14.3 Hz, 1 H),
7.42 - 7.23 (m, 1 H), 7.08 (br s, 1 H), 6.86 (td, J=11.4, 16.4 Hz, 1 H), 6.57 (br s, 1 H), 6.18-6.06 (m, 1 H), 5.70 (t, J=10.2 Hz, 1 H), 4.71 (d, J=9.8 Hz, 1H), 4.48-4.30 (m, 1 H), 4.03 (d, J=11.8 Hz, 1 H), 2.79 - 2.54 (m, 1 H), 2.42 - 2.14 (m, 1 H), 2.06 (d, J=12.5 Hz, 1 H), 1.63 (br s, 1 H), 1.39 -1.17 (m, 1 H), 0.99 - 0.87 (m, 3H). LCMS (M+H) = 285.9. Peak 2: 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1 H), 8.10 (d, J=14.6 Hz, 1 H), 7.38 - 7.23 (m, 1 H), 7.08 (br s, 1 H), 6.94 - 6.79 (m, 1 H), 6.56 (br s, 1H), 6.12 (dd, J=7.8, 16.8 Hz, 1H), 5.75-5.64 (m, 1 H), 4.71 (d, J=11.8 Hz, 1 H), 4.49 - 4.30 (m, 1 H), 4.03 (d, J=11.5 Hz, 1 H), 2.81 - 2.54 (m, 1 H), 2.42 - 2.15 (m, 1 H), 2.06 (d, J=12.3 Hz, 1H), 1.62 (br s, 1H), 1.38 -1.18 (m, 1 H), 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)-5fluoropiperidin-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.turns at 0 °C. The reaction mixture was stirred at room température for 12 hours. After TLC (DCM/MeOH, 10:1) showed the reaction complété, 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 give (2S,4R)-methyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate (30 g, 66%) as a yellow oil. 1H NMR (400MHz, CDCI3) 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 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 °C under N2. The reaction mixture was stirred at -78 °C for 0.5 hours and then warm to room température for 2 hours. After TLC (petroleum ether/ethyl acetate,
1:1) showed starting material to be consumed, the reaction mixture was quenched with saturated sodium carbonate (200 ml). The organic layer was separated out and the aqueous layer was extracted with CH2CI2 again. The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated to dryness, 5 the crude product was purified by sp1 (EtOAc/petroleum ether, 10% to 80%) to give (2S,4S)-methyl 1-benzyl-4-fluoropyrrolidine-2-carboxylate (2 g, 34%) as a yellow oil. 1H NMR (400MHz, CDCI3) 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 LÎAIH4 (1.28 g, 33.7 mmol, 1 eq.) in anhydrous THF (50 mL) was added dropwise a solution of (2S,4S)-methyl 1-benzyl-4-fluoropyrrolidine-2-carboxylate (8 g, 33.7 mmol, 1 eq.) in anhydrous THF (50 mL) at 0 °C. The reaction mixture was stirred at room température for 10 hours. After TLC (petroleum ether/ethyl acetate, 4:1) showed starting material to be consumed, the reaction mixture was cooled to 0 °C and sequentially quenched with water (1.3 ml), 15 % NaOH solution (1.3 ml) and water (3.9 ml). MgSO4 (5 g) was added and the mixture was warmed to room température and stirred for 0.5 hours. The mixture was filtered and concentrated in vacuum to give the crude product, which was purified by sp1 (EtOAc/petroleum ether, 40% to
100%) to give (2S,4S)-1-benzyl-4-fluoropyrrolidin-2-yl)methanol (6 g, 70%) as a yellow oil. 1H NMR (400MHz, CDCI3) 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)-1benzyl-4-fluoropyrrolidine. To a stirred solution of (2S,4S)-1-benzyl-4fluoropyrrolidin-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 XtaIFluor® (4.8 g, 21 mmol, 1.1 eq.) at -78 °C under N2 protection. The reaction mixture was stirred at -78 °C for 6 hours.
After TLC (petroleum ether/ethyl acetate, 4:1) showed starting material to be 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 give 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 via SFC (ChiralPak AD, 300 x 50 mm, 10 pm, 15% MeOH/NH4OH, 180 mL/min) to give (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, CDCIs) 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)-310 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 température. The reaction mixture was stirred at rt for 3 hours. Then water (0.7 ml) was added dropwise to the mixture and heated to 60 °C for 10 hours. After TLC (petroleum ether/ethyl acetate, 4:1) showed starting material to be consumed, the reaction mixture was concentrat15 ed to dryness, and purified by sp1 (MeOH/ CH2CI2 0% to 10%) to give (3R,5S)-1benzyl-5-fluoropiperidin-3-amine (1.1 g, 80%) as a colorless oil. LC/MS (M+H) =
209.2. 1H NMR (400MHz, CDCI3) 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[2,3d]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-pyrrolo[2,3djpyrimidine (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 complété, the reaction mixture was cooled to room température and evaporated to dryness in vacuo at 45 °C. 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 give crude product, which was purified via chromatography (EtOAc/petroleum ether, 10% to
80%) to give N-((3R,5S)-1-benzyl-5-fluoropiperidin-3-yl)-2-chloro-7H-pyrrolo[2,3d]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 dry Parr hydrogénation bottle, 10% dry Pd/C (50 mg) was added under Ar atmosphère. A solution of N-((3R,5S)-1-benzyl-5-fluoropiperidin-3-yl)-2-chloro-7Hpyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.84 mmol) in MeOH (20 mL) was added and the resulting mixture was hydrogenated under 50 psi of H2 at 35 °C 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 give N((3R,5S)-5-fluoropiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 100%) as a white solid. 1H NMR (400MHz, 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 (brs, 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.
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 aq. NaHCO3 solution (3 mL) at 0 °C was added acryloyl chloride (42 mg, 0.468 mmol) dropwise at 0 °C carefully. The resulting mixture was stirred at 0 °C for 2 hours. After TLC (DCM/MeOH, 10:1) showed starting material to be 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 give crude product, which was further purified by column chromatography on silica gel (MeOH/DCM, 0% to 8%) to give 1-((3R,5S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2en-1-one (60 mg, 50 %) as a white solid. The solid was further purified by RP-HPLC to give pure product (25.7 mg). HPLC: Column: DIKMA Diamonsil(2) C18 200x20mm*5pm; 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 (400MHz, 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 (brs, 1 H) 8.15 (s, 1 H) 11.35 (brs, 1 H).
Example 16:1-((1R,2R,5R)-2-((7H-Pyrrolo[2,3-d]pyiïmidin-4-yl)amino)-8azabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1 -one.
Step 1. Rac-N-(8-Methyl-8-azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-amine. A solution ofthe 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 the pyrrolopyrimidine was consumed, and ionization consistent with the desired product. The reaction was concentrated in vacuo, and the crude material was partitioned between ethyl acetate (10 mL) and water (20 mL). The mixture was filtered and the solid was washed with ether to give 6g of rac-N-(8-methyl-8-azabicyclo[3.2.1 ]octan-2-yl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine. LC/MS (M+H) = 412.1.
Step 2. N-((1 R,2R,5S)-8-Azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7H-pyrrolo[2,3d]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 was added NaHCO3 (10 eq, 97.2 mmol, 8.25 g mg ) in DCE (50 mL) followed by 1-chloroethyl chloroformate (10 eq, 10.6 mL, 97.2 mmol). After 10min, the reaction was allowed to warm to room température. The resulting mixture was heated to 50°C for 4 hrs. After cooling to room température, 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 4h. Ail 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 solvent was removed to give 4.0 g of crude product. The crude product was purified by CombiFlash® (40g gold column, 0 to 10% 2M NH3 in MeOH in DCM) to give 2 g of racemic N-((1 R,2R,5S)-8azabicyclo[3.2.1 ]oc-tan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. LC/MS (M+H) = 398.1 (M+H). 1H NMR (400MHz, CDCI3) δ 8.42 (s, 1 H), 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, 1 H), 3.76 (bs, 1 H), 3.60 (bs, 1 H), 2.37 (s, 3H), 2.03-1.26 (m, 9H).
racemic N-((1 R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-amine (1g ) was purified by chiral SFC to provide 400 mg of two peaks:
enantiomer 1 (pk1): N-((1 R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine and enantiomer 2 (pk2): N-((1S,2S,5R)-8azabicyclo[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 5um Isocratic Conditions: Mobile Phase A:
80% CO2; Mobile Phase B: 20%; Methanol+0.2%NH4OH; Détection 210 nM; Flow:
80.0 mL/min; Backpressure: 120 Bar.
Step 3. 1 -((1 R,2R,5R)-2-((7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one. To a solution N-((1 R,2R,5S)-8azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (pk1) in chlo10 roform (10 mL) was added DIPEA . The solution was cooled to 0 °C and acryloyl chloride (in 1mL of CHCI3) was added over 5min. 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 (300mg) was purified by CombiFlash®(12 g gold column, 20 to 100% EA in Hept) to give 208 mg of 1-((1 R,2R,5R)-2-((7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one . LC/MS (M+H): 452.2. 1H NMR (400MHz, CDCIs) 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), 5.80-5.71 m, 1H), 5.01-4.97 ( m, 1H), 4.78-4.73 (m, 1H), 4.69-4.60 (brs, 1H), 4.26-4.16 (m, 1H), 2.40 (s, 3H), 2.01-1.53 (m, 8H).
Step 4. 1-((1 R,2R,5R)-2-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8azabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1 -one. 1 -((1 R,2R,5R)-2-((7-Tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (200 mg) was dissolved in 5 mL of THF. TBAF (1M in THF, 1.9 mL) was added. The 25 reaction was heated to 60 °C for 48 hrs. The solvent was removed in vacuo and the residue was treated with EtOAc and NH4CI (10%) (5 mL each). The layers were separated and the organic layer collected, washed with NH4CI (10%) and satd.
NaHCO3 and brine. The organic fraction was collected, dried (Na2SÛ4) and the solvent removed to give 200 mg of crude product, which was purified by RP-HPLC to 30 provide 90 mg of product. The product was further purified by CombiFlash® (12 g gold column, 0 to 10% MeOH in DCM) give 55 mg of 1-((1R,2R,5R)-2-((7Hpyrrolo[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 (400MHz, CDCIg) δ 11.58-11.47 (m, 1 H) 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) 4.84-4.82 (m, 1H), 4.48-4.30 (m, 1H), 2.17-1.69 (m, 8H).
Example 17:1-((3R,5S)-3-(7H-Pyrrolo[2,3-cl]pyrimidin-4-ylamino)-55 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 éthanol solution was degassed with argon for 15 mins after which 10% Pd/C (400 mg) was added and the résultant mixture was hydrogenated 10 using a hydrogen bladder for 16 h. After TLC (5% MeOH in DCM) showed starting material to be consumed, the reaction mixture was filtered through a Celite® bed, and the filtrate was concentrated to obtain 3g crude (3S,5S)-5-((tertbutyldimethylsilyl)oxy)piperidin-3-ol as light yellow oil. Crude (3S,5S)-5-((tertbutyldimethylsilyl)oxy)piperidin-3-ol was directly used for the next step.
Step 2. (3S,5S)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-hydroxypiperidine-1carboxylate. 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 °C was added TEA (3.12 ml, 22.385 mmol) and Boc2O (3.086 ml, 13.431 mmol in a DCM (4 ml) solution). The reaction mixture was allowed to warm to room température over 45 min. After TLC (70%
EtOAc in hexane) indicated 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 afford 3.2 g (86%) (3S,5S)-tert-butyl 3-((tert25 butyldimethylsilyl)oxy)-5-hydroxypiperidine-1-carboxylate as a light brown oil. 1H NMR (400MHz, CDCI3) 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 (brs, 1 H) 3.39 (brs, 2 H) 3.57 (dd, J=13.69, 3.42 Hz, 1 H) 3.87-4.11 (m, 2H).
Step 3. (3S,5S)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-530 ((methylsulfonyl)oxy)piperidine-1-carboxylate. To a stirred solution of (3S,5S)-tertbutyl 3-((tert-butyldimethylsilyl)oxy)-5-hydroxypiperidine-1-carboxylate (3.5 g, 10.557 mmol) in DCM (25 ml) at 0 oC was added TEA (4.414 ml, 31.671 mmol) 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) indicated clean 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 4.5g crude (3S,5S)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-5-((methylsulfonyl)oxy)piperidine-1 carboxylate as light yellow oil, which was used for the next step directly. 1H NMR (400MHz, CDCIs) 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 (brs, 1 H) 4.94 (brs, 1 H).
Step 4. (3R,5S)-tert-Butyl 3-azido-5-((tert-butyldimethylsiIyl)oxy)piperidine-1 carboxylate. To a stirred solution of (3S,5S)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((methylsulfonyl)oxy)piperidine-1 -carboxylate (4.32 g, 10.546 mmol) in DMF (35 ml) was added NaN3 (2.057 g, 31.639 mmol). 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 into 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 CombiFlash® (EtOAc/hexane, 100% hexane to 20 % EtOAc in hexane ) afforded 1.9 g (51%) (3R,5S)-tert-butyl 3-azido-5-((tertbutyldimethylsilyl)oxy)piperidine-1-carboxylate as a light yellow oil. 1H NMR (400MHz, CDCIs) 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-1carboxylate. To a stirred solution of (3R,5S)-tert-butyl 3-azido-5-((tert25 butyldimethylsilyl)oxy)piperidine-1 -carboxylate (1.9 g, 5.329 mmol) in THF (100 ml) was added H2O (0.671 ml, 37.303 mmol) and PPh3 (2.097 g, 7.993 mmol). 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 100200 silica and MeOH/DCM as eluent (100% DCM to 5% MeOH in DCM) to afford
1.52 g (86%) of (3R,5S)-tert-butyl 3-amino-5-((tert-butyldimethylsilyl)oxy)piperidine1-carboxylate as a light yellow oil. 1H NMR (400MHz, 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. (3S,5R)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a stirred solution of (3R,5S)-tert5 butyl 3-amino-5-((tert-butyldimethylsilyl)oxy)piperidine-1 -carboxylate (1.52 g, 4.598 mmol) in n-butanol (10 ml) was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.698 g, 5.518 mmol) and DIPEA (1.642 ml, 9.197 mmol). 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 afford 2g (72%) (3S,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate as a light yellow solid. 1H NMR (400MHz, 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 (brs, 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-7Hpyrrolo[2,3-d]pyrimidin-4-amine. To a stirred solution of (3S,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (1 g, 1.662 mmol) in DCM (10 ml) at 0 °C was added TFA (0.763 ml,
9.969 mmol). The reaction mixture was allowed to corne to ambient temp and stirred for 16 h. The reaction mixture was quenched with aq 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 afford 520 mg (62%) N-((3R,5S)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine as light yellow solid. 1H NMR (400MHz, 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[2,3d]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 was added TEA (0.437 ml, 3.109 mmol) and Acryloyl chloride (0.084 ml, 1.036 mmol). 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® (EtOAc/hexane, 100% hexane to 70% EtOAc in hexane) to afford 450 mg 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 off white solid. 1H NMR (400MHz, 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-4yl)amino)piperidin-1-yl)prop-2-en-1-one. To a stirred solution of 1-((3S,5R)-3-((tertbutyldimethylsilyl)oxy)-5-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1yl)prop-2-en-1-one (450 mg, 0.81 mmol) in THF (5 ml) at 0 °C was added 1M TBAF in THF (1.21 ml, 1.21 mmol). The reaction mixture was allowed to corne to ambient temp 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-7Hpyrrolo[2,3-d]pyrimidin-4-yl)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]pynmidin-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-pyrroIo[2,3d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (300 mg, 0.679 mmol) in MeOH (5 ml) at 0 °C was added H2O (1 ml) and K2CO3 (132.724 mg, 1.019 mmol). The reaction mixture was allowed to corne to ambient température 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 Na2SO4and concentrated to provide crude material, which after purification by préparative HPLC afforded 30 mg of 1-((3R,5S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-5-hydroxypiperidin-1-yl)prop-2-en-1-one as white solid.
Prep -HPLC: Instrument: Waters auto purification instrument; Column: Zorbax SBC18 (250x21.2 mm); Mobile Phase: Gradient of Methanol 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)amîno)-2methylpîperidin-1-yl)prop-2-en-1-one
Step 1. (2S,5R)-Benzyl 5-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperidine-1-carboxylate. Prepared as in Example 13: (2S,5R)-benzyl 5-((5chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1 -carboxylate (190 15 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-4amine. To a flask containing (2S,5R)-benzyl 5-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)amino)-2-methylpiperidine-1-carboxylate (190 mg, 0.47 mmol) was added DCM (5 mL) and HBr/AcOH (5 mL). After stirring at 25 °C for 3 hrs, 50 mL of diethyl ether 20 was added and the reaction stirred for 15 min and filtered. The solid was dried to give 5-chloro-N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as the HBr sait (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)-2methylpiperidin-1 -yI)prop-2-en-1 -one
To a flask containing 5-chloro-N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3d]pyrimidin-4-amine -HBr (170 mg, 0.49 mmol) sait was added DCM (5 mL) and Hunigs base (0.24 mL, 2.8 mL). 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 rt for 1 hr and then poured into water. The layers were sepa30 rated and the organic layer collected, dried (Na2SO4) and the solvent removed to give a yellow solid, which was purified by RP-HPLC to give 1-((2S,5R)-5-((5-chIoro7H-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-c/4) d ppm 1.24 -1.45 (m, 3H) 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]pyrimiciin-4-yl)amino)-5methoxypiperidin-1 -yl)prop-2-en-1 -one.
Step 1. (3S,5R)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a solution of (3R,5S)-tert-butyl
3- amino-5-((tert-butyldimethyl-silyl)oxy)piperidine-1 -carboxylate (from ex 17:step 6) (700 mg, 2.117 mmol) in n-BuOH (10 mL) was added 4-chloro-7-trityl-7H-pyrrolo[2,3djpyrimidine (1.257 g, 3.176 mmol), followed by DIPEA (802 mg, 6.351 mmol) at room température. The résultant mixture was heated to 120 °C overnight. After TLC (Petroleum ether: EtOAc, 2:1) showed the starting material to be consumed, the mixture was concentrated to dryness to give crude product which was purified by col15 umn chromatography (silica, EtOAc/Petroleum ether, 0-45%) to give (3S,5R)-tertbutyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (708 mg, 48%) as a white solid. LC/MS (M+H) 690.9.
Step 2. (3S,5R)-tert-Butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-420 yl)amino)piperidine-1-carboxylate. To a solution of (3S,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (708 mg, 1.026 mmol) in THF (15 mL) was added TBAF (536.5 mg, 2.052 mmol) at room température. The resulting solution was warmed and stirred at 40 °C overnight. After TLC (EtOAc) showed 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 give crude (3S,5R)-tert-butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-
4- yl)amino)piperidine-1-carboxylate (550 mg, 93%) as a white solid, which was directly used to next step without further purification. LC/MS (M+H) 576.3.
Step 3. (3S,5R)-tert-Butyl 3-methoxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a solution of (3S,5R)-tert-butyl 3-hydroxy-5((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (550 mg,
0.955 mmol)) in anhydrous THF (10 mL) was added NaH (84 mg, 2.101 mmol) at 0 °C under N2. The résultant suspension was stirred at 0 °C for 10 min. Mel (162.8 mg, 1.146 mmol) in anhydrous THF (40 mL) was the added. The résultant mixture was stirred at room température overnight. After TLC (EtOAc) showed the starting material to be consumed, the reaction mixture was quenched with water, and extracted with EtOAc (10 mLx2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give crude product which was purified by column chromatography (silica, EtOAc : Petroleum ether, 0-60%) to give (3S,5R)-tert-butyl 3-methoxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-410 yl)amino)piperidine-1 -carboxylate (400 mg, 71%) as a white solid. LC/MS (M+H) =
590.3.
Step 4. N-((3R,5S)-5-Methoxypiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4amine
To a solution of (3S,5R)-tert-butyl 3-methoxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-415 yl)amino)piperidine-1 -carboxylate (400 mg, 0.68 mmol) in anhydrous DCM (4 mL) was added 4M HCI/dioxane (4mL) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 1 h. After TLC (EtOAc) showed the starting material to be consumed, yhe mixture was concentrated to dryness to give N-((3R,5S)-5methoxypiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (356 mg, 100 %) 20 as a white solid.
Step 5. 1 -((3S,5R)-3-Methoxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yl)prop-2-en-1-one. To a solution of N-((3R,5S)-5methoxypiperidin-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) was added acryl-CI (73.3 mg, 25 0.815 mmol) at 0 °C. The résultant mixture was stirred at 0 °C for 1 h. TLC (EtOAc) showed the starting material was consumed completely. The reaction mixture was separated between THF and water. The aqueous layer was extracted with EtOAc (10 mLx2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give crude 1-((3S,5R)-3-methoxy-5-((7-trityl-7H30 pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (348 mg, 100%) as a white solid. which was directly used to 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[2,3d]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 the starting material was consumed completely. The mixture was diluted with THF and concentrated to dryness to give crude product which was purified by column chromatography (silica, MeOH: EtOAc= 0-33%) and RP-HPLC to give 1-((3R,5S)-3-((7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)-5-methoxypiperidin-1-yl)prop-2-en-1-one (12.1mg, 6.3 %) as a white solid. LC/MS (M+H) = 302.1. 1H NMR (400MHz, 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 -Acryloylpiperîdin-3-yl)amino)-7H-pyrrolo[2,3d]pyrimidin-5-yl)acetonitrile.
Similarto préparation of Example 12, except using Het-CI as 2-(4-chloro-7Hpyrrolo[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]pyrimidïn-4-yl)hexahydro1 H-pyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1 -one.
Similar to préparation of rac-1-((3aS,7aS)-1-(7H-pyrrolo[2,3-d]pyrimidin-4yl)hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1-one (ex 8), except using rac-(3aR,7aR)-benzyl hexahydro-1H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate through the synthetic sequence. LC/MS (M+H) = 298.1. 1H NMR (400MHz, DMSOd6) δ 11.583 (s, 1H) 78.09-8.07 (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), 5.695-5.851 (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)-5methylpiperidin-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) was added saturated aq.NaHCO3 (15 mL) at 0 °C was added acryloyl chloride (149 mg, 1.643 mmol, 1.1 eq.) slowly. The reaction was stirred at 0 °C for 2 hours. After TLC (EtOAc: MeOH = 10:1) showed the reaction to be complété, the reaction mixture was diluted with water (80 mL), and extracted with
EtOAc (80 mLx2). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by flash column chromatography (EtOAc/MeOH, 10:1) to give 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 (400MHz, DMSO-d6) δ 11.52 (brs, 1H), 8.10 (d, J=14.3 Hz, 1H), 7.39 - 7.22 (m, 1H), 7.07 (brs, 1H), 6.94-6.78 (m, 1H), 6.56 (brs, 1H), 6.12 (dd, J=8.9, 16.2 Hz, 1 H), 5.69 (t, J=10.4 Hz, 1 H), 4.71 (d, J=10.0 Hz, 1 H), 4.47 - 4.29 (m, 1 H), 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,
H), 2.19 (t, J=11.5 Hz, 1 H), 2.05 (d, J=11.8 Hz, 1 H), 1.36 -1.17 (m, 1 H), 0.97 - 0.89 10 (m, 3H). LCMS (M+H) 285.9.
Examples 23-40
Example LC/MS IUPAC NAME
23 367 1-[(3R)-3-{[5-(5-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
24 379 1-[(3R)-3-{[5-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]amino}piperidin-1 -yl]prop-2-en-1 -one
25 364 1-[(3R)-3-{[5-(2-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
26 349 1-[(3R)-3-{[5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
27 419 4-(4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-N,N-dimethylbenzamide
28 352 1 -[(3 R)-3-{[5-( 1 -methyl-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3d]pyrimidin-4-yl]amino}pipendin-1 -yl]prop-2-en-1 -one
29 434 4-(4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-N-(propan-2-yl)benzamide
30 363 1-[(3R)-3-{[5-(6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
66 363 (R)-1-(3-((5-(6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1 -yl)prop-2-en-1 -one
31 466 4-(4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-2-chloro-N-cycIopropylbenzamide
32 427 1-[(3R)-3-({5-[3-(methylsulfonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)piperidin-1 -yl]prop-2-en-1 -one
33 393 1-[(3R)-3-{[5-(6-ethoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
34 402 1 -[(3R)-3-{[5-(1 -methyl-1 H-indazol-5-yl)-7H-pyrrolo[2,3d]pyrimidin-4-yl]amino}piperidin-1 -yl]prop-2-en-1 -one
35 435 1-[(3R)-3-({5-[2-(morpholin-4-yl)pyrimidin-5-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)piperidin-1 -yl]prop-2-en-1 -one
36 435 1-[(3R)-3-({5-[6-(morpholin-4-yl)pyridin-3-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)piperidin-1 -yl]prop-2-en-1 -one
37 312 1-{(3R)-3-[(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]piperidin-1 -yl}prop-2-en-1 -one
38 364 1-[(3R)-3-({5-[(E)-2-(furan-3-yl)ethenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}amino)piperidin-1 -yl]prop-2-en-1 -one
39 328 1-[(3R)-3-{[5-(2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
40 298 1-{(3R)-3-[(5-ethenyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]piperidin-1 -yl}prop-2-en-1 -one
Examples 23-40 were prepared as described in the scheme below using parallel methods known to those of ordinary skill in the art, and in light of the description herein.
Pd-118/K3PO4/dioxane/
H2O/ N2/110 °C/16 hrs
HCl/EtOH/80 °C/16 hrs
MeOH/ NH3 H2O/ °C/16hrs
NaHCO3/ H2O/ EtOAC/30 °C/2hrs
Step 1: Suzuki Coupling. A 0.16 M solution of (R)-tert-butyl 3-((5-iodo-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-110 carboxylate in dioxane is prepared. A 0.63 M solution of K3PO4 in H2O is prepared. A monomer boronate/boronic acid (225 pmol, 1.8 eq) is dispensed to 8 ml reaction vials. A volume of 800 pL of (R)-tert-butyl 3-((5~iodo-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (125 pmol, 1.0 eq) solution is then dispensed to the vial, followed by 400 pL of K3PO4 (250 pmol, 2.0 eq) solution and then Pd-118((1,1 '-bis(di-tert butylphosphino) ferrocene palladium dichloride) (4.9 mg, 7.5 pmol, 0.06 eq), ail under N2 atmosphère. The vials are capped and shaken at 110 °C for 16 hrs. Reaction progress is checked by LC-MS. Upon completion, each reaction mixture is filtered and concentrated by Speedvac®. The residue is washed with H2O and extracted with EtOAc (1ml x 3). The organic layers were collected, dried over anhydrous Na2SO4, filtered and concentrated by Speedvac® to give a crude intermediate, which was used in the next step directly.
Step 2: De-protection. A mixed solution of conc. HCl (37% aqueous solution) in EtOH (v/v 1:6) is prepared. One ml of the HCl solution is dispensed to 8ml vials containing the crude intermediate from Step 1. The vials are capped and shaken at 80 °C for 16 hrs. Solvent is evaporated by Speedvac®. A mixed solution of NH3H2O in MeOH (v/v 1:4) is prepared, and 1ml is dispensed to each vial. The vial is capped and shaken at 30 °C for 16 hrs. Reaction progress is checked by LC-MS. Upon completion, the reaction is filtered and concentrated to give the crude intermediate, which was used for final step directly.
Step 3: Acylation. A saturated solution of NaHCO3 in H2O is prepared and one ml is dispensed to the vials containing the product of step 2. One ml of EtOAc is then dispensed to each vial, followed by acryloyl chloride (250 pmol, 2.0 eq). The vials are capped and shaken at 30 °C for 2 hours. Reaction progress is checked by LC-MS. Upon completion, the mixture is concentrated. The residue is purified by préparative HPLC to give the final product.
Example 41: 1 -((3aS,7aS)-1 -(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1 Hpyrrolo[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-1 H-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) was 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 give an oil, which was purified by column chromatography (silica, DCM/MeOH, 25 g) to give a
major fraction. This was further purified by RP-HPLC to give pure 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.
Example 42-46:
wherein R = F, Me, Et, CN, CH2CH2OMe
Examples 42-46 were prepared as described in Examples 1-3, but using Het-CI = 4chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine or 4-chloro-5-methyl-7H-pyrrolo[2,3djpyrimidine or 4-chloro-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine or4-chloro-5-(210 methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine.
Example LC/MS (M+H) IUPAC Name
42 290 1-{(3R)-3-[(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]piperidin-1 -yl}prop-2-en-1 -one
43 286 1-{(3R)-3-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]piperidin-1 -yl}prop-2-en-1 -one
44 300 1-{(3R)-3-[(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]piperidin-1 -yl}prop-2-en-1 -one
45 297 4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-7H-pyrrolo[2,3- d]pyrimidine-5-carbonitrile
46 330 1-[(3R)-3-{[5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
Example 47:1 -{(3R)-3-[(3-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin1-yl}prop-2-en-1-one. LC/MS (M+H) 285.
Example 48: 1 -[(3aS,7aS)-1 -(5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-415 yl)octahydro-6H-pyrrolo[2,3-c]pyridîn-6-yl]prop-2-en-1 -one.
100
Step 1. (3aS,7aS)-Benzyl 1-(2,2,2-trifluoroacetyl)hexahydro-1H-pyrrolo[2,3-
c]pyridine-6(2H)-carboxylate
To a solution of (-)-(3aS,7aS)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate (3.85 g, 14.8 mmol) in DCM (15 mL) at 0 °C was added DIPEA (5.72 mL, 32.5 mmol) followed by trifluoroacetic anhydride (2.2 mL, 15.5 mmol). The reaction mixture was stirred at rt for 2hrs and then poured into saturated NaHCO^DCM. The layers were separated and the organic layer dried (Na2SO4) and the solvent removed to give the crude (3aS,7aS)-benzyl 1-(2,2J2-trifluoroacetyl)hexahydro-1 Hpyrrolo[2,3-c]pyridine-6(2H)-carboxylate, which was used without purification in the next step. LC/MS (M+H) 357.1.
Step 2. 2,2,2-Trifluoro-1 -((3aR,7aS)-octahydro-1 H-pyrrolo[2,3-c]pyridin-1 yl)ethanone. To a Parr bottle was added 3aS,7aS)-benzyl 1-(2,2,2trifluoroacetyl)hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate (5.27 g, 14.8 mmol), éthanol (30 mL) and 5% Pd/C (500 mg). The mixture was shaken overnight at 40 psi at 25 °C. The reaction mixture was filtered through Celite® and the solvent removed to give 2,2,2-trifluoro-1-((3aR,7aS)-octahydro-1 H-pyrrolo[2,3-c]pyridin-1yl)ethanone. The material was used in the next step without further purification. LC/MS (M+H) 223.1.
Step 3. (3aS,7aS)-2-(Trimethylsilyl)ethyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate. To a flask containing 2,2,2-trifluoro-1-((3aR,7aS)-octahydro-1 Hpyrrolo[2,3-c]pyridin-1-yl)ethanone (3.29, 14.8 mmol) was added DCM (30 mL), TEA (10.3 mL, 73.9 mmol) and Teoc-OSuc (4.19 g, 16.3 mmol). The reaction mixture was stirred at 25 °C overnight and then poured into saturated NaHCOs/DCM. The layers were separated and the organic layer dried (Na2SO4) and the solvent removed to give (3aS,7aS)-2-(trimethylsilyl)ethyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate. To (3aS,7aS)-2-(trimethylsilyl)ethyl hexahydro-1 H-pyrrolo[2,3-
c]pyridine-6(2H)-carboxylate (5.42 g, 14.8 mmol) was added MeOH (25 mL) and K2CO3 (4.09 g, 29.6 mmol). The mixture was stirred at rt for 4 hrs and then filtered and concentrated. The residue was taken up into DCM and washed with saturated NaHCO3 and brine. The organic extract was dried (Na2SO4) and the solvent removed to give the desired product (3.2 g, 80%). LC/MS (M+H) 271.2. 1H NMR (400 MHz, CDCI3) δ-0.17-0.03 (m, 9 H) 0.80- 1.00 (m, 2 H) 1.26 (dd, 1 H) 1.33-1.72
101 (m, 4H) 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 was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 17.89 mmol), Cul (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 rt for 16 hrs. The solvent was removed in vacuo and the residue taken up into DCM (300 mL). The mixture was washed with water (3 x 75 mL), dried (Na2SO4) and the solvent removed to give an oil, which after chromatography (silica, 70% EtOAc/Hep) gave the desired product (3.8 g, 85%). LC/MS (M+H) 250.0. 1H NMR (400MHz, DMSO-de) δ 0.26 (br s, 9 H), 8.09 (d, J=2.34 Hz, 1 H), 8.64 (s, 1 H).
Step 5. (3aS,7aS)-2-(Trimethylsilyl)ethyl 1-(5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)hexahydro-1H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate. To a round bottom flask containing (3aS,7aS)-2-(trimethylsilyl)ethyl hexahydro-1 H-pyrrolo[2,3-
c]pyridine-6(2H)-carboxylate (1.94 g, 7.17 mmol) was added i-PrOH (20 ml), DIPEA (1.89 mL, 10.8 mmol) and 4-chloro-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3djpyrimidine (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 give the crude, which was purified by chromatography (silica, EtOAc/MeOH) to give (3aS,7aS)-2-(trimethylsilyl)ethyI 1-(5((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1H-pyrrolo[2,3-
c]pyridine-6(2H)-carboxylate (1.3 g, 38%). LC/MS (M+H) 484.2. 1H NMR (400 MHz, CDCI3) 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-Ethynyl-4-((3aR,7aS)-octahydro-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7Hpyrrolo[2,3-d]pyrimidine.
To a flask containing (3aS,7aS)-2-(trimethylsilyl)ethyl 1-(5-((trimethylsilyl)ethynyl)7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate (800 mg, 1.65 mmol) was added THF (10 mL) and TBAF (3.64 mL, 1M
102 in THF). After stirring at rt for 48 hrs 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 give 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 give crude 1-((3aS,7aS)-1-(5ethynyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-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-Ethynyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1 Hpyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1-one. To flask containing 5-ethynyl-4((3aR,7aS)-octahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine (442 mg, 1.65 mmol) was added DCM (7 mL) and TEA (0.51 mL, 3.64 mmol). The flask was cooled to 0 °C and acryloyl chloride (189 mg in 5 mL DCM) was added dropwise over 5 minutes. After addition was complété the reaction was stirred for 30 min. 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 give an oil, which was purified by RP-HPLC to give 1-((3aS,7aS)-1-(5-ethynyI-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)hexahydro-1 H-pyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1 -one (197 mg, 37%). LC/MS (M+H) 322.1. 1H NMR (400MHz, 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 (brs, 1 H).
Example 49: 1 -[(3aS,7aR)-1 -(7H-Pyrrolo[2,3-d]pyrimîdin-4-yl)octahydro-6Hpyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1 -one.
Step 1. Dimethyl 3-(cyano((diphenylmethylene)amino)methyl)pentanedioate. To a flask containing 2-((diphenylmethylene)amino)acetonitrile (4.0 g, 18.16 mmol) in THF at -78 °C was added DBU (1.6 mL, 9.08 mmol) and (E)-dimethyl pent-2enedioate. The mixture was stirred at -78 °C overnight and then rt for 24 hrs. The solvent was removed in vacuo and the crude material purified by chromatography (silica, EtOAc/Hep, 0 to 30%) to give 3.9 g of dimethyl 3(cyano((diphenylmethylene)amino)methyl)pent-anedioate. GC/MS 378. 1H NMR (400 MHz, CDCI3) 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).
103
Step 2. Methyl 2-(1-benzhydryl-2-cyano-5-oxopyrrolidin-3-yl)acetate. To aflask containing dimethyl 3-(cyano((diphenylmethylene)amino)methyl)pentanedioate was 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 NaHCOs/EtOAc. The layers were separated and the organic layer washed with water, brine and dried (MgSO4). The solvent was removed to give crude material, which after chromatography (silica, EtOAc/Hep, 0 to 50%) gave methyl 2-(1-benzhydryl-2-cyano-5oxopyrrolidin-3-yl)acetate (2.5 g, 73%). LC/MS (M+H) 349.2. 1H NMR (400 MHz, CDCI3) 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 bottle was added methyl 2-(1-benzhydryl-2-cyano-5-oxopyrrolidin-3-yl)acetate (
2.5 g, 12 mmol), MeOH (10 mL) and PtO2(200 mg). The reaction was shaken overnight at 40 psi H2, 60 °C for 30 hrs. The reaction mixture was filtered through Celite® and the solvent removed in vacuo to give crude 1-benzhydryltetrahydro-1Hpyrrolo[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 1benzhydryltetrahydro-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 worked up using a Fisher workup. The reaction mixture was filtered through Celite® and washed with methanol. The solvent was concentrated to give crude 1-benzhydryloctahydro-1H-pyrrolo[2,3-c]pyridine (900 mg, 98%), which was used without further purification. LC/MS (M+H) 293.2. Step 5. 1-Benzhydryl-6-tosyloctahydro-1 H-pyrrolo[2,3-c]pyridine. To a flask containing 1-benzhydryl-6-tosyIoctahydro-1H-pyrrolo[2,3-c]pyridine (900 mg, 3.08 mmol) was added DCM (10 mL), TEA (0.89 mL, 6.16 mmol) and TsCI (719 mg, 3.69 mmol). The reaction was stirred at rt overnight and the poured into DCM/water. The layers were separated and organic layer collected, dried (Na2SO4). The solvent was re
104 moved to give crude, which was purified by chromatography to give 1 -benzhydryl-6tosyloctahydro-1 H-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 bottle containing 1-benzhydryl-6-tosyloctahydro-1H-pyrroIo[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 shaken at 40 psi H2 overnight. The reaction mixture was filtered through Celite® and the solvent removed to give crude 1 -benzhydryl-6-tosyloctahydro-1 Hpyrrolo[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-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7Hpyrrolo[2,3-d]pyrimidine.
To aflask containing 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (276 mg, 0.89 mmol) was 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 hrs and then diluted with water/ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to give the crude, which was purified by chromatography (silica, EtOAc/Hep, 0 to 40%) to give two peaks with same molecular weight. Pk1 (cis isomer, 25 mg), compared to Example 8, Step 8 material treated with TsCI. LC/MS (M+H) 552.0. Pk2 (trans-isomer, 85 mg): LC/MS (M+H) 552.1.
Step 8. 4-((3aR,7aR)-Octahydro-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3djpyrimidine. To a flask containing 7-tosyl-4-((3aS,7aR)-6-tosyloctahydro-1Hpyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3-d]pyramid-ine pk2 (100 mg, 0.18 mmol) in MeOH (5 mL) was added NaHPO4 (109 mg, 0.90 mmol) and Na/Hg (20-30 beads). The reaction mixture was stirred at rt overnight and then filtered through Celite®. The solvent was removed and the crude material diluted with ethyl acetate/water. The pH of 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 give 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-1 H-pyrrolo[2,3-
c]pyridin-6(2H)-yl)prop-2-en-1-one. To a flask containing 4-((3aR,7aR)-octahydro17901
105
H-pyrrolo[2,3-c]pyridin-1 -yl)-7H-pyrro)o[2,3-d]pyrimidine (20 mg, 0.08 mmol) in DCM at 0 °C was added DIPEA (0.06 mL, 0.33 mmol) and acryloyl chloride (8.0 mg, 0.08 mmol). The mixture was stirred for 3 hrs 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 give crude material, which after chromatography (silica, MeOH/DCM, 0 to 10%) gave 1-((3aS,7aR)-1-(7H-pyrrolo[2,3-
d]pyrimidin-4-yl)hexahydro-1 H-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-410 ylamino)pîperidin-1-yl]prop-2-en-1-one. Préparation of rac-1-((3R,4S)-3-((7Hpyrrolo[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)-7Hpyrrolo[2,3-d]pyrimidin-4-amine (410 mg, 1.530 mmol) in THF (20 mL) and aq.NaHCO3 (15 mL) at 0 °C 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 (EtOAc/MeOH,
10:1) showed the reaction to be complété, the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (50 mLx2). 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 give 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 (400MHz, DMSO-d6) δ 11.53 (br s, 1 H), 8.08 (d, J=15.1 Hz, 1 H), 7.32 - 7.20 (m, 1 H), 7.08 (br s, 1 H), 6.81 (dt, J=10.5, 17.3 Hz, 1H), 6.59 (brs, 1H), 6.12 (d, J=14.8 Hz, 1 H), 5.69 (d, J=10.3 Hz, 1 H), 4.65-4.39 (m, 1 H), 4.27 - 4.04 (m, 1 H), 3.94 - 3.71 (m, 1H), 3.16 (d, J=5.3
Hz, 1 H), 3.08 - 2.96 (m, 1 H), 2.89 - 2.77 (m, 1 H), 2.71 - 2.60 (m, 1 H), 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-6Hpyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one. Prepared as in Example 8, except us30 ing rac-(3aR,7aR)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate instead of optically active material in Step 7.
106
LC/MS (M+H) 298.2. Ή NMR (400MHz, 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 52:1-[2-(Hydroxymethyl)-5-(7H-pyrrolo[2,3-d]pyrimîdin-4ylamino)piperidin-1-yl]prop-2-en-1-one (rac-cis/trans). Prepared as in Example
7, except no séparation of diastereomers or enantiomers is carried out. 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)piperîdin-1 -yl)prop-2-en-1 -one.
Step 1. 1-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpropan-2-ol. To a solution of NaH (343 mg, 8.57 mmol) in 20mL of THF cooled with ice bath, was added 5bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1000 mg, 4.32 mmol). After 10 min, the reaction was cooled with dry ice/acetone bath. BuLi (1.6M; 4.02 mL, 6.43 mmol) was added. After 30min, 2,2-dimethyloxirane (927 mg, 12.9 mmol) was added slowly. The reaction was allowed to warm to rt slowly then it was stirred at rt overnight. NH4CI (10%, 20 mL) was added slowly. The reaction was stirred for 15min. The mixture was concentrated under vacuum to remove organic solvent. The aqueous solution was extracted with ethyl acetate (2x10 mL). The combined organic layer . was dried and concentrated. The residue was purified by CombiFlash® (40g column, 10 to 100%EA in heptane) to give 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. 1HNMR (400MHz, CDCI3) 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 3-((5-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a solution ofthe pyrrolopyrimidine 1-(4-chloro7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpropan-2-ol (140 mg, 0.62 mmol) in 5 mL of dioxane/H2O (8:4) was added (R)-tert-butyl 3-aminopiperidine-1 -carboxylate ( 124 mg, 0.62 mmol) and potassium carbonate (172 mg, 1.24 mmol). The résultant 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
107 and dried (Na2SO4) then filtered and concentrated. The residue was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give (R)-tert-butyl 3((5-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (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-5yl)propan-2-ol. To a solution of (R)-tert-butyl 3-((5-(2-hydroxy-2-methylpropyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (85mg, 0.22 mmol) in 5 mL of THF was added HCl (4M in dioxane) (5mL) and the resulting mixture stirred at RT for 3h. The reaction was concentrated. The residue was dissolved in DCM and concentrated. The process was repeated 3 times to give 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 sait. LC/MS (M+H) 290.3.
Step 4. (R)-1 -(3-((5-(2-Hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1 -yl)prop-2-en-1 -one. To a flask containing (R)-2-methyl-1 -(4(piperidin-3-yIamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propan-2-ol (65 mg, 0.2mmol), DIPEA (10 eq needed to get the sait neutralized and homogenous) and DCM (5 mL) at 0°C was added acryloyl.chloride (18 mg, 0.200mmol solution in 1 mL of DCM) was added. After 45 mins, the reaction mixture was quenched with a saturated solution of NaHCO3 (5mL) and the layers were partitioned. The aqueous layer was extracted (2x) with DCM and the combined organic layers were concentrated to afford the crude product as a white solid. The solid was purified by reverse phase HPLC to give 15 mg of desired product. LC/MS (M+H) 344.2. 1H NMR (400MHz, MeOH-d4) δ 8.19 (s, 1H), 7.12 (s. 1H), 6.88-6.76 (m, 1H), 6.22-6.14 (m, 1 H), 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), 1.73-1.58(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)-4fluoropiperidin-1 -yl)prop-2-en-1 -one.
Step 1. (3S,4R)-Benzyl 4-fluoro-3-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a solution of 4-chloro-7-trityl-7H-pyrrolo[2,3djpyrimidine (308 mg, 0.779 mmol) and césium fluoride (474 mg, 3.12 mmol) in DMSO (3.0 mL) was added (3S,4R)-benzyl 3-amino-4-fluoropiperidine-1-carboxylate (prepared according to WO2010/16005 and W02011/101161) (225 mg, 0.779
108 mmol). The reaction mixture was heated to 120 °C for 16 hours. After LCMS showed that 4-chloro-7-trityI-7H-pyrrolo[2,3-d]pyrimidine was consumed completely, 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 back extracted 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 yield crude product which was dry loaded with Celite® onto a Silicycle® 80 g HP column and purified via normal phase column chromatography (25-75% EtOAc/heptanes over 10 column volumes) to afford (3S,4R)-benzyl 4-fluoro-3-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)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 hydrogénation bottle, 10% Pd/C (175 mg) was added under nitrogen atmosphère. A solution of (3S,4R)-benzyl 4-fluoro-3-((7-trityl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (400 mg, 0.654 mmol) in anhydrous éthanol (13.0 mL) was added and the resulting mixture was hydrogenated under 50 psi of H2 at ambient température for 3 hours. After LCMS showed the starting material to be consumed completely, the reaction mixture was filtered through a thin pad of Celite® and the filter cake was washed with éthanol. The combined filtrate was evaporated, azeotroped with toluene (5 x) at 75 °C to afford compound N-((3S,4R)-4fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (312 mg, 100%) as a colorless solid, which was used directly to next step without further purification.
Step 3. 1 -((3S,4R)-4-Fluoro-3-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yI)prop-2-en-1-one. To a solution of N-((3S,4R)-4fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (312 mg, 0.653 mmol) in anhydrous CHCI3 (15.0 mL) is added Hunig’s base (0.6 mL, 4.0 mmol). 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 CHCI3 (3.0 mL). The reaction mixture was allowed to warm to ambient température and after 35 minutes, LCMS showed compound N-((3S,4R)-4-fluoropiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4amine was consumed completely. The reaction mixture was cooled to 2 °C and quenched with 10% aqueous sodium bicarbonate (15 mL). The organic layer was
109 extracted and the aqueous layer was back extracted with chloroform (2x10 mL). The organic extracts were combined, dried over magnésium sulfate, filtered, and concentrated in vacuo to yield crude product which was dry loaded with Celite® onto a Silicycle® 80 g HP column and purified via normal phase column chromatography (50-85% EtOAc/heptanes over 10 column volumes) to afford 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 ambient température for 19 hours. The reaction mixture was concentrated in vacuo and dry loaded with Celite® onto a Silicycle® 80 g HP column and purified via normal phase column chromatography (0-20% MeOH/DCM over 10 column volumes) to afford 1-((3S,4R)-3-((7Hpyrrolo[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 (400MHz, DMSO-d6) δ
11.58 (S, 1H), 8.13 (s, 1H), 7.47 (s, 1 H), 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, 1 H), 4.51 - 4.36 (m, 1 H), 4.21 2.97 (m, 5H).
Example 55: (R)-1-(3-((5-(2-Hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)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[2,3djpyrimidine as the Het-CI partner. LC/MS (M+H) 316.3. 1H NMR (400MHz, DMSOd6) 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 (brs, 1 H).
Example 56: 1-(2-((7H-Pyrrolo[2,3-d]pyrimidîn-4-yl)amïno)-8azabicyclo[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-l -yl)prop-2-en-1 -one.
110
Step 1. (R)-tert-Butyl 3-oxo-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate
To a solution of (3S,5R)-tert-butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (5.0 g, 8.68 mmol) in DCM (100 mL) was added
Dess-Martin periodinane (4.0 g, 9.55 mmol), then the mixture was stirred at room température for 18 hours. After TLC (DCM/MeOH, 10:1) showed starting material to be consumed completely, the reaction mixture was concentrated to give crude product (7.8g) as yellow solid, which was purified by prep-HPLC to give (R)-tert-butyl 3oxo-5-((7-trityl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (3.7 g, 10 74 %) as a white solid. LC/MS (M+H) 574.5.
Step 2. (3S,5R)-tert-Butyl 3-(dimethylamino)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a dry hydrogénation bottle, 10% dry Pd/C (300 mg) was added under Ar atmosphère. A solution of (R)-tert-butyl 3-oxo-5-((7trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (600 mg, 1.05 mmol) in 2M NHMe2/MeOH (20 mL) was added and the resulting mixture was hydrogenated at 45 psi H2 at 20 °C overnight. After TLC (DCM/MeOH/NH3OH = 10:1:1) indicated starting material to be consumed completely, and two new spots were formed, 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 give 20 crude product, which was purified by column chromatography (silica,
MeOH/NHs/DCM , 0-8%) to provide (3S,5R)-tert-butyl 3-(dimethylamino)-5-((7-trityl7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pip-eridine-1-carboxylate (100 mg, 15.8%) as an oil and (3S,5S)-tert-butyl 3-(dimethylamino)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin4-yl)amino)piperidine-1-carboxylate (300 mg, 47.6%) as a white solid. LC/MS (M+H) 25 603.5 (pk1 ); LC/MS (M+H) 603.5 (pk2).
Step 3. (3S,5R)-N3,N3-Dimethyl-N5-(7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)piperidine-3,5-diamine. To a solution of (3S,5R)-tert-butyl 3-(dimethylamino)-5((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidine-1-carboxylate (100 mg, 0.660 mmol) in dioxane (10 mL) was added 4N HCl/ dioxane (6mL) dropwise at 0 °C 30 and stirred at rt for 4h. After TLC (DCM/MeOH, 10:1) indicated the reaction to be complété, the reaction mixture was concentrated to give crude product, which was purified by column chromatography (silica, MeOH/DCM, 0-10%) to give (3S,5R)17901
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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-4yl)amino)piperidin-1-yl)prop-2-en-1-one. To a stirred solution of (3S,5R)-N3,N35 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) /aq. 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) showed starting material to be consumed completely, 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 give crude product, which was used to 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-l -yl)prop-2-en-1 -one. 1 -((3S,5R)-3-(Dimethylamino)-5-((715 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) indicated starting material was consumed completely, the reaction mixture was concentrated under vacuum to give crude product, which was purified by chromatography (silica, MeOH/NHs/DCM, 0-10%) and further purified via prep20 HPLC to give 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 (400MHz, DMSO-d6) δ 11.53 (brs, 1 H), 8.16 - 8.07 (m, 1 H), 7.49-7.31 (m, 1 H), 7.12 - 7.06 (m, 1H), 6.81 (dd, J=10.5, 16.8 Hz, 1H), 6.55 (br s, 1 H), 6.13 (d, J=16.8 Hz, 1 H), 5.71 (d, J=10.8 Hz, 1 H), 4.68 - 4.49 (m, 1 H),
4.27 (d, J=12.0 Hz, 0.69H), 4.11 (brs, 1.51 H), 2.98 - 2.81 (m, 1 H), 2.64 (t, J=11.5
Hz, 1 H), 2.44 (d, J=12.5 Hz, 1 H), 2.36 - 2.16 (m, 6H), 1.72 -1.50 (m, 1 H).
Example 58: (3S35R)-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-430 yl)amino)piperidine-1 -carboxylate
To a mixture of (R)-tert-butyl 3-oxo-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (see Example 57) (1.0 g, 1.74 mmol) and
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TOSMIC (693.7 mg, 3.83 mmol) in DME (30 ml) at 0 °C was added t-BuOK (624.4 mg, 5.58 mmol) and EtOH (176.3 mg, 3.83 mmol) portionwise. The resulting mixture was stirred at 0 °C for 0.5 hour, then the mixture was warmed to room température and stirred for 2 hours. After TLC (DCM/MeOH, 10:1) indicated the reaction to be complété, the reaction solution was filtered, and concentrated to dryness to afford a crude product which purified by prep-TLC (Petroleum ether/EtOAC, 2:1) to afford (5R)-tert-butyl 3-cyano-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (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-3carbonitrile. 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 rt for 12 hours. After TLC (Petroleum ether/EtOAC, 1:1) indicated the reaction to be complété, the reaction mixture was concentrated in vacuo to give (5R)-5-((7-trityl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piper-idine-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-3carbonitrile. To a stirred solution of (5R)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-3-carbonitrile (100 mg, 0.206 mmol) in THF (3 mL)/ aq. NaHCOs 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) indicated the reaction to be complété, 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 give crude product, which was further purified by prep. TLC (Petroleum ether/EtOAC, 1:1) to give (5R)-1-acryloyl-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-3carbonitrile (80 mg, 72 %) as yellow solid. LC/MS (M+H) 539.2.
Step 4. (3S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1 -acryloylpiperidine-3carbonitrile. A solution of (5R)-1-acryloyl-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-3-carbonitrile (80 mg, 0.272 mmol) in TFA (1 mL) was stirred at room température for 12 hours. After TLC (Petroleum ether/EtOAC, 1:1) indicated 20% starting material to be remaining, the reaction was heated to 30 °C for another
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5h. After LCMS indicated completion, the reaction mixture was concentrated to give crude product, which was further purified by prep. TLC (Petroleum ether/EtOAc, 1:1) to give (5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1 -acryloylpiperidine-3carbonitrile (12 mg, 10 % for 3 steps) as a white solid. Chiral HPLC showed it was a mixture of trans/cis, which was purified by SFC affording 1.4 mg of peakl (trans) and 3.3 mg of peak2 (cis): SFC séparation conditions: Column: ChiralPak AD (250 mm x 30 mm, 20 pm), Mobile phase: 50% EtOH+NH3H2O, 80 mL/min. SFC analytical conditions: Column: Chiralpak AD-H 250x4.6mm I.D., 5 pm Mobile phase: éthanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35ml_/min; Wavelength: 220nm. Peak 2: 1H NMR (400MHz, MeOH-d4) δ 8.20 (brs, 1H), 7.09 (d, J=3.5 Hz, 1H), 6.90 - 6.54 (m, 2H), 6.32 - 6.07 (m, 1 H), 5.90 - 5.57 (m, 1 H), 4.71 - 4.41 (m, 2H), 4.40 4.01 (m, 2H), 3.71 - 3.40 (m, 2H), 2.39 (br s, 1 H), 2.17 (d, J=9.0 Hz, 1 H). LC/MS (M+H) 297.1.
Example 59:1 -((3aS,7aS)-3a-Methyl-1 -(7H-pyrrolo[2,3-d]pyrîmidin-4yl)hexahydro-1 H-pyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1-one (racemic-cis).
Step 1. rac-(3aS,7aS)-6-Benzyl-3a-methylhexahydro-1 H-pyrrolo[2,3-c]pyridin7(7aH)-one. To a mixture of (3aS,7aS)-1,6-dibenzyl-3a-methylhexahydro-1 Hpyrrolo[2,3-c]pyridin-7(7aH)-one (975 mg, 2.92 mmol), cyclohexene (7.5 mL, 73 mmol) and 10% Pd/C (1.75 mg, 0.16 mmol) in éthanol (14 mL) was stirred at reflux for 1.5 h. After TLC indicated complété conversion of starting material, the reaction was cooled, diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under reduced pressure, giving (3aS,7aS)-6-benzyl-3amethylhexahydro-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 flask containing 3aS,7aS)-6-benzyl-3a-methylhexahydro-1 H-pyrrolo[2,3-c]pyridin7(7aH)-one (677 mg, 2.77 mmol) in THF (10 mL) at 0 °C was added LAH (150 mg,
3.95 mmol). 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
114 methyloctahydro-1 H-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-1 H-pyrrolo[2,3-c]pyridin-1yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine. To a flask containing (3aS,7aS)-6-benzyl-3a5 methyloctahydro-1 H-pyrrolo[2,3-c]pyridine (607 mg, 2.64 mmol) was added nbutanol (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 rt and the solvent removed in vacuo. The crude material was purified by chromatography (silica, EtOAc/Heptane) to give 4-((3aS,7aR)-610 benzyl-3a-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-7-tosyl-7H-pyrrolo[2,3djpyrimidine (913 mg, 69%) as an off-white solid. LC/MS (M+H) 502.2.
Step 4. rac-4-((3aS,7aR)-6-Benzyl-3a-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1yl)-7H-pyrrolo[2,3-d]pyrimidine. To a flask containing 4-((3aS,7aR)-6-benzyl-3amethyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (908 mg, 1.81 mmol) was added MeOH (14.4 mL), water (4.0 mL) and LiOH (124 mg, 5.1 mmol). 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 1M 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 give 4-((3aS,7aR)-6-benzyl-3a-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-7Hpyrrolo[2,3-d]pyrimidine (628 mg) as a pale yellow solid. LC/MS (M+H) 348.2. Step 5. Chiral séparation of rac-4-((3aS,7aR)-6-benzyl-3a-methyloctahydro-1Hpyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine. 4-((3aS,7aR)-6-Benzyl-3a25 methyloctahydro-1 H-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 COs/MeOH, 0.2% iPrNH2) to give two peaks, pk1 assigned as (4-((3aS,7aR)-6-benzyl-3amethyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine, 263 mg, Rt = 3.97 min) and pk 2 assigned as (4-((3aR,7aS)-6-benzyl-3a-methyloctahydro-1 H30 pyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, 233 mg. Rt = 5.31 min). Step 6. 4-((3aR,7aS)-3a-Methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7Hpyrrolo[2,3-d]pyrimidine. To a flask containing (4-((3aR,7aS)-6-benzyl-3a
115 methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine was added éthanol (8.0 mL), cyclohexene ( 2.0 mL, 20 mmol) and Pd(0H)2 on carbon(263 mg, 0.38 mmol). 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 give 4-((3aR,7aS)-3amethyloctahydro-1 H-pyrrolo[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-1 Hpyrrolo[2,3-c]pyridin-6(2H)-yl)prop-2-en-1 -one. To a flask containing 4-((3aR,7aS)3a-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.19 mmol) in DCM (3.0 mL) at 0 °C was added DIPEA (0.2 mL, 0.96 mL) and acryloyl chloride (19 mg, 0.20 mmol). The reaction was stirred at 0 °C for 3h and then 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 give the crude product. The product was precipitated with ethyl acetate/heptanes to give 1-((3aS,7aS)-3a-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4yl)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)-5hydroxypiperidin-1 -yl)prop-2-en-1 -one.
Step 1. N-((3R,5R)-1-Benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine. To a stirred solution of (3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)oxy)piperidin-3-amine (4 g, 12.479 mmol) in n-butanol (25 ml) was added 4-chloro-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 ambient temp. After TLC (70% EtOAc in hexane) indicated 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 afford 5 g (68%) of N-((3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)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, CDCI3) δ -0.07 (s, 6 H) 0.87 (s, 9 H) 1.44 (d, J=1 8.10 Hz, 1 H) 1.93 - 2.31 (m, 3 H) 2.37 (s, 3 H) 2.65 (d,
116
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 (brs, 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,
H) 8.06 (d, J=8.31 Hz, 2 H) 8.39 (s, 1 H).
Step 2. N-((3R,5R)-1 -Benzyl-5-((tert-butyldimethyIsilyl)oxy)piperidin-3-yl)-7Hpyrrolo[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 was added H2O (3 ml) and K2CO3 (1.053 g, 7.603 mmol. The reaction was allowed to warm to rt and stirred for 16 h. After TLC (70% EtOAc in hexane) indicated starting material to be consumed completely, the solvent was removed in vacuo and the crude was purified by chromatography (silica, EtOAc/hexane, 0 to 70%) to afford 1.5 g (68%) N-((3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)oxy)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as white solid. LC/MS (M+H) 437.8. 1H NMR (400MHz, 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,
H) 4.11 (brs, 1 H).4.62 (brs, 1 H) 6.60 (brs, 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-ButyldimethylsiIyl)oxy)piperidin-3-yl)-7H-pyrrolo[2,3d]pyrimidin-4-amine. A solution of N-((3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)oxy)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (600 mg, 1.371 mmol) in éthanol was degassed with argon for 15 min and then charged with 10% Pd/C (60 mg). The mixture was hydrogenated using a hydrogen balloon for 16
h. After TLC (10% MeOH/DCM) indicated no starting material to be présent, the reaction mixture was filtered through Celite®, and the filtrate was concentrated to give the crude material. The crude material was purified by column chromatography (100-200 silica, MeOH/DCM, 0 to 8%) to afford 380 mg (80%) N-((3R,5R)-5-((tertbutyldimethylsilyl)oxy)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid.
1H NMR (400MHz, 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).
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Step 4.1 -((3R,5R)-3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-((tertbutyldimethyIsilyl) 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-4amine (400 mg, 1.151 mmol) in DCM (10 ml) at 0 °C was added TEA (0.481 ml, 3.453 mmol), 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) indicated 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. NaHCO3 (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 afford 180 mg (39%) 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 light yellow solid. LC/MS (M+H) 401.8. 1H NMR (400MHz, 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 (brs,
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[2,3d]pyrimidin-4-yl)amino)-5-((tert-butyldimethyl-silyl)oxy)piperidin-1-yl)prop-2-en-1-one (100 mg, 0.249 mmol) in THF (1 ml) was added 6N HCl (1 ml) at 0°C. The résultant mixture was allowed to corne to ambient température, and stirred for 4 h. After TLC (10% MeOH/DCM) indicated starting material to be consumed, the reaction mixture was basified with saturated aq. 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 . give 25 mg of 1-((3R,5R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5hydroxypiperidin-1-yl)prop-2-en-1-one as a white solid. LC/MS (M+H) = 288.0. 1H NMR (400 MHz, MeOH-c/4) δ 1.78 - 2.28 (m, 3 H) 2.83 - 3.01 (m, 1 H) 3.33 - 3.63 (m,
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).
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Example 61: 1-[(5R)-2,2-Dimethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)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-4amine. A flask containing 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (212mg 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) were heated to 110°C overnight. The mixture was concentrated under reduced pressure, and the residue was purified via flash chromatography (CombiFlash®, 12g gold column, 10 to 50% EA in heptane) to give 140 mg (41.6%) of N-(1-benzyl-6,6-dimethylpiperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3d]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[2,3d]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 hrs. The reaction was allowed to cool to rt and filtered. The filtrate was concentrated. The residue was dissolved in DCM and washed with water. The organic layer was separated and concentrated to give 70 mg of N-(6,6dimethylpiperidin-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 N-(6,6-dimethylpiperidin-3-yl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine ( 70 mg, 0.18 mmol) in chloroform (5 mL)) was added DIPEA (0.124 mL, 0.700 mmol). The solution was cooled to 0 °C and acryloyl chloride (23.7 mg, 0.26 mmol ) in 1 mL of CHCI3 was added. After 30 min, saturated NaHCO3 (5 mL) was added and the reaction mixture was stirred for 30min. The organic layer was separated and concentrated to give 80 mg of 1-(2,2-dimethyl-5-((7tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1 -yl)prop-2-en-1 -one. 1H NMR (400MHz, CDCIs) 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/z454.1 (M+H).
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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 flask containing 1-(2,2-dimethyl-5-((7-tosyl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (80mg, 0.17) was added THF (2ml). The reaction mixture was cooled to 0 °C and t-BuOK (0-.348 mL, 0.3 mmol) was added. The ice bath was removed after 1hr. After 1.5hr, 0.5 mL (0.5 mmol) of additional t-BuOK was added and the reaction stirred at rt. After 2hrs, the reaction was quenched with NH4CI (aq) and the mixture extracted with DCM. The DCM layer was dried and the solvent removed to give the crude product, which was purified by chromatography (silica, MeOH/DCM) to give rac-1 -(5-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2,2-dimethylpiperidin-1-yl)prop-2-en-1-one . The racemate was separated by chiral HPLC to give two peaks. Example 61a: Enantiomer 1, 3^2 mg, RT 3.27, m/z299.9 (M+H). Example 61b: Enantiomer 2, 4.4 mg, RT 3.92, m/z299.8 (M+H).
Example 62: 3-(4-{[(3R)-1 -Acryloylpiperidin-3-yl]amino}-7H-pyrrolo[2,3d]pyrimidin-5-yl)propanenitrile.
Step 1. (R)-tert-Butyl 3-((5-(2-cyanoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. (a) To a flask containing (R)-tert-butyl 3-((5-(2hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (400 mg, 1.11 mmol) in DCM (6.0 mL) at 0 °C was added CH3SO2CI (0.10 mL, 1.33 mmol) and DIPEA (0.6 mL, 3.32 mmol). The mixture was stirred at 0 °C for 30 min and then poured into water/DCM. The layers were separated and the organic extracts collected and dried (Na2SO4). The solvent was removed to give crude (R)-tertbutyl 3-((5-(2-((methylsulfonyl)oxy)ethyl)-7H-pyrroIo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (540 mg), which was used in the next step without purification, (b) To the crude (R)-tert-butyl 3-((5-(2-((methylsulfonyl)oxy)ethyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (540 mg, 1.23 mmol) was added DMF (5 mL) and NaCN (303 mg, 6.1 mmol). The reaction was stirred at 50 °C for 30 mins and then poured into water/ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to give the crude, which after chromatography (silica, MeOH/DCM 0 to 5%) gave (R)tert-butyl 3-((5-(2-cyanoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (302 mg, 66%).
LC/MS (M+H) 371.4.
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Step 2. (R)-3-(4-(Piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propanenitrile. (c) To a flask containing (R)-tert-butyl 3-((5-(2-cyanoethyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (302 mg, 0.82 mmol) was added DCM (2 mL) and TFA (0.32 mL). The mixture was stirred at rt for 4 hrs and the solvent removed to give crude (R)-3-(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)propanenitrile, 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-5yl)propanenitrile. To a flask containing (R)-3-(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3d]pyrimidin-5-yl)propanenitrile (53 mg, 0.20 mmol) in DCM (1.5 mL) at 0 °C was added DIPEA (0.10 mL, 0.58 mmol). 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 NaHCOs/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 give (R)-3-(4-(piperidin-3-ylamino)-7Hpyrrolo[2,3-d]pyrimidin-5-yl)propanenitrile (32 mg, 50%). LC/MS (M+H) 325.4. 1H NMR (400MHz, 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 (brs, 1 H).
Example 63:1 -[(3R)-3-{[2-(Pyridin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4yl]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 wt%, 510 mg, 12.76 mmol) in DMF (15 mL) at 0°C was added dropwise a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 10.63 mmol) in anhydrous DMF (5 mL). When addition was complété, 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 give the crude material, which after chromatography (silica, EtOAc/Hex, 0-5%) to provide
3.1 g (92%) of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3d]pyrimidine as a light yellow liquid. LC/MS 318.0.
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Step 2. (R)-tert-Butyl 3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate. To a stirred solution of 2,4dichloro-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.85 g, 8.95 mmol) in n-butanol (100 mL) was added (R)-tert-butyl 3-aminopiperidine-15 carboxylate (1.79 g, 8.95 mmol) and DIPEA (7.80 mL, 44.77 mL). The reaction mixture was heated at 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)-tert-butyl 3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)10 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate as colorless sticky solid. LC/MS (M+H) 482.4.
Step 3. (R)-tert-Butyl 3-((2-(pyridin-3-ylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a stirred solution of (R)-tert-butyl 3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,315 d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (1.4 g, 2.90 mmol) in dioxane (30 mL) was 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 subsurface flow of argon 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) indicated 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 (R)-tert-butyl 3-((2-(pyridin-
3-ylamino)-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-2,4diamine. To a stirred solution of (R)-tert-butyl 3-((2-(pyridin-3-ylamino)-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (300 mg, 0.556 mmol) in DCM (5 mL) was added TFA (5 mL) dropwise at 0°C. The reaction mixture was stirred at room température for 3 hours. After TLC (50% EtOAc in hexane) indicated completion of the reaction, the reaction was concentrated under reduced pressure. The crude material was dissolved in methanol (6
122 mL) and ethylene diamine (0.5 mL) was added dropwise at 0°C. The mixture was stirred at room température for 2 hours. The reaction was concentrated and partitioned between DCM and water. The organic layer was separated and washed with water, brine, dried over Na2SO4 and concentrated to give 210 mg (-100%) of (R)5 N4-(piperidin-3-yl)-N2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine as brown sticky solid. LC/MS (M+H) 310.4.
Step 5. (R)-1 -(3-((2-(Pyridin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yl)prop-2-en-1-one. To a stirred solution of (R)-N4-(piperidin-3yl)-N2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (210 mg, 0.679 mmol) in DCM (5 mL) was added DIPEA (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) indicated completion ofthe 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 15 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-3ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1 -yl)prop-2-en-1 -one as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ 11.07 (br, 1 H), 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), 6.9020 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 (1 H), 3.21 -2.60(m, 2H), 2.20-1.92 (m 1 H), 1.90-1.82 (m, 1 H), 1.75-1.32 (m, 2H); m/z364.2 (M+H).
Example 64: 1 -[(3S,4R)-4-Hydroxy-3-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1-yl]prop-2-en-1-one ) (rac-cïs).
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 (74.8mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and then at room température for 3 h. Saturated NaCI solution was added to the reaction mixture and the aqueous mixture extracted with diethyl ether. The or- ganic layer was dried (Na2SO4), and concentrated to give tert-butyl 5,6dihydropyridine-1 (2H)-carboxylate (39.6 g, 81.8 %) as pale yellow liquid. TLC System: Rf = 0.5 (20% ethyl acetate in petroleum ether). 1H NMR (400MHz, DMSO-d6)
123 δ 5.75-5.85 (m, 1 Η), 5.6-5.72 (m, 1 Η), 3.8 (d, 2Η), 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 in portions to a solution of tert-butyl 5,6dihydropyridine-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 portionwise at 0 °C and stirred for 2 h at the same température, and then at room température for another 2 h. The insoluble material was filtered away and the filtrate was washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica (100-200 mesh), eluting with 10% ethyl acetate in petroleum ether to give tert-butyl 7-oxa-3-azabicyclo[4.1.0]hep-tane-3-carboxylate (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 (overlapping signais, 4H), 1.72.0 (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-4hydroxypiperidine-1 -carboxylate. To a solution of tert-butyl 7-oxa-3azabicyclo[4.1.0]heptane-3-carboxylate (29 g, 145.7 mmol) in 1,4-Dioxane (406 mL), was added water (81 mL) and sodium azide (13.8 g, 212.7 mmol) at room température and the resulting mixture was heated at 110 °C for 12 h. After cooling to rt, water was added to the reaction mixture and the resulting aqueous mixture 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 give tert-butyl 4-azido-3-hydroxypiperidine-1-carboxylate (16.9 g) as pale yellow liquid and tert-butyl 3-azido-4-hydroxypiperidine-1-carboxylate (4 g) as yellow liquid. (Combined yield: 59%). TLC System: Rf = 0.3 (40% Ethyl acetate in petroleum ether). tert-butyl 4-azido-3-hydroxypiperidine-1-carboxylate: 1H NMR (300MHz, DMSO-de) 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%).
tert-butyl 3-azido-4-hydroxypiperidine-1-carboxylate: 1H NMR (300MHz, DMSO-d6) δ 5.35 (d, 1H), 3.7-3.85 (broad, 1H), 3.6-3.7 (broad, 1H), 3.4-3.55 (m, 1H), 3.2-3.35
124 (broad, 1H), 2.6-3.0 (overlapping, 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 portionwise to a solution of tert-butyl 4-azido-3-hydroxypiperidine-1carboxylate (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 the residual Pd. The filtrate was concentrated to give 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 (400MHz, DMSO-d6) δ 4.9-5.1 (brs, 1H), 3.60-4.0 (2H), 2.85-2.95 (m, 2H), 2.60-2.80 (br, 1H), 2.35-2.45 (m, 1H), 1.50-
1.80 (overlapping, 3H), 1.40 (s, 9H). LCMS: (m/z) = 217.15 (M+H)+; (Purity: 96.5%). Step 5. Rac-(3S,4S)-tert-Butyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4hydroxypiperidine-1 -carboxylate. To a flask containing rac-(3S,4S)-tert-butyl 4amino-3-hydroxypiperidine-1-carboxylate ( 460 mg, 2.13 mmol) was 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 give the crude, which after chromatography (silica, EtOAc/ Heptane) gave rac-(3S,4S)-tert-butyl 3-((2-chIoro7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-hydroxypiperidine-1 -carboxylate (549 mg, 70%). LC/MS (M+H) 368.1. 1H NMR (400 MHz, CHCI3) 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. Rac-(3S,4R)-tert-Butyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4((4-nitrobenzoyl)oxy) piperidine-1-carboxylate. To a mixture of rac-(3S,4S)-tert-butyl
3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-hydroxypiperidine-1carboxylate (0.4 g, 1.09 mmol) in toluene (6 mL) was added 4-nitrobenzoic acid (0.254 g, 1.52 mmol) and triphenylphosphine (0.461 g, 1.74 mmol)). The mixture was degassed with nitrogen and sealed in a vial with a septa top. DEAD (0.316 mL,
1.74 mmol) was added dropwise to the slurry. Ail solids dissolved and the mixture
125 was stirred at room température for 4 h. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic phase washed with 1N HCl, saturated sodium bicarbonate and then brine. The organic phase was dried over anhydrous magnésium sulfate and concentrated under reduced pressure. The residue was purified via chromatography (silica, EtOAc/Heptane) to give rac(3S,4R)-tert-butyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-((4nitrobenzoyl)oxy)piperidine-1-carboxylate (499.5 mg, 88%). LC/MS (M+H) 517.2. Step 7. Rac-(3S,4R)-tert-Butyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4hydroxypiperidine-1-carboxylate. To a flask containing (3S,4R)-tert-butyl 3-((2chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-((4-nitrobenzoyl)oxy)piperidine-1carboxylate (499 mg, 0.96 mmol) was added dioxane (8 mL) and NaOH (5 mL, 1M solution). The mixture was heated to 50 °C for 1h and the poured into brine/EtOac. The layers were separated and the aqueous phase extracted twice with 25 mL ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous magnésium sulfate and concentrated under reduced pressure to give crude, which was purified by chromatography (silica, EtOAc/Hep, 0 to 100%) to give rac-(3S,4R)-tert-butyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4hydroxypiperidine-1-carboxylate (183 mg, 51%). LC/MS (M+H) 368.2. 1H NMR (400 MHz, CHCI3) 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 éthanol (2 mL) was added cyclohexene (2 mL) and 1.25 M HCl in methanol (1 mL). The mixture was placed under nitrogen and 10%Pd/C was added and refluxed overnight. After cooling to rt, the mixture was filtered through Celite® and the filtrate concentrated to give 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-c/4) 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 (brs, 1 H).
Step 9. Rac-1 -((3S,4R)-3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4hydroxypiperidin-1-yl)prop-2-en-1-one. To a mixture of rac-(3S,4R)-3-((7H
126 pyrrolo[233-d]pyrimidin-4-yl)amino)piperidin-4-ol (75 mg, 0.24 mmol) in DCM (2 mL) and acetonitrile (2 mL) was added NMM (0.083 mL, 0.73 mmol). The mixture was stirred in an ice bath for 10 minutes at 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 température for 1 h. The mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give rac-1-((3S,4R)-3-((7H-pyrrolo[2,3d]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)amîno)-5methylpîperidin-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 bottle was added Pd/C (200 mg) under N2 atmosphère. Then, a solution of rac-(3R,5R)-benzyl 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidine-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 °C under 50 psi of H2 for 3 days. LCMS indicated the reaction was completed. The reaction mixture was filtered and the filter cake was washed with MeOH. The combined filtrate was evaporated to give rac-N-((3R,5R)-5methylpiperidin-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-methylpiperidin1-yl)prop-2-en-1-one. To a solution of rac-N-((3R,5R)-5-methylpiperidin-3-yl)-7Hpyrrolo[2,3-d]pyrimidin-4-amine ( (413 mg, 1.542 mmol) in THF (20 mL) was added saturated aq.NaHCO3 (15 mL) and acryloyl chloride (154 mg, 1.70 mmol, 1.1 eq.) at 0 °C. After 2hrs at 0 °C, TLC (EtOAc: MeOH = 10:1) indicated the reaction was complété. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (50 mLx2). 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 give rac-1-((3R,5R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one (221 mg, 50 %) as a white solid. 1H NMR (400MHz, DMSO-de) δ 11.48 (br s, 1 H), 8.30 - 8.04 (m, 1 H), 7.13 - 6.96 (m,
127
2H), 6.83 (dd, J=10.3, 16.8 Hz, 1 H), 6.69 - 6.54 (m, 1 H), 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, 1 H), 4.47 - 4.20 (m, 1 H), 4.04 - 3.84 (m, 2H), 3.61 - 3.37 (m, 2H), 2.88 -2.75 (m, 1H), 2.15 (brs, 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]pyrimïdin-4yl)amino)piperidin-1-yl)prop-2-en-1-one. Prepared as the dérivatives in Examples 23-40. LC/MS (M+H) 363.2.
Example 67.1-(5-((7H-Pyrrolo[2,3-d]pyrîmîdin-4-yl)amino)-2,2dîmethylpiperidin-1-yl)prop-2-en-1-one. Prepared as described in Example 61, except no chiral séparation.
Example 68. 1 -((2R,5S)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperidin-1-yl)prop-2-en-1-one. Prepared as described in Example 5, Step 9; pk1 : 1H NMR (400MHz, DMSO-d6) δ 11.53 (brs, 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, 1 H), 6.56 (d, J=1.8 Hz, 1H), 6.10 (dd, J=2.1, 16.7 Hz, 1H), 5.72-5.61 (m, 1 H), 4.81 (brs, 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; 19exp. LC/MS (M+H) 286.2. OR = [a]D 20 = +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 séparation 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]pyrimidîn-4-yl)amino)-3methylpiperidin-1 -yl)prop-2-en-1 -one.
Example 71:1 -(3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-methylpîperidin-1 yl)prop-2-en-1 -one.
Example 72: (R)-1 -(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3methylpiperidin-1 -yl)prop-2-en-1 -one.
Step 1. 1-tert-Butyl 3-methyl 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)
128 was added LHMDS (74.4 ml, 0.074 mol) dropwise at -65 °C under N2 protection .
The reaction mixture was stirred at -65 °C for 1 h. Mel (10.5 g, 0.074 mol) was added dropwise. The resulting solution was stirred at -65 °C for 2 h and at room température for 1 h. The resulting solution was quenched with sat.NH4CI (aq) (200 ml). The organic layer was separated and the aqueous layer was extracted with MTBE (200 ml x2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 1 -tert-butyl 3-methyl 3-methylpiperidine-1,3dicarboxylate (15.86 g, 100%) as yellow oil. 1H NMR (400MHz, 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 2.1 -tert-Butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of
1-tert-butyl 3-methyl 3-methyIpiperidine-1,3-dicarboxylate (15.86 g, 0.062 mol) in THF (100 ml) and H2O (10 ml) was added LiOH-H2O (7.76 g, 0.186 mol) at room température. The mixture was refluxed at 70 °C for 6 h. After TLC (Petroleum ether/EtOAc , 4:1, stained by iodine) showed 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 1M HCl (aq.) and then extracted with MTBE twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 1-tert-butyl 3-methyl 3methylpiperidine-1,3-dicarboxylate (13.97 g, 93%) as a white solid.
Step 3. tert-Butyl 3-isocyanato-3-methylpiperidine-1-carboxylate. To a solution of 1tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (5.97 g, 24.5 mmol) in anhydrous toluene (65 mL) was TEA (3.5 mL, 24.5 mmol) and DPPA (6 mL, 27 mmol) dropwise at room température. The reaction mixture was stirred at rt for 30 min 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 give tert-butyl 3-isocyanato-3methylpiperidine-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 tertbutyl 3-isocyanato-3-methylpiperidine-1-carboxylate (5.89 g, 24.54 mmol) in THF
129 (140 ml) was added 2M NaOH (aq) (140 ml). The resulting solution was stirred vigorously at room température overnight. TLC showed the desired product was formed. The reaction mixture was acidified to pH 1 with 1M 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 1M NaOH (aq.) and then extracted with MTBE (250 ml x 3). The combined organic layers were washed with brine to neutral pH, dried over Na2SO4 and concentrated to dryness to give tert-butyl 3-amino-3methylpiperidine-1-carboxylate (3.7 g, 36%) as colorless oil which was directly used to the next step without further purification. 1H NMR (400 MHz, CHCI3) 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-4yl)amino)piperidine-1 -carboxylate. tert-ButyI 3-amino-3-methylpiperidine-1 carboxylate (3.3 g, 15.398 mmol) and tert-butyl 3-amino-3-methylpiperidine-1carboxylate ( 3.9 g, 12.7 mmol) was stirred at 140 °C overnight. After TLC showed tert-butyl 3-amino-3-methylpiperidine-1 -carboxylate to be consumed, the mixture was diluted with DCM (80 ml). The DCM layer was washed with sat NaHCO3 (aq) and brine and concentrated to dryness to give crude product which was purified by chromatography (silica, EtOAc /Petroleum ether, 0-40%) to give tert-butyl 3-methyl-3-((7tosyl-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-4yl)amino)piperidine-1-carboxylate (3g, 6.2 mmol) in dioxane (30 ml) was added 4 M HCI/dioxane (30 ml) dropwise at 0 °C. Then the reaction mixture was warmed to room température and stirred for 2 h. After LC-MS showed the starting material to be consumed, the reaction mixture was concentrated to dryness to give crude product (2.6 g, 100%) as a white solid which was directly used to 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-one. To a solution of N-(3-methylpiperidin-3-yl)-7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine (2.5g, 5.93 mmol) in THF (100 ml) /sat.NaHCO3(aq) (100 ml) was added acryloyl chloride (0.64 g, 7.115 mmol) dropwise at 0 °C. The re
130 action mixture was stirred at 0 °C for 1 h. After TLC showed the starting material to be 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 give crude product which was purified by chromatography (silica, EtOAc/petroleum ether = 0-66%) to give 1-(3-methyl-3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)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-2en-1-one. To a solution of 1-(3-methyl-3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-410 yl)amino)piperidin-1-yl)prop-2-en-1-one (1g, 2.277 mmol) in THF (10 ml) and H2O (2 ml) was added LiOH-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 to be consumed mostly, the mixture was neutralized with AcOH and concentrated to dryness to give crude product, which was purified by chromatography (sil15 ica, MeOH/EtOAc, 0-6%, 6-8%) to give 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 further purified by SP1 (MeOH/EtOAc, 0-2%) to give 70 mg (12%) of a white solid. 1H NMR (400MHz, DMSO-d6) δ 1.51 (s, 3 H) 1.58 (brs, 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 give two peaks, arbitrarily assigned: pk1, (R)-1-(3-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one (17 mg) and pk 2, (S)-1-(3-((7Hpyrrolo[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-230 en-1 -one: 1H NMR (400MHz, 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,
131
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 (brs, 2H) 7.03 (brs, 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-2en-1-one. 1H NMR (400MHz, 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]pyrimidîn-4yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one.
Step 1. (3aS,7aS)-Benzyl 1-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1Hpyrrolo[2,3-c]pyridine-6(2H)-carboxylate. A mixture of (3aS,7aS)-benzyl hexahydro-
H-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) indicated the reaction be complété, the reaction mixture was cooled to room température and evaporated to dryness and the residue was purified by chromatography (silica, DCM/MeOH, 1 %-12%) to give (3aS,7aS)-benzyl 1-(2amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-1H-pyrrolo[2,3-c]pyridine-6(2H)carboxylate (350 mg, 50%) as a brown solid. LC/MS (M+H) 393.4. 1H NMR (400 MHz, CHCI3) δ 1.73-1.76 (m, 1H), 2.17-2.04 (m, 3 H), 2.51 (br. s, 1H), 3.05-2.41 (m,
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-1 H-pyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3d]pyrimidin-2-amine. To a dry Parr bottle, Pd/C (50 mg) was added under Ar atmosphère. Then a solution of (3aS,7aS)-benzyl 1-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-4yl)hexahydro-1H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate (200 mg, 0.510 mol) in EtOH (15 mL) was added and the resulting mixture was hydrogenated under 45 psi of H2 at 25 °C for 18 hours. After TLC (DCM/MeOH, 10:1) indicated starting material to be consumed, the reaction mixture was filtered and the filter cake was washed with EtOH. The combined filtrate was evaporated to give 4-((3aR,7aS)-octahydro1H-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.
132
Step 3. 1 -[(3aS,7aS)-1 -(2-Amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-6Hpyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one. To a stirred solution of 4-((3aR,7aS)octahydro-1 H-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 addition, the resulting mixture was stirred at room température for 6 hours. After LC-MS showed 4((3aR,7aS)-octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2amine to be consumed, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x4), the combined organic layer was concentrated to give crude product, which was purified by column chromatography to give 1 -[(3aS,7aS)-1 (2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6yl]prop-2-en-1-one (56 mg, 30.9%) as a white solid. 1H NMR (400MHz, 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-4ylamino)piperidin-1 -yl]prop-2-en-1 -one.
Example 75: 1 -((3S,5S)-3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidin-1-yl)prop-2-en-1-one. See Example 14 (Step 5) and Example 65 (Step 2).
Step 1. 1-[(3R,5R)-3-MethyI-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1yl]prop-2-en-1 -one and 1 -((3S,5S)-3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidin-1 -yl)prop-2-en-1 -one. rac-trans: 1 -((3R,5R)-3-((7H-Pyrrolo[2,3d]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 give two peaks arbitrarily assigned: 1 -((3R,5R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5methylpiperidin-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-en1-one (pk 2, 60 mg, 80%) as a white solid. SFC conditions: ChiralPak AD (250mmx30mm, 5 pm); 20% EtOH, NH3H2O; 60mL/min. Pk1: 1-((3R,5R)-3-((7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-methylpiperidin-1-yl)prop-2-en-1-one: 1H NMR (400MHz, DMSO-d6) δ 11.51 (br s, 1 H), 8.19 - 8.07 (m, 1 H), 7.06 (d, J=6.0 Hz, 2H),
133
6.84 (dd, J=10.2, 16.4 Hz, 1 H), 6.70 - 6.55 (m, 1 H), 6.35 (dd, J=10.4, 16.7 Hz, 1 H), 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, 1 H), 4.41 - 4.21 (m, 1 H), 4.06 - 3.84 (m, 2H), 3.61 - 3.42 (m,
H), 2.85 - 2.75 (m, 1 H), 2.15 (br s, 1 H), 1.99 - 1.78 (m, 1 H), 1.73 -1.50 (m, 1 H),
1.23 (s, 1 H), 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 (400MHz, DMSO-d6) δ 11.51 (brs, 1H), 8.19 - 8.05 (m, 1H), 7.06 (brs, 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, 1 H), 4.42 - 4.19 (m, 1 H), 4.06 - 3.82 (m, 1 H), 3.62 - 3.44 (m, 1 H), 2.86 -
2.73 (m, 1H), 2.15 (brs, 1H), 1.96-1.77 (m, 1H), 1.72-1.53 (m, 1H), 1.23 (brs,
H), 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-6Hpyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one. Prepared as in Example 8, except using rac-(3aS,7aS)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine-6(2H)-carboxylate in step 7. LC/MS (M+H) 298.0. 1H NMR (400MHz, DMSO-d6) δ 11.58 (s, 1 H) 8.098.07 (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-4ylamino)piperidin-1 -yl]prop-2-en-1 -one.
Example 78: 1 -{(3R,5R)-3-Methoxy-5-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4yl)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-7Hpyrrolo[2,3-d]pyrimidin-4-amine. To a mixture of 4-chloro-7-trityl-7H-pyrrolo[2,3djpyrimidine (16.3 g, 41.18 mmol) and (3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)oxy)piperidin-3-amine (12 g, 37.44 mmol) in n-BuOH (250 mL) was added DIPEA (14.5 g, 112.32 mmol). The mixture was heated to 110 °C for 3 days. After TLC (DCM/MeOH, 10:1) indicated the reaction to be complété, the reaction mixture was cooled to room température and evaporated to dryness. The residue
134 was diluted into EtOAc (800 mL) and water (500 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified by chromatography (silica, EtOAc/PE, 0% to 30%) to give N-((3R,5R)-1benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-7-trityl-7H-pyrrolo[2,3-d]pyrimidin4-amine (15 g, 65%) as a yellow solid. 1H NMR (400 MHz, CHCI3) 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), 4.00-3.98 (m, 1 H), 4.49 (br. s, 1 H), 5.57 (brs, 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. (3R,5R)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a Parr bottle, 10% dry Pd/C (1.5 g) was added under Ar atmosphère. Then a solution of N-((3R,5R)-1-benzyl-5-((tertbutyldimethylsilyl)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 50 psi of H2 at 40 °C for 12 hours. After TLC (PE/EtOAc, 4:1) indicated the reaction to be complété, the reaction solution was filtered through a pad of Celite® and the filter cake was washed three times with MeOH. The combined filtrate was concentrated to give (3R,5R)-tert-butyl 3((tert-butyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (14.8 g, -100%) as a yellow solid, which was used directly to next step without further purification. 1H NMR (400 MHz, CHCI3) 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. (3R,5R)-tert-Butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a solution of (3R,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (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) showed the reaction to be complété, the reaction solution was diluted with water (300 mL) and then extracted with EtOAc (200 mL x2). The combined organic layers were washed with water and brine in turns, dried over Na2SO4 and concentrated to give (3R,5R)-tert-butyl 3-hydroxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4
135 yl)amino)piperidine-1-carboxylate (14.6 g, -100%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CHCI3) δ 8.01 (s, 1H), 7.37
- 7.08 (m, 17H), 6.91 (d, J=3.5 Hz, 1 H), 6.30 (br s, 1 H), 4.48 (d, J=3.5 Hz, 1 H), 4.05 (br s, 1 H), 3.83 - 3.51 (m, 4H), 3.23 (br s, 1 H), 1.58 - 1.29 (m, 10H).
Step 4. (3R,5R)-tert-Butyl 3-methoxy-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1 -carboxylate and (3R,5R)-tert-butyl 3-methoxy-5-(methyl(7-trityl7H-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-4yl)amino)piperidine-1-carboxylate (0.6 g, 1.043 mmoL) in DMF (1 mL) was added
Ag2O (0.48 g, 2.086 mmol), followed by Mel (0.6 g, 4.22 mmol). The reaction mixture was sealed and heated to 30 °C for 48 hours. After LC-MS showed the starting material to be consumed, and -20% of dimethylation product was formed, the mixture was filtrated through a pad of Celite® and the cake was washed with EtOAc. The combined filtrâtes were washed with water, brine, dried (Na2SO4) and the sol15 vent removed to give crude product, which was purified by chromatography (silica, EtOAc/PE, 0% to 50%) to give (3R,5R)-tert-butyl 3-methoxy-5-((7-trityl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate and (3R,5R)-tert-butyl 3methoxy-5-(methyl(7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (250 mg, 50 %) as a white solid. LC-MS showed the ratio mono20 méthylation and di-methylation 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-4amine and N-((3R,5R)-5-methoxypiperidin-3-yl)-N-methyl-7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-amine. To a solution of mono and dimethylated compound (250 mg,
0.36 mmol) in DCM (2 mL) was added 4M HCI (g)/dioxane (2 mL) at 10-15 °C. After stirring for 2 h, LC-MS showed the reaction was completed. The reaction solution was concentrated to give N-((3R,5R)-5-methoxypiperidin-3-yl)-7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-amine and N-((3R,5R)-5-methoxypiperidin-3-yl)-N-methyl-7-trityl-7Hpyrrolo[2,3-d]pyrimidin-4-amine (208 mg, 100%), which was used directly to 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-4yl)amino)piperidin-1 -yl)prop-2-en-1 -one and 1 -((3R,5R)-3-Methoxy-5-(methyl(7-trityl7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one. To a stirred
136 solution of mono/dimethylated compound (208 mg, 0.36 mmol) in THF (5 mL) and saturated aqueous NaHCOa solution (5 mL) was added acryloyl chloride (40 mg, 0.43 mmol) dropwise at 0-5 °C. After the resulting mixture was stirred at 0~10 °C for 2 hours, TLC (DCM/MeOH/NH4OH, 10:1:1) indicated amine consumed completely. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (30 mLx3), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to afford crude 1-((3R,5R)-3-methoxy-5-((7-trityl-7H-pyrrolo[2,3d]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 was used directly to 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]pyrimidin4-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 ambient température (10-20 °C) overnight. After TLC (DCM/MeOH/NH4OH, 10:1:1) showed -30% of starting material to remain, the reaction was heated to 40 °C for another 6 h, whereupon LC-MS showed the starting material was consumed. The reaction solution was diluted with THF and concentrated to give crude product, which was purified by prepHPLC directly to give 1-((3R,5R)-3-((7H-pyrrolo[2,3-d]pyrim-idin-4-yl)amino)-5methoxypiperidin-1-yl)prop-2-en-1-one (32 mg, 24% for 3 steps) and 1-((3R,5R)-3methoxy-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1one (25 mg) as a white solid. Pk1 (mono-Me): 1H NMR (400MHz, DMSO-d6) δ 11.32 (brs, 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, 1 H), 4.40 (brs, 1H), 4.14 (brs, 1 H), 3.65 (brs, 1H), 3.32 (s, 3H), 3.20 (d, J=14.1 Hz, 2H), 2.15 (brs, 1H), 1.85 (brs, 1H). Pk2 (di-Me): 1H NMR (400MHz, 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, 1 H), 5.73 - 5.58 (m, 1 H), 5.03 - 4.80 (m, 1 H), 4.72 (d, J=13.7 Hz, 1 H), 4.45 (d, J=11.7Hz, 1H), 4.19 (d, J=14.1 Hz, 1 H), 4.03 (d,J=12.1 Hz, 1 H), 3.69 - 3.55 (m, 2H), 3.28 - 3.10 (m, 6H), 2.96 (t, J=11.5 Hz, 1 H), 2.78 - 2.68 (m, 1 H), 2.18 -1.90 (m, 2H).
137
Example 79: 1 -[(1 S,2S,5S)-2-(7H-Pyrrolo[2,3-d]pyrimidin-4-ylamino)-8azabîcyclo[3.2.1]oct-8-yl]prop-2-en-1-one. Prepared as described in Example 16, except pk2 after chiral séparation was carried through Steps 3 and 4.
Example 80-87: The following compounds were prepared as in Example 41, using 5 the appropriate acid or acid chloride.
Example LC/MS Name
80 348.2 (2E)-4,4-difluoro-1-[(3aS,7aS)-1-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]but-2-en-1-one
81 366.2 (2E)-4,4,4-trifluoro-1-[(3aS,7aS)-1-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]but-2-en-1-one
82 355.2 (2E)-4-(dimethylamino)-1 -[(3aS,7aS)-1 -(7H-pyrrolo[2,3d]pyrimidin-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]but-2en-1-one
83 355.2 (2E)-4-(dimethylamino)-1 -[(3aS,7aS)-1 -(7H-pyrrolo[2,3d]pyrimidin-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]but-2en-1-one
84 312.2 (2E)-1 -[(3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]but-2-en-1-one
85 312.2 2-methyl-1 -[(3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one
86 324.2 cyclobut-1 -en-1 -yl[(3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methanone
87 330.2 (2E)-4-fluoro-1 -[(3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4- yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]but-2-en-1-one
Example 88:1 -[(3R,5R)-3-(Dimethylamino)-5-(7H-pyrrolo[2,3-d]pyrimïdin-4ylamino)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-4yl)piperidine-3,5-diamine
To a solution of (3R,5R)-tert-butyl 3-(dimethyIamino)-5-((7-trityl-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (300 mg, 0.498 mmol) in dioxane (15
138 mL) was added 4N HCl/ Dioxane (10 mL) dropwise at 0 °C and stirred at rt for 4h. TLC (CH2CI2/MeOH = 10:1) indicated the reaction was complété. The reaction solution was concentrated to provide crude (3R,5R)-N3,N3-dimethyl-N5-(7-trityl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3,5-diamine (300 mg, 100%) as a yellow solid.
Step 2. 1-((3R,5R)-3-(Dimethylamino)-5-((7-trityl-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yl)prop-2-en-1-one. To a stirred solution of (3R,5R)-N3,N3dimethyl-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 aq. 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 the reaction was complété. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (30 mLx2), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was used to next step directly without further purification.
Step 3. 1-((3R,5R)-3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5(dimethylamino)piperidin-l -yl)prop-2-en-1 -one. 1 -((3R,5R)-3-(Dimethylamino)-5-((7trityl-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 starting material was consumed completely.
The reaction mixture was concentrated in vacuo to give crude product, which was purified by chromatography (silica, MeOH/NH3/DCM = 0-10%) and further purified via pre-HPLC to give 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 (400MHz, DMSO-d6) δ 11.26 (brs, 1H), 8.13 (s, 1H),
7.04 (br s, 1 H), 6.81 (br s, 1 H), 6.60 (br s, 2H), 5.98 (d, J=15.8 Hz, 1 H), 5.49 (br s,
H), 4.47 (br s, 1 H), 3.59 (br s, 4H), 2.66 - 2.53 (m, 1 H), 2.29 (s, 6H), 2.08 (br s, 1 H), 1.87 (br s, 1H).
Example 89: 1 -{(3aS,7aS)-1 -[5-(2-Methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl]octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl}prop-2-en-1-one. Prepared as in Ex30 ample 8, except using rac-(3aS,7aS)-benzyl hexahydro-1 H-pyrrolo[2,3-c]pyridine6(2H)-carboxylate and 4-chloro-5-(2-methoxyethyl)-7-tosyl-7H-pyrrolo[2,3djpyrimidine in step 7. LC/MS (M+H) 356.2. . 1H NMR (400 MHz, CHCI3) δ 1.44 17901
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, 7=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 (brs, 1 H).
Example 90: 1-[(4aR,8aS)-4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-2Hpyrido[4,3-b][1,4]oxazin-6(5H)-yl]prop-2-en-1 -one.
Step 1. (4aR,8aS)-tert-Butyl 4-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-2H10 pyrido[4,3-b][1,4]oxazine-6(7H)-carboxylate. To a flask containing (4aR,8aS)-tertbutyl hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(7H)-carboxylate (500 mg, 2.06 mmol) and 4-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 2.0 mmol) in nbutanol (2 mL) was added DIPEA (0.9 mL, 5 mmol). The reaction was heated to 85 °C 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 magnésium sulfate and concentrated under reduced pressure. The residue was purified via flash chromatography (silica, 12 g, EtOAc/Hep) to give (4aR,8aS)-tert-butyl 4-(7-tosyl-7Hpyrrolo[2,3-d]pyrimidin-4-yl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(7H)20 carboxylate (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. Similarto Example 12 (Steps 2-4). LC/MS (M+H) 314.2. 1H NMR (400 MHz, CHCIg) δ 1.70 - 2.07 (m, 2 H) 2.90 (t, 7=12.59 Hz, 1 H) 3.16 - 3.65 (m, 3 H) 3.70 - 3.99 (m, 3 H) 4.15 (d, 7=8.98 Hz, 1 H) 4.36 (d,
7=11.13 Hz, 1 H) 4.48 - 4.87 (m, 2 H) 5.52 - 5.77 (m, 1 H) 6.32 (d, 7=16.79 Hz, 1 H)
6.44 - 6.70 (m, 2 H) 7.13 (d, 7=3.71 Hz, 1 H) 8.18 - 8.42 (m, 1 H) 10.95 (br s, 1 H). Example 91-107:
140
Prepared as in Example 12, except for final step the corresponding acid or acid chloride was used.
Example LC/MS Name
91 290 2-fluoro-1 -[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1 -yl]prop-2-en-1 -one
92 329 2-[(dimethylamino)methyl]-1-[(3R)-3-(7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)piperidin-1 -yl]prop-2-en-1 -one
93 302 2-(hydroxymethyl)-1-[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino)piperidin-1 -yl]prop-2-en-1 -one
94 316 2-(methoxymethyl)-1-[(3R)-3-(7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)piperidin-1 -yl]prop-2-en-1 -one
95 286 (2E)-1-[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)piperidin-1 -yl]but-2-en-1 -one
96* 325 3-methyl-2-{[3-(7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)piperidin-1-yl]carbonyl}but-2-enenitrile
97 344 methyl (3E)-5-oxo-5-[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino)piperidin-1-yl]pent-3-enoate
98 318 (2E)-3-(methylsulfanyl)-1-[(3R)-3-(7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)piperidin-1 -yl]prop-2-en-1 -one
99 325 (2E)-2-{[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)piperidin-1-yl]carbonyl}pent-2-enenitrile
100 302 (2Z)-4-hydroxy-1-[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)piperidin-1 -yl]but-2-en-1 -one
101 367 3-oxo-3-[(3R)-3-(7H-pyrroIo[2,3-d]pyrimidin-4ylamino)piperidin-1-yl]-2-(tetrahydro-4H-pyran-4ylidene)propanenitrile
102 286 (2Z)-1-[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)piperidin-1 -yl]but-2-en-1 -one
103 272 1 -[3-(7H-pyrroIo[2,3-d]pyrimidin-4-ylamino)piperidin-1 yl]prop-2-en-1-one
104 272 1-[(3S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)piperidin-1 -yl]prop-2-en-1 -one
105 286 (2E)-1 -[(3R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1 -yl]but-2-en-1 -one
106 329 (2E)-4-(dimethylamino)-1-[(3S)-3-(7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)piperidin-1 -yl]but-2-en-1 -one
107 338 (2E)-3-(1 H-imidazol-4-yl)-1 -[(3R)-3-(7H-pyrrolo[2,3d]pyrimidin-4-ylamino)piperidin-1 -yl]prop-2-en-1 -one
Example 108-111:
Prepared as in Example 12, except in the final step, the corresponding acid or acid chloride was used.
RCO2H or RCOCI o—
Example LC/MS Name
108 387 (2E)-4-(dimethylamino)-1-[(3R)-3-{[5-(2-methoxyethyl)7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl]but2-en-1-one
109 344 (2E)-1-[(3R)-3-{[5-(2-methoxyethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino}piperidin-1 -yl]but-2-en-1 -one
110 344 1-[(3R)-3-{[5-(2-methoxyethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino}piperidin-1-yl]-2-methylprop-2-en- 1-one
Example 111:1 -[(3aR,7aR)-1 -(5-Acetyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one.
Step 1. 1 -[(3aR,7aR)-1 -(5-Acetyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-6Hpyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one. To a flask containing 1-((3aR,7aR)-1-(510 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 rt for 2 hrs and then the solvent removed in vacuo to give the crude product, which was purified by RP-HPLC to give 1-[(3aR,7aR)-1-(5acetyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-6H-pyrro!o[2,3-c]pyridin-6-yl]prop-215 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-4ylamino)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-en1-one (pk 1) and 1-((3S,4R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-420 methylpiperidin-1-yl)prop-2-en-1-one (pk2). rac-1-((3R,4S)-3-((7H-Pyrrolo[2,3d]pyrimidin-4-yl)amino)-4-methylpiperidin-1-yl)prop-2-en-1-one (120 mg) was separated by chiral chromatography to give 1-((3R,4S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4
143 yl)amino)-4-methylpiperidin-1-yl)prop-2-en-1-one (peak 1,47.8 mg, 80 %) as a white solid 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, 48.2 mg, 80%) as a white solid. Chiral SFC: ChiralPak AD (250 x 30 mm, 5 pm); 30% EtOH/NH4OH; 30% EtOH (0.05% NH3 in H2O) in CO2), 60 mL/min. Peak 1 data (Example 11): 1H NMR (400MHz, DMSO-d6) δ 11.50 (brs, 1H), 8.08 (d, J=14.3 Hz, 1H), 7.33-7.16 (m, 1 H), 7.08 (brs, 1H), 6.88-6.72 (m, 1H), 6.59 (brs, 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, 1 H), 3.93 - 3.71 (m, 1 H), 3.09 - 2.97 (m, 1 H), 2.83 (t, J=11.8 Hz, 1 H), 2.66 (t, J=12.8 Hz, 1 H), 2.46 - 2.35 (m, 1 H), 1.82 (d, J=11.5 Hz, 2H), 1.28 - 1.13 (m, 1 H), 0.94 (dd, J=6.1, 11.7 Hz, 3H). LCMS (M+H) = 285.9. Peak 2 data (Example 112): 1H NMR (400MHz, DMSO-de) δ 11.50 (brs, 1H), 8.09 (d, J=14.1 Hz, 1H), 7.33-7.16 (m, 1H), 7.08 (br s, 1 H), 6.89 - 6.72 (m, 1 H), 6.59 (br s, 1 H), 6.12 (d, J=16.6 Hz, 1 H), 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, 1 H), 2.66 (t, J=12.0 Hz, 1 H), 2.42 (t, J=11.5 Hz, 1 H), 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-4ylamino)piperidin-1-yl]prop-2-en-1-one. Prepared as in Example 5, except using the amine (rac-(3R,4R)-tert-butyl 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-en1-one. To a solution of rac-(3R,4R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-4-ol (100 mg, 0.33 mmol) in DCM (5 mL) at 0 °C was added DBU (0.20 mL, 1.3 mmol), followed by acryloyl chloride (29.6 mg, 0.33 mmol). The reaction mixture was stirred at 60 °C for 4 hrs. The reaction mixture was concentrated and a portion of the crude material (50 mg) purified by RP-HPLC to give rac-1 [(3S,4S)-4-hydroxy-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en1-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]pyrîmîdin-4ylamino)piperidin-1 -yl]prop-2-en-1 -one.
144
Example 115: 1-[(2R,5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1-yl]prop-2-en-1-one. Prepared as in Example 5, except using the rac-trans-(2S,5S)-tert-butyl 5-amino-2-methylpiperidine-1 -carboxylate.
Step 1. (2R,5R)-Benzyl 5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperidine-1 -carboxylate. A mixture of 2,4-dichloro-7H-pyrrolo[2,3djpyrimidine (266.5 mg, 1.425 mmol), DIPEA (613 mg, 4.75 mmol) and rac-(2R,5R)benzyl 5-amino-2-methylpiperidine-1-carboxylate (270 mg, 0.950 mmol) in n-BuOH (10 mL) was heated to 130 °C overnight. LC-MS indicated rac-(2R,5R)-benzyl 5amino-2-methylpiperidine-1-carboxylate was consumed completely. The reaction mixture was cooled to room température and evaporated to dryness in vacuo and the residue purified by chromatography (silica, PE/EA , 12%-100%) to give (2R,5R)benzyl 5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1carboxylate (290 mg, 76.5%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.70 (br s, 1 H), 7.57 (d, J=5.8 Hz, 1 H), 7.21 - 6.98 (m, 6H), 6.78 (br s, 1 H), 5.04 - 4.92 (m, 1 H), 4.92 - 4.79 (m, 1 H), 4.34 (br s, 1 H), 4.29 - 4.14 (m, 2H), 3.19 (d, J=12.3 Hz, 1 H), 2.27 - 2.12 (m, 1 H), 2.08 -1.95 (m, 1 H), 1.66 (d, J=11.5 Hz, 1 H), 1.44 -1.30 (m, 1 H), 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 bottle, 10% Pd/C (100 mg) was added under Ar atmosphère. Then a solution of (2R,5R)-benzyl 5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperidine-1-carboxylate (290 mg, 0.727 mmol) in MeOH (20 mL) was added and the resulting mixture was hydrogenated under 45 psi of H2 at 25 °C for 18 hours. After TLC (DCM/MeOH, 10:1) indicated the starting material to be consumed, the reaction mixture was filtered and the filter cake was washed with MeOH. The combined filtrate was evaporated to give rac-N-((3R,6R)-6-methylpiperidin-3-yl)-7Hpyrrolo[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-methylpiperidin1-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 aq. NaHCO3 solution (1mL) and THF (1 mL) at 0 °C was 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 (CH2CI2/MeOH/NH4OH = 10:1:1) indicated rac-N-((3R,6R)-6-methylpiperidin-3
145 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 give crude product, which was purified by prep TLC to give rac-1 -((2R,5R)-5-((7Hpyrrolo[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-pyrroIo[2,3-d]pyrimidin-4ylamino)piperidin-1-yl]prop-2-en-1-one . rac- 1-((2R,5R)-5-((7H-Pyrrolo[2,3d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one was purified by chiral SFC to give two peaks, stereochemistry arbitrarily assigned: Pk1, 1-[(2S,5S)-2methyl-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)piperidin1-yl]prop-2-en-1-one (5.2 mg).
SFC Conditions: Column: ChiralPak IC 250x4.6mm I.D., 5 pm; Mobile phase: éthanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35mL/min; Wavelength: 215nm
Pk1: 1H NMR (400MHz, MeOH-d4) δ 8.15 (s, 1H), 7.06 (d, J=3.5 Hz, 1H), 6.64 (d, J=3.3 Hz, 1 H), 6.28 (br s, 1 H), 5.95 (br s, 1 H), 5.34 (br s, 1 H), 4.59 (br s, 1 H), 4.38 (br s, 2H), 3.53 - 3.34 (m, 1 H), 2.25 - 2.09 (m, 2H), 1.80 (br s, 1 H), 1.57 -1.45 (m, 1H), 1.29 (d, J=6.8 Hz, 3H). Pk2: 1H NMR (400MHz, MeOH-d4) δ 8.16 (s, 1H), 7.07 (d, J=3.5 Hz, 1 H), 6.65 (d, J=3.3 Hz, 1 H), 6.30 (br s, 1 H), 5.96 (br s, 1 H), 5.35 (br s, 1 H), 4.59 (s, 1 H), 4.50 - 4.22 (m, 2H), 3.52 - 3.34 (m, 1 H), 2.23 - 2.17 (m, 2H), 1.89 1.76 (m, 1 H), 1.57 -1.48 (m, 1 H), 1.29 (s, 3H).
Example 116: Rac-1-((1 R,4R,5S)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2azabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one. For préparation of similar ring System see (Tetrahedron, 2012, 68, 7848). Step 1. Rac-(1 R,3S,4S)-Methyl 2-benzyl-2azabicyclo[2.2.1]heptane-3-carboxylate. To a Parr bottle was added rac-(1S,3S,4R)methyl 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 shaken for 4 hrs @ 40 psi H2. The reaction was filtered through a pad of Celite® and the solvent removed to give rac-(1 R,3S,4S)-methyl 2-benzyl-2-azabicyclo[2.2.1]heptane-3
146 carboxylate (990 mg). GC/MS 245. 1H NMR (400 MHz, CHCh) 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-((1 R,3S,4S)-2-Benzyl-2-azabicyclo[2.2.1]heptan-3-yl)methanol. To a solution of rac-(1 R,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 was added LAH (9.05 mL, 1M in THF). After the addition the reaction was allowed to warm to rt and stirred for 12 hrs. The reaction mixture was poured into 1N 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 remove to give an oil (1.52 g, 78%), which was used without further purification. GC/MS 217. 1H NMR (400 MHz, CHCI3) δ 1.11 -1.43 (m, 3 H) 1.51 - 1.72 (m, 2H) 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-(1 R,4R,5S)-4-azido-2-benzyl-2-azabicyclo[3.2.1]octane To a flask containing rac-((1 R,3S,4S)-2-benzyl-2-azabicyclo[2.2.1]heptan-3-yl)methanol (2.0 g,
9.20 mmol) in DCM (150 mL) at rt was added Bu4N3 (2.97 g, 10.1 mmol). 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 rt over 2 hrs. After 2 hrs, the reaction was quenched with 3.75 N NaOH (100 mL). The layers were separated and the organic layer collected, dried (Na2SO4) and solvent removed to give the crude product, which was purified by chromatography (silica, EtOAc/Hep, 5 to 45%) to give 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, CHCI3) 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 (brs, 1 H) 3.34 - 3.60 (m, 3 H) 7.14 - 7.44 (m, 5 H).
Step 4.Rac-(1 R,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 rt. The solvent was removed in vacuo to give a white solid. The crude material was purified by chromatography (silica, MeOH/DCM/NH4OH (10:1 MeOH/NH4OH), 5 to 20%) to give rac-(1 R,4R,5S)17901
147
2-benzyl-2-azabicyclo[3.2.1]octan-4-amine (1.25 g, 73%) as an oil. GC/MS 216. 1H NMR (400 MHz, CHCI3) 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 (brs, 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-7Hpyrrolo[2,3-d]pyrimidin-4-amine. To a flask containing rac-(1 R,4R,5S)-2-benzyl-2azabicyclo[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 give an oil, which after chromatography (silica, EtOAc/Hep, 80 to 100%) gave rac-N-((1 R,4R,5S)-2benzyl-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, CHCI3) 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-((1 R,4R,5S)-2-Azabicyclo[3.2.1]octan-4-yl)-7H-pyrrolo[2,3d]pyrimidin-4-amine. To a round bottom flask containing rac-N-((1 R,4R,5S)-2benzyl-2-azabicyclo[3.2.1]octan-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.22 g, 3.3 mmol) was 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 hrs. The reaction was filtered through a pad of Celite® and the solvent removed to give the crude rac-N-((1 R,4R,5S)-2-azabicyclo[3.2.1]octan-4-yl)-7H-pyrroIo[2,3d]pyrimidin-4-amine,which was used without further purification. LC/MS (M+H)
244.1. 1H NMR (400 MHz, MeOH-c/4) 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, <7=4.68 Hz, 1 H) 3.49 (brs, 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-((1 R,4R,5S)-4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2azabicyclo[3.2.1 ]octan-2-yl)prop-2-en-1 -one. To a flask containing rac-N((1R,4R,5S)-2-azabicyclo[3.2.1]octan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (129
148 mg, 0.53 mmol) in DCM at 0 °C was added DIPEA (0.31 mL, 1.75 mL). After 30 min, acryloyl chloride (59.3 mg, 0.64 mmol in 5 mL DCM) was added. The reaction was stirred at rt for 1 hr and then poured into water/DCM. The layers were separated and aqueous layer extracted (2 x DCM). The organic extracts were combine, dried (Na2SO4) and the solvent removed to give crude rac-1-((1R,4R,5S)-4-((7Hpyrrolo[2,3-d]pyrimidin-4-yI)amino)-2-azabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one (110 mg), a portion (50 mg) was purified by RP-HPLC to give (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]pyrimîdîn-4ylamino)piperidin-1 -yl]prop-2-en-1 -one.
Example 118:1 -[2-(Hydroxymethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1-yl]prop-2-en-1-one. Example 118: Prepared as described in Example 7, except (2S,5S)-benzyl 5-((2-chloro-7-tosyI-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2-(hydroxymethyl)piperidine-1-carboxylate (other cis isomer, pk 2) was carried through Steps 7-10. LC/MS (M+H) 302.2. 1H NMR (400 MHz, MeOH-c/4) 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, 7=12.10 Hz, 1 H) 6.26 (d, 7=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-2Hpyrido[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)carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1 -carboxylate. LC/MS (M+H) 314.2.1H NMR (400 MHz, CHCI3) 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, 7=12.49 Hz, 1 H) 5.10 (d, 7=12.88 Hz, 1 H) 5.74 (d, 7=11.52 Hz, 1 H) 6.22 - 6.57 (m, 2 H) 6.90 (dd, 7=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-f luoropiperidin-3-yl]amino}-7Hpyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one.
Example 121 : rac-1-((2R53S)-3-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2methylpiperïdin-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.
149
Example 122:1-((3aR,7aR)-3a-Methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4yl)hexahydro-1 H-pyrrolo[2,3-c]pyrîdin-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]pyridin6(2H)-yl)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)-7Hpyrrolo[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-4ylamino)piperidin-1-yl]prop-2-en-1-one. For préparation, see Example 61 and Example 67.
Examples 124 and 125:
Example 124: 1-[(2R,5R)-2-Ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1 -yl]prop-2-en-1 -one.
Example 125: 1-[(2S,5S)-2-Ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1 -yl]prop-2-en-1 -one . Prepared as Example 9 for cisderivative, starting from optically pure trans-amines isolated by chiral SFC (Peaks 1 and 2). Pk1: 1-[(2R,5R)-2-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1yl]prop-2-en-1-one. LC/MS (M+H) 300.3. 1HNMR appeared to show two sets of signais possibly derived from rotamers at RT. 1HNMR at 345 K: (500MHz, DMSO-d6) δ 11.22 (br s, 1 H), 8.05 (br s, 1 H), 6.96 - 6.94 (m, 1 H), 6.69 - 6.63 (m, 1 H), 6.58 - 6.55 (m, 1 H), 6.35 (s, 1 H), 5.82 - 5.78 (m, 1 H), 5.30 - 5.28 (m, 1 H), 4.30 - 4.24 (m, 3H), 3.07 (apparent br s, water + 1 H), 2.05 (m, 1 H), 1.95 (m, 1 H), 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[2,3d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en-1-one. LC/MS (M+H) 300.3. 1H NMR at 345 K: (500MHz, DMSO-d6) δ 11.22 (br s, 1 H), 8.05 (br s, 1 H), 6.96 - 6.94 (m, 1 H), 6.69 - 6.63 (m, 1 H), 6.58 - 6.55 (m, 1 H), 6.35 (s, 1 H), 5.82 - 5.78 (m, 1 H), 5.30 - 5.28 (m, 1 H), 4.30 - 4.24 (m, 3H), 3.07 (apparent br s, water + 1 H), 2.05 (m, 1 H),
1.95 (m, 1 H), 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-ylamïno)-2azabicyclo[3.2.1 ]octan-2-yl)prop-2-en-1 -one.
Example 127:1-((1R,4R,5S)-4-(7H-pyrrolo[2J3-d]pyrimidin-4-ylamino)-2azabicyclo[3.2.1]octan-2-yl)prop-2-en-1-one . Examples 126 and 127 were pre
150 pared by purifying the racemic product of Example 116 by chiral RP-HPLC (IA, 21x250 mm, 5um, CO2/0.1%NH4OH in EtOH, 80:20 A/B hold for 10 min, 40 oC, 75 mL/min), absolute stereochemistry arbitrarily assigned.
Pk1 : Rt = 5.67 min (IA, 4.6x100mm, 5um, CO2/0.1 % NH4OH in EtOH, 800:20 hold for 10 min), Example 126: LC/MS (M+H) 297.9. Pk2: Rt = 5.72 min (same as above), Example 127: LC/MS (M+H) 297.9.
Example 128: 1-[(3R,5S)-3-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidîn-4ylamino)piperidin-1 -yl]prop-2-en-1 -one. For préparation 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 (400MHz, DMSO-d6) δ 11.53 (br s, 1H), 8.10 (d,
J=14.6 Hz, 1 H), 7.38 - 7.23 (m, 1 H), 7.08 (br s, 1 H), 6.94 - 6.79 (m, 1 H), 6.56 (br s, 1H), 6.12 (dd, J=7.8, 16.8 Hz, 1 H), 5.75 - 5.64 (m, 1 H), 4.71 (d, J=11.8 Hz, 1 H), 4.49 -4.30 (m, 1 H), 4.03 (d, J=11.5 Hz, 1 H), 2.81 -2.54 (m, 1 H), 2.42 - 2.15 (m, 1H), 2.06 (d, J=12.3 Hz, 1H), 1.62 (brs, 1H), 1.38-1.18 (m, 1H), 0.99 - 0.88 (m, 3H). LCMS (M+H) 285.9.
Example 129: rac-1 -[(2SJ5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1 -yl]prop-2-en-1 -one. For préparation of rac-1 -[(2S,5R)-2methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1 -yl]prop-2-en-1 -one, see
Example 5, Step 8. . 1H NMR (400MHz, DMSO-d6) δ 11.53 (br s, 1 H), 8.12 (d,
J=12.8Hz, 1 H), 7.30 (dd, J=6.8, 18.8 Hz, 1 H), 7.10 (brs, 1 H), 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, 1 H), 4.81 (brs, 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-425 yl)amino]pîperidin-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-4amine as the amine partner. LC/MS (M+H) 300.1. 1H NMR (400MHz, 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 (brs, 1 H) 5.48 - 5.78 (m, 1 H) 6.12 (d, J=16.39 Hz, 1 H) 6.56 (brs, 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 -[(1 S,6R)-8-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3,8diazabicyclo[4.2.0] oct-3-yl]prop-2-en-1-one. Prepared as in Example 12, except
151 using (1 S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]oc-tane-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-4ylamino)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 (400MHz, DMSO-d6) δ 0.97 (d, 7=6.87 Hz, 3 H) 1.39 -1.63 (m, 1 H) 1.84 (d, 7=10.44 Hz, 1 H) 2.00 - 2.22 (m, 1 H) 2.89 (t, 7=10.30 Hz, 1 H) 3.98 - 4.19 (m, 1 H) 4.26 - 4.52 (m, 1 H) 5.33 (d, 7=9.34 Hz, 1 H) 5.66 (d, 7=8.79 Hz, 1 H) 5.89 (d, 7=16.21 Hz, 1 H) 6.06 (d, 7=15.66 Hz, 1 H) 6.33 (dd, 7=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-4yl)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-76) δ ppm 1.49-1.53 (m, 1 H), 1.80-1.82 (d, 7=9.28 Hz, 2 H), 1.90-1.95 (m, 1 H), 2.55-2.63 (m, 1 H), 2.85-2.90 (t, 7=11.48 Hz, 0.5 H), 2.99-3.04 (t, 7=12.7 Hz, 0.5 H), 3.22-3.24 (d, 7=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, 7=13.2 Hz, 1 H), 6.09-6.12 (dd, 7=2.0,16.7 Hz, 1 H), 6.55-6.57 (d, 7=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 (brs, 1 H).
Example 134: 1-[(1 R,6S)-8-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3,8diazabicyclo[4.2.0]oct-3-yl]prop-2-en-1-one. Prepared as in Example 12, except using (1 R,6S)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate 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-4yl](methyl)amino}-piperidin-1 -yl]but-2-en-1 -one.
Example 136: 1-[(3R)-3-{[5-(2-Methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl](methyl)amino}piper-idin-1-yl]prop-2-en-1-one. Prepared as in Example 12, except using (R)-tert-butyl 3-(methylamino)piper-idine-1-carboxylate and 4-chloro-5(2-methoxyethyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine in step 1 and for step 4, (E)-but-
2-enoic acid and acrylic acid was used in combination with EDCI/DIEA/DCM. Ex 135: LC/MS (M+H) 358.1. Ex 136: LC/MS (M+H) 344.1.
152
Example 137: 1-[(3R)-3-{[5-(4-Hydroxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl]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 Stepl and the additional step of removing benzyl protecting group after chloro displacement. 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]pyrïmidîn4-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 chloro displacement. 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-4yl]amino}pîperidin-1-yl]-2-methylprop-2-en-1-one. Prepared as in Example 12, except using 5-(4-(benzyloxy)benzyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine in Stepl and the additional step of removing benzyl protecting group after chloro displacement. For Step 4, (E)-but-2-enoic acid was used in combination with EDC/DIPEA/ DMAP/DMF was used in combination with EDC/DIPEA/DMAP/DMF. Ex 139:
LC/MS (M+H) 392.3.
Examples 140-148:
Examples 140-148 were prepared according to the scheme below
Example 140
Step 1.4-Chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. To a flask was 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) was added. The reac
153 tion mixture was stirred at rt for 2 hrs 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 give the crude, which was purified by chromatography (silica, MeOH/DCM, 0 to 10%) to give 4-chloro-N,N-dimethyl-7Hpyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 44%). LC/MS (M+H) 225.1. Step 2. (R)-tert-Butyl 3-((5-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate. To a microwave tube containing 4-chloro-N,Ndimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 0.44 mmol) in dioxane/water (2 mL/ 0.5 mL) was added (R)-tert-butyl 3-aminopiperidine-1-carboxylate (267mg, 1.34 mmol) and K2CO3 (123 mg, 0.89 mmol). 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 give the crude, which was purified by chromatography (silica, EtOAc/Hep, 90 to 100%) to give (R)-tertbutyl 3-((5-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (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-5carboxamide. A flask containing (R)-tert-butyl 3-((5-(dimethylcarbamoyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)-piperidine-1-carboxylate (70mg, 0.18 mmol) in DCM (2mL) was treated with 4N HCl in dioxane (0.360mL, 1,44mmoL). The reaction was stirred at rt for 2 hrs and then the solvent was removed to give (R)-N,Ndimethyl-4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (50 mg, 70%).
Step 4. (R)-4-((1 -acryloyIpiperidin-3-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3d]pyrimidine-5-carboxamide.
To a flask containing (R)-N,N-dimethyl-4-(piperidin-3-ylamino)-7H-pyrrolo[2,3d]pyrimidine-5-carboxamide (40 mg, 0.14 mmol) in DMF (2 mL) was 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 rt for 2 hrs 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 give crude (R)-4-((1-acryloylpiperidin-3
154 yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, which was purified by RP-HPLC to give pure product (48 mg, 63%). LC/MS (M+H) 343.3.
Ex LC/MS Name
142 343 4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-N,N-dimethyl-7H- pyrrolo[2,3-d]pyrimidine-5-carboxamide
143 359 4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-N-(2-hydroxyethyl)-7H- pyrrolo[2,3-d]pyrimidine-5-carboxamide
144 343 4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-N-ethyl-7H-pyrrolo[2,3- d]pyrimidine-5-carboxamide
145 329 4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-N-methyl-7H-pyrrolo[2,3- d]pyrimidine-5-carboxamide
146 369 1-[(3R)-3-{[5-(pyrrolidin-1-ylcarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino}piperidin-1 -yl]prop-2-en-1 -one
147 383 (2E)-1 -[(3 R)-3-{[5-(pyrrol id in-1 -ylcarbonyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl]amino}piperidin-1 -yl]but-2-en-1 -one
148 373 4-({(3R)-1-[(2E)-but-2-enoyl]piperidin-3-yl}amino)-N-(2- hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
149 387 4-({(3R)-1-[(2E)-but-2-enoyl]piperidin-3-yl}amino)-N-(2- methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
150 373 4-{[(3R)-1-acryloylpiperidin-3-yl]amino}-N-(2-methoxyethyl)-7H- pyrrolo[2,3-d]pyrimidine-5-carboxamide
Example 151 : (2E)-1-[(3R)-3-{[5-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-45 yl]amino}piperidin-1 -yl]but-2-en-1 -one.
Step 1. (R)-tert-Butyl 3-((5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a flask containing 5-(2-((tertbutyldimethylsilyl)oxy)ethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 3.2 mmol) in dioxane/water (10 mL/6 mL) was added (R)-tert-butyl 3-aminopiperidine-110 carboxylate and K2CO3 (1.33 g, 9.6 mmol). The mixture was heated to 100 °C for 30 hrs and the cooled to rt. The reaction was poured into ethyl acetate/brine and the layers separated. The organic extract was collected, dried (Na2SO4) and the solvent
155 removed to give an oil, which after chromatography (silica, MeOH/DCM, 0 to 10%) gave (R)-tert-butyl 3-((5-(2-((tert-butyIdimethylsilyl)-oxy)ethyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)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 flask containing (R)-tert-butyl 3-((5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (914 mg, 1.92 mmol) was added dioxane (8 mL) followed by 4M HCI/dioxane (3 mL). The reaction mixture was stirred for 4h. Ether was added, and the solid filtered to give (R)-2-(4-(piperidin-3ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethanol (750 mg) as the HCl sait. LC/MS (M+H) 262.3.
Step 3. (2E)-1 -[(3R)-3-{[5-(2-Hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl]amino}piperidin-1-yl]but-2-en-1-one. To a flask containing (R)-2-(4-(piperidin-3ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethanol (100 mg, 0.38 mmol) in DCM (3 mL) was 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 hrs, and then poured into water/DCM. The layers were separated and the organic extract dried (Na2SO4) and the solvent removed to give 114 mg of crude material, which was purified by chromatography (silica, MeOH/DCM, 0 to 10%) and then RP-HPLC to give (2E)-1-[(3R)-3-{[5-(2-hydroxyethyl)-7H-pyrrolo[2,3d]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-cfe) δ 1.33 -1.86 (m, 5 H) 2..Ί1 (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-4yl]amino}piperidin-1-yl]-2-methylprop-2-en-1-one. Prepared as in Example151, 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-1,5,6,8tetraazaacenaphthylen-5(1 H)-yl)piperïdin-1 -yl]prop-2-en-1 -one.
Step 1. (R)-tert-Butyl 3-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a solution of 5-bromo-4-chloro7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 5.5 mmol) in
156 dioxane/water (10 mL:5 mL) was added (R)-tert-butyl 3-aminopiperidine-1carboxylate (2.21 g, 11.0 mmol) and K2CO3 (1.52 g, 11.0 mmol). The reaction mixture was heated to 100 °C for 72 hrs and then cooled to rt. 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 give an oil, which after chromatography (silica, EtOAc/Hep, 0 to 50%) gave (R)-tert-butyl 3-((5-bromo-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1 -carboxylate (600 mg, 41%). LC/MS (M+H) 528.3. 1H NMR (400 MHz, CDCI3) 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. (R)-tert-Butyl 3-(allyl(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a flask containing (R)-tert-butyl 3-((5-bromo-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (100 mg, 0.19 mmol) in THF (4 mL) was added NaH (8.4 mg, 0.21 mmol). After 15 min, allyl iodide (64 mg, 0.38 mmol) was added and the reaction stirred at 40 °C for 2 hrs. The mixture was poured into water/EtOAc and the layers separated. The organic layer was collected, dried . (Na2SO4) and the solvent removed to give (R)-tert-butyl 3-(allyl(5-bromo-7-((2(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate. LC/MS (M+H) 568.3. 1H NMR (400 MHz, CDCI3) 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. (R)-tert-Butyl 3-(3-methylene-1-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-
1,5,6,8-tetraazaacenaphthylen-5(1 H)-yl)piperidine-1 -carboxylate. To a flask containing (R)-tert-butyl 3-(alIyl(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (400 mg, 0.71 mmol) was added 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 hrs and then cooled to rt. The reaction mixture was
157 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 give the crude product, which after chromatography (silica, EtOAc/Hep, 0 to 25%) gave two main fractions, F1 : (R)-tert-butyl 3-(3-methylene-3,4dihydro-1,5,6,8-tetraazaacenaphthylen-5(1 H)-yl)piperidine-1-carboxylate and F2: (R)-tert-butyl 3-(3-methyl-1,5,6,8-tetraazaacenaphthylen-5(1 H)-yl)piperidine-1 carboxylate. F1 : LC/MS (M+H) 486.3. F2: LC/MS (M+H) 486.3.
Step 4. (3R)-tert-Butyl 3-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-
1,5,6,8-tetraaza-acenaphthylen-5(1 H)-yl)piperidine-1 -carboxylate. To a Parr bottle containing (R)-tert-butyl 3-(3-methylene-3,4-dihydro-1,5,6,8-tetraazaacenaphthylen5(1 H)-yl)piperidine-1 -carboxylate (420 mg, 0.86 mmol) was added éthanol (10 mL) and 10% Pd/C (104.8 mg). The reaction was shaken at rt at 40 psi H2for 3 hrs and then filtered through a pad of Celite®. The pad was washed with methanol and the solvent removed to give (3R)-tert-butyl 3-(3-methyl-3,4-dihydro-1,5,6,8tetraazaacenaphthylen-5(1H)-yl)piper-idine-1-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-1,5,6,8tetraazaacenaphthylene. To a flask containing (3R)-tert-butyl 3-(3-methyl-1 -((2(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1,5,6,8-tetraaza-acenaphthylen-5(1H)yl)piperidine-1-carboxylate (422 mg, 0.86 mmol) was added DCM (10 mL) and TFA (5 mL). The reaction mixture was stirred at rt for 3 hrs and then concentrated in vacuo. The residue was dissolved in methanol and then NH4OH (10 mL) was added. The mixture was stirred for 3 hrs at rt and the solvent removed in vacuo and the residue purified by chromatography (silica, MeOH/DCM, 0 to 10%) to give 3-methyl-
5-((R)-piperidin-3-yl)-1,3,4,5-tetrahydro-1,5,6,8-tetraazaacenaphthylene (300 mg, 135% sait contaminant). LC/MS (M+H) 258.3.
Step 6. 2-Methyl-1-((3R)-3-(3-methyl-3,4-dihydro-1,5,6,8-tetraazaacenaphthylen5(1 H)-yl)piperidin-1 -yl)prop-2-en-1 -one. To a flask containing 3-methyl-5-((R)piperidin-3-yl)-1,3,4,5-tetrahydro-1,5,6,8-tetraazaacenaphthylene (75 mg, 0.29 mmol) was added THF (5 mL) and TEA (0.1 mL, 0.58 mmol). The mixture was cooled to 0 °C and then methacryloyl chloride (30.4 mg, 0.29 mmol) was added. After stirring at rt for 5 hrs, the reaction was diluted with ethyl acetate/water. The lay
158 ers were separated and the organic layer collected, dried (Na2SO4) and the solvent removed to give crude material, which after chromatography (silica, MeOH/DCM, 0 to 15%) gave 2-methyl-1-((3R)-3-(3-methyl-3,4-dihydro-1,5,6,8tetraazaacenaphthylen-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, CDCI3) 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-1,5,6,8tetraazaacenaphthylen-5(1H)-yl)piper-îdin-1-yl]but-2-en-1-one. Prepared as in Example 153, except for Step 6 in which trans-crotonyl 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-tetraazaacenaphthylen5(1H)-yl)piperidin-1-yl]prop-2-en-1-one. Prepared as in Example 153, except for Step 6 in which acryloyl chloride was used instead of methacryloyl chloride. LC/MS (M+H) 312.2.
Example 156: 4-{[(3R)-1 -Acryloylpiperidin-3-yl]amino}-1 H-pyrrolo[2,3-
b]pyridine-5-carbonitrile.
Step 1. (R)-4-((1 -Benzylpiperidin-3-yl)amino)-1 H-pyrrolo[2,3-b]pyridine-5carbonitrile. To a microwave tube was added 4-chloro-1 H-pyrrolo[2,3-b]pyridine-5carbonitrile (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 rt. 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 give the crude, which after chromatography (silica, EtOAc/Hep, 0 to 100%) gave (R)-4-((1-benzylpiperidin-3-yl)amino)-1 H-pyrrolo[2,3-b]pyridine-5carbonitrile (249 mg, 77%). LC/MS (M+H) 332.3. 1H NMR (400 MHz, DMSO-cfe) 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 (brs, 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)-1 H-pyrrolo[2,3-b]pyridine-5carbonitrile (155 mg, 0.47 mmol) was added éthanol (3 mL), ammonium formate
159 (296 mg, 4.68 mmol) and Pd(OH)2 (32.3 mg, 0.02 mmol). The mixture was heated to 100 °C for 2 hrs and then cooled to rt. The mixture was filtered through Celite® and the solvent removed to give the crude, which after chromatography (silica, MeOH/DCM 0 to 40%) gave (R)-4-(piperidin-3-ylamino)-1 H-pyrrolo[2,3-b]pyridine-5carbonitrile (71 mg, 63%). LC/MS (M+H) 242.3.
Step 3. 4-{[(3R)-1-Acryloylpiperidin-3-yl]amino}-1 H-pyrrolo[2,3-b]pyridine-5carbonitrile. To a flask containing (R)-4-(piperidin-3-ylamino)-1H-pyrrolo[2,3b]pyridine-5-carbonitrile (25 mg, 0.1 mmol) was added THF (1 mL) and TEA (30 pL, 0.2 mmol). The mixture was cooled to 0 °C and then acryloyl chloride (7.5 pL, 0.10 mmol) was added and the reaction stirred for 1 hr. 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 give the crude, which after chromatography (silica, MeOH/DCM, 0 to 15%) gave 4-{[(3R)-1acryloylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbo-nitrile (17 mg, 55%). LC/MS (M+H) 296.2. 1H NMR (400 MHz, DMSO-cfe) δ 1.47 (brs, 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 (brs, 1 H).
Example 157: 3-[4-({(3R)-1 -[(2E)-4-(Dimethylamino)but-2-enoyl]piperidin-3yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]propanenitrile.
Step 1. (R)-tert-Butyl 3-((5-(2-cyanoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate.
To a flask containing (R)-tert-butyl 3-((5-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)amino)piperidine-1-carboxylate (400 mg, 1.11 mmol) in DCM (6.0 mL) at 0 °C was added CH3SO2CI (0.10 mL, 1.33 mmol) and DIPEA (0.6 mL, 3.32 mmol). The mixture was stirred at 0 °C for 30 min and then poured into water/DCM. The layers were separated and the organic extracts collected and dried (Na2SO4). The solvent was removed to give crude (R)-tert-butyl 3-((5-(2-((methylsulfonyl)oxy)ethyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (540 mg), which was used in the next step without purification. To the crude (R)-tert-butyl 3-((5-(2((methylsulfonyl)oxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1carboxylate (540 mg, 1.23 mmol) was added DMF (5 mL) and NaCN (303 mg, 6.1
160 mmol). The reaction was stirred at 50 °C for 30 mins and then poured into water/ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to give the crude, which after chromatography (silica, MeOH/DCM 0 to 5%) gave (R)-tert-butyl 3-((5-(2-cyanoethyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)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)propanenitrile. To a flask containing (R)-tert-butyl 3-((5-(2-cyanoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (302 mg, 0.82 mmol) was added DCM (2 mL) and TFA (0.32 mL). The mixture was stirred at rt for 4 hrs and the solvent removed to give crude (R)-3-(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propanenitrile, 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)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]propanenitrile. To a flask containing (R)-3-(4-(piperidin-
3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propanenitrile (100 mg, 0.37 mmol) was added 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 rt. 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 give crude 3-[4-({(3R)-1-[(2E)-4(dimethylamino)but-2-enoyl]piperidin-3-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-5yljpropanenitrile, which was purified by RP-HPLC to give 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]propanenïtrile. 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[2,3d]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 final step. Example 160: rac-(2E)-1 -[(3S,4R)-4-Hydroxy-3-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)piperidin-1-yl]but-2-en-1-one. Prepared as in Example 64, except in the
161 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-4ylamino)piperidin-1-yl]prop-2-en-1-one. For préparation, see Example 7. Example 162:1 -{(3R,5S)-3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5hydroxypiperidin-1 -yl}prop-2-en-1 -one.
Step 1. (3S,5R)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-((5-chloro-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. A mixture of (3R,5S)-tert-butyl 3amino-5-((tert-butyldimethylsilyl)-oxy)piperidine-1-carboxylate (200 mg, 0.61 mmol),
4,5-dichloro-7H-pyrrolo[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°C for 20 hours. LC-MS showed about 60% 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine was remaining. 200 mg of (3R,5S)-tert-butyl 3-amino-5-((tert-butyldimethylsilyl)oxy)piperidine-1 -carboxylate was added, and the reaction mixture was heated to 90 °C for 20 hours. The reaction mixture was evaporated to dryness to give crude material, which after chromatography (silica, DCM/MeOH, 100:0-90:10) gave (3S,5R)-tert-butyl 3-((tertbutyldimethylsilyl)oxy)-5-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine1-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-7Hpyrrolo[2,3-d]pyrimidin-4-amine. To a OoC stirred solution of (3S,5R)-tert-butyl 3((tert-butyldimethylsilyl)oxy)-5-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidine-1-carboxylate (290 mg, 0.60 mmol) in CH2CI2 (10 mL) was added TFA (3 mL). After the resulting mixture was stirred at room température for 2 hours, TLC (DCM/MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was evaporated to dryness and then purified by chromatography (silica, EtOAc/MeOH, 100:0-80:20) to give N-((3R,5S)-5-((tertbutyldimethylsilyl)oxy)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[2,3d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one. To a 0 °C stirred solution of N-((3R,5S)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-5-chloro-7H-pyrrolo[2,3d]pyrimidin-4-amine (100 mg, 0.26 mmol) and DIPEA (68 mg, 0.52 mmol) in THF
162
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 température for 20 min. TLC (DCM/MeOH, 10:1) showed starting material was consumed completely. 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)-5hydroxypiperidin-1-yl)prop-2-en-1-one. To a flask containing crude 1-((3S,5R)-3((tert-butyldimethylsilyl)oxy)-5-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yl)prop-2-en-1-one was dissolved in THF (5 mL) at 0 °C was added TBAF (0.3 mL, 1 M in THF). After the addition, the resulting mixture was stirred at room for 18 hours. LC-MS showed starting material was consumed completely. The reaction mixture was evaporated to dryness and the crude material was purified by RP-HPLC (base modifier) to give 1-((3R,5S)-3-((5-chloro-7H-pyrrolo[2,3d]pyrimidin-4-yl)amino)-5-hydroxypiperidin-1-yl)prop-2-en-1-one (31 mg,) as a white solid. HNMR showed some TBAF présent, thus further purification by RP-HPLC (TFA modifier) gave 1-((3R,5S)-3-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-
5-hydroxypiperidin-1-yl)prop-2-en-1-one (13 mg, 16.7) as a white solid. 1H NMR (400MHz, DMSO-de) δ 11.82 (br s, 1 H), 8.20 (br s, 1 H), 8.13 (d, J=12.3 Hz, 1 H),
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, 1 H), 4.45 (br s, 1 H), 4.39 - 4.27 (m, 1 H), 4.04 - 3.74 (m, 3H), 3.51 (d, J=14.3 Hz, 1 H), 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-methylpiperidîn-3-yl]amino}-7Hpyrrolo[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, CDCI3) 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) 4.44-4.82 (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-methylpiperîdin-3-yl]amino}-7Hpyrrolo[2,3-d]pyrimidine-5-carboxamide. Prepared as in Example 18, except us
163 ing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile in Step 1. Amide is byproduct 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-methylpiperidîn-3-yl]amino}-1 Hpyrrolo[2,3-b]pyridine-3-carbonitrile. Prepared as in Example 2, except using (2S,5R)-tert-butyl 5-amino-2-methyIpiperidine-1 -carboxylate instead of (R)-tert-butyl
3-aminopiperidine-1-carboxylate. LC/MS (M+H) 310.3. 1H NMR (400 MHz, CDCI3) 10 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)-1,4,6,715 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-4chloro-5-nitropyridine (10 g, 42 mmol) in THF (100 mL) was added slowly 30% MeNH2/H2O (20 mL, 210 mmol) at room température. After the addition, the reaction mixture was stirred at room température for 3 hours. TLC (Petroleum ether/EtOAc, 20 4:1) showed starting material was consumed completely. 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 give 3-bromo-N-methyl-5nitropyridin-4-amine (8 g, 80%) as a yellow solid, which was used directly to next step without further purification. 1H NMR (400 MHz, CDCI3) δ 3.22 (d, J=5.52 Hz, 3 25 H) 7.15 (brs, 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-Nmethyl-5-nitropyridin-4-amine (8 g, 34.56 mmol) in AcOH (200ml) was added Fe (11.6 g, 207.34 mmol) at room température. The resulting mixture was heated to 80 °C for 3 hours. TLC (EtOAc) showed starting material was consumed completely.
The reaction mixture was filtered and the filtrate was concentrated to dryness and then purified by chromatography (silica, MeOH/DCM, 0% to 10%) to give 8 g of 5bromo-N4-methyl-pyridine-3,4-diamine (yield 100%).
164
Step 3. 7-Bromo-1-methyl-1 H-imidazo[4,5-c]pyridine. To a stirred solution of 5bromo-N4-methylpyridine-3,4-diamine (8 g, 40 mmol) in trimethyl ortho-formate (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 starting material was consumed completely. The reaction mixture was concentrated to dryness and then purified by chromatography (silica, MeOH/EtOAc, 0% to 10%) to give 6.5 g of 7-bromo-1-methyl-1Himidazo[4,5-c]pyridine (yield 77%). 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 anhydrous toluene (200 mL) was added BINAP (1.7 g, 2.62 mmol) and Cs2CO3 (34 g, 104.8 mmol). 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 into 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 starting material was consumed completely. The reaction mixture was filtrated and the filtrate was concentrated to dryness and then purified by chromatography (silica, MeOH/EtOAc, 0% to 10%) to give 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-HCI (2.78 g, 40 mmol). After the mixture with stirred at 80 °C for 12hours, TLC (DCM/ MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was filtered and the filtrate was concentrated to dryness and then purified by chromatography (silica, MeOH/DCM, 0% to 30%) to give 1-methyl-1H-imidazo[4,5-c]pyridin-7amine (5 g, 100% including some inorganic sait) as a white solid.
Step 6. N-(1-Methyl-1H-imidazo[4,5-c]pyridin-7-yl)acetamide. A solution of 1-methyl1 H-imidazo[4,5-c]pyridin-7-amine (3.3 g, 22.3 mmol) in acetic anhydride (20 mL) was stirred at 60 °C for4hours. TLC (DCM/ MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was quenched with saturated sodium
165 carbonate (20 ml). The solution was concentrated to dryness and the crude product was purified by chromatography (silica, MeOH/DCM, 0% to 30%) to give N-(1methyl-1 H-imidazo[4,5-c]pyridin-7-yl)acetamide (2 g, 47% for 2 steps) as a yellow oil. Step 7. 7-Aacetamido-5-benzyl-1-methyl-1 H-imidazo[4,5-c]pyridin-5-ium. To a stirred solution of N-(1 -methyl-1 H-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 with stirred at 110 °C for 12 hours, TLC (DCM/ MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was filtered to give 7-acetamido-5benzyl-1-methyl-1 H-imidazo[4,5-c]pyridin-5-ium (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-1 H-imidazo[4,5-c]pyridin-7yl)acetamide. To a stirred solution of 7-acetamido-5-benzyl-1 -methyl-1 Himidazo[4,5-c]pyridin-5-ium (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 with stirred at the same température for 30 mins. TLC (DCM/ MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was concentrated to dryness and the crude product was purified by chromatography (silica, MeOH/DCM, 0% to 10%) to give N-(5-benzyl-1 -methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-7yl)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-1 H-imidazo[4,5-c]pyridin-7yl)acetamide (100 mg, 0.36 mmol) in 6M HCl solution (5 mL) was stirred at 70 °C for 12 hours. TLC (DCM/ MeOH, 10:1) showed starting material was consumed completely. The reaction mixture was azeotroped with EtOH three times to give compound 5-benzyl-1 -methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-7-amine (100 mg, 95%) as a yellow solid. 1H NMR (400 MHz, CHCI3) 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-4,5,6,7tetrahydro-1 H-imidazo[4,5-c]pyridin-7-amine. A mixture of 5-benzyl-1 -methyl4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-7-amine (300 mg, 1.08 mmol), DIPEA ♦
166 (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 the reaction was complété. The reaction mixture was cooled to room température 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 (30mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to give crude product, which was purified via chromatography (silica, EtOAc/petroleum ether, 10% to 80%) to give 5-benzyl-N-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-7-amine (250 mg, 60 %) as a yel10 low 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-1 Himidazo[4,5-c]pyridin-7-amine. To a Parr hydrogénation bottle, 10% dry Pd/C (10 mg) was added under Ar atmosphère. Then a solution of 5-benzyl-N-(2-chloro-7Hpyrrolo[2,3-d]pyrimidin-4-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-715 amine (100 mg, 0.25 mmol) in MeOH (10 mL) was added and the resulting mixture was hydrogenated under 50 psi of H2 at 30 °C for 72 hours. The reaction solution was filtered through a pad of Celite® and the cake was washed with MeOH for three times. The combined filtrate was concentrated to give 1-methyl-N-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1 H-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 work up.
Step 12. 1-(7-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1-methyl-6,7-dihydro-1 Himidazo[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 25 (60 mg, 0.22 mmol) in THF (2 mL) and water (2 mL) at 0 °C was 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 starting material was consumed completely. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mLx2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to give crude product, which was further purified by HPLC to give 1-(7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1-methyl-6,7-dihydro-1Himidazo[4,5-c]pyridin-5(4H)-yl)prop-2-en-1-one (1.5 mg, 2.5 %) as a white solid.
167
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 (brs, 1 H).
Examples 167-196
O
N-displacement
SEM
DMF/DIEA/0 °C/15 min;
°C/ 2 hrs
1. TFA/ DCM/ 30 °C/4hrs;
2. NH3.H2O/ MeOH/ 30 °C/ 2 hrs
----------------------- R3'N'R2
H
329
SEM
Starting templates A (2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2,3-b]pyrazine-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 of Médicinal Chemistry, 56(4), 1677-1692 (2013).
Examples 165-196 were prepared according to the synthetic procedure below. Stepl: (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 pmol, 2.0 eq.) were dispensed to 8 ml reaction vials. CS2CO3 (48.9 mg, 150 pmol, 2.0 eq.) was dispensed to each vial.
750 μΙ (75 μηηοΙ, 1.0 eq.) of 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)eth-oxy)methyl)5H-pyrrolo[2,3-b]pyrazine-7-carboxamidesolution was added to each vial, followed by Pd2(dba)3 (6.9 mg, 7.5 pmol, 0.1 eq.) and then dppf (2.5 mg, 10 pmol, 0.13 eq.) under N2 atmosphère. Vials were capped and shaken at 100 °C for 16 hrs. After reactions were deemed complété by LC-MS, 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 of step 1.
«
168 (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 pmol, 2.0 eq.) were dispensed to 8 ml reaction vials. t-BuONa (14.4 mg, 150 pmol, 2.0 eq.) was added to each vial, followed by 750 μΙ (75 pmol, 1.0 eq.) of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3bjpyrazine solution, Pd2(dba)3 (6.9 mg, 7.5 μιτιοΙ, 0.1 eq.) and Ruphos (4.2 mg, 9 pmol, 0.12 eq.) under N2 atmosphère. Vials were capped and shaken at 110 °C for 16 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure. The crude product was washed with H2O (1 mL) and exact 10 with EtOAc (1 mL x 3). The organic layer was collected and concentrated to obtain the intermediates of step 1.
Step 2: De-protection (De-Boc & De-SEM). One mL of TFA/ DCM (v/v= 1/ 7) was dispensed to vials containing intermediates of step 1. Vials were capped and shaken at 30 °C for 4 hrs. Solvents were evaporated under reduced pressure. One and 15 two tenths mL of NH3-H2O/ MeOH (v/v= 1/3) were added to each vial. Vials were capped and shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to obtain the intermediate of Step 2.
Step 3: Acylation. Five hundred μΙ of anhydrous DMF were dispensed to vials con20 taining the intermediate of Step 2. DIEA (29 mg, 225 pmol, 3.0 eq.) was added to each vial, followed by acryloyl chloride (8.1 mg, 90 pmol, 1.2 eq.) at températures under 0 °C. Vials were kept at 0 °C for 15 mins, and then shaken at 30 °C for 2 hrs.
After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure, and the residue was purified by prep. HPLC to give final product.
Example MW MW (obs) Name
167 257.3 258 N-[1-(5H-pyrrolo[2,3-b]pyrazin-2-yl)pyrrolidin-3- yl]prop-2-enamide
168 356.43 257 2-[(1-acryloylpiperidin-4-yl)amino]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
169 370.46 371 2-{4-[acryloyl(methyl)amino]piperidin-1-yl}-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
170 368.44 369 2-[(3aR,6aR)-1-acryloylhexahydropyrrolo[3,4b]pyrrol-5(1H)-yl]-N-(propan-2-yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
171 342.4 343 2-{[(3S)-1-acryloylpyrrolidin-3-yl]amino}-N-(propan- 2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
172 257.3 258 1 -[4-(5H-pyrrolo[2,3-b]pyrazin-2-yl)piperazin-1 yl]prop-2-en-1-one
173 328.38 329 2-[3-(acryloylamino)azetidin-1-yl]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
174 342.4 343 2-(4-acryloylpiperazin-1-yl)-N-(propan-2-yl)-5H- pyrrolo[2,3-b]pyrazine-7-carboxamide
175 269.31 270 1-[6-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,6- diazaspiro[3.3]hept-2-yl]prop-2-en-1-one
176 271.32 272 1-[4-(5H-pyrrolo[2,3-b]pyrazin-2-ylamino)piperidin- 1 -yl]prop-2-en-1 -one
177 356.43 357 2-({[(2S)-1-acryloylpyrrolidin-2-yl]methyl}amino)-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
178 368.44 369 2-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)yl)-N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
179 358.4 359 2-[(1-acryloyl-4-hydroxypyrrolidin-3-yl)amino]-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
180 356.43 357 2-({[(2R)-1-acryloylpyrrolidin-2-yl]methyl}amino)-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
181 342.4 343 2-[(3R)-3-(acryloylamino)pyrrOlidin-1-yl]-N-(propan-
170
2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
182 370.46 371 2-{[cis-4-(acryloylamino)cyclohexyl]amino}-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
183 368.44 369 2-{( 1 R,5S)-1 -[(acryloylamino)methyl]-3azabicyclo[3.1.0]hex-3-yl}-N-(propan-2-yl)-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide
184 342.4 343 2-{[cis-3-(acryloylamino)cyclobutyl]amino}-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
185 356.43 357 2-(4-acryloyl-1,4-diazepan-1 -yl)-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
186 257.3 258 N-[(3S)-1-(5H-pyrrolo[2,3-b]pyrazin-2-yl)pyrrolidin- 3-yl]prop-2-enamide
187 342.4 343 2-{3-[acryloyl(methyl)amino]azetidin-1-yl}-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
188 328.38 329 2-[(1-acryloylazetidin-3-yl)amino]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
189 354.41 355 2-{[(1 R,5S,6s)-3-acryIoyl-3-azabicyclo[3.1.0]hex-6yl]amino}-N-(propan-2-yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
190 356.43 357 2-{(3R)-3-[acryloyl(methyl)amino]pyrrolidin-1-yl}-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
191 356.43 357 2-({[(3S)-1-acryloylpyrrolidin-3-yl]methyl}amino)-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
192 243.27 244 N-[1-(5H-pyrrolo[2,3-b]pyrazin-2-yl)azetidin-3- yl]prop-2-enamide
193 370.46 371 2-{[(1-acryloylpiperidin-4-yl)methyl]amino}-N-
171
(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7- carboxamide
194 342.4 343 2-[(3S)-3-(acryloylamino)pyrrolidin-1-yl]-N-(propan- 2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
195 342.4 343 2-[3-(acryloylamino)pyrrolidin-1-yl]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
196 372.43 373 2-{[(3R,4R)-1-acryloyl-3-hydroxypiperidin-4- yl]amino}-N-(propan-2-yl)-5H-pyrrolo[2,3- b] py razine-7-carboxam ide
197 283.34 284 N-{[(1R,5S)-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-3- azabicyclo[3.1.0]hex-1 -yl]methyl}prop-2-enamide
198 342.4 343 2-{[trans-3-(acryloylamino)cyclobutyl]amino}-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
Examples 199-212 were prepared as described in the Scheme below.
NaHCO3/ H20/ CH3CN/ toluene / Pd(dppf)CI2/ N2/ 65 °C/ 4 hrs dioxane/ t-BuONa/ Pd2(dba)3 ) / RuPhns/ N2/1in°C/16hrs
TFA/ DCM/ 30 °C/16 hrs;
MeOH/ NH3.H2O/ 30 °C/ 2 hrs
O
DMF/DIEA/0 °C/15 min;
°C/ 30 min
Step 1 : Suzuki Coupling. Boronic acids/boronates (200 pmol, 2.0 eq.) were dispensed to 8 mL reaction vials, followed by 600 μΙ (100 pmol, 1.0 eq.) of 2-bromo-7iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine solution (0.167 M) in CH3CN, 200 μΙ of toluene, 400 μΙ (400 μιτιοΙ, 4.0 eq.) of NaHCO3 solution (1.0 M in H2O), and then Pd(dppf)CI2 (7.3 mg, 10 pmol, 0.1 eq.) under N2 atmosphère. Vials
172 were capped and shaken at 65 C for 4 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure, and the residue was washed with H2O (1 mL) and extracted with EtOAc (1 mL x 3). Organic layers were concentrated under reduced pressure to obtain intermediates of step 1.
Step 2: N-Displacement. A solution of t-BuONa (19.2 mg, 200 pmol, 2.0 eq.) to the vials containing intermediates from step 1, followed by 800 μΙ (200 pmol, 2.0 eq.) of tert-butyl 4-aminopiperidine-1 -carboxylate solution (0.25 M in dioxane), Pd2(dba)3 (9.2 mg, 10 pmol, 0.1 eq.), and RuPhos (5.6 mg, 12 pmol, 0.12 eq.) under N2 atmosphère. Vials were capped and shaken at 110 °C for 16 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure, and the residue was washed with H2O (1 mL) and extracted with EtOAc (1 mL x 3).
Organic layers were concentrated under reduced pressure to obtain intermediates of step 2.
Step 3 & 4: De-protection (De-Boc & De-SEM). One mL of TFA/ DCM (1:7, v/v) was dispensed to vials containing step 2 intermediates. Vials were capped and shaken at 30 °C for 16 hrs. Solvents were evaporated under reduced pressure. One and two tenths mL of NH3-H2O/ MeOH (1:3, v/ v) solution were added to each vial. Vials were capped and shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to afford the intermediates of step 3/4.
Step 5: Acylation. Eight hundred (800) pl of DMF were dispensed to vials containing intermediates of Steps 3 and 4, followed by DIEA (38.7 mg, 300 pmol, 3.0 eq.) and acryloyl chloride (18 mg, 200 pmol, 2.0 eq.) at 0 °C. Vials were kept at 0 °C for 15 min, and then shaken at 30 °C for 30 min. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure. The residue was purified by prep. HPLC to give final product.
Ex MW MW (obs) Name
199 362.44 362 1-(4-{[7-(6-methylpyridin-3-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
• 173
200 366.4 366 1-(4-{[7-(3-fluoropyridin-4-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
201 362.44 362 1-(4-{[7-(2-methylpyridin-4-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
202 349.4 349 1-(4-{[7-(pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2- yl]amino}piperidin-1 -yl)prop-2-en-1 -one
203 425.51 426 1-[4-({7-[4-(methylsulfonyl)phenyl]-5H-pyrrolo[2,3- b]pyrazin-2-yl}amino)piperidin-1 -yl]prop-2-en-1 -one
204 404.47 404 3-{2-[(1-acryloylpiperidin-4-yl)amino]-5H-pyrrolo[2,3- b]pyrazin-7-yl}-N-methylbenzamide
205 362.44 348 1-(4-{[7-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2- yl]amino}piperidin-1 -yl)prop-2-en-1 -one
206 373.42 373 5-{2-[(1-acryloylpiperidin-4-yl)amino]-5H-pyrrolo[2,3- b]pyrazin-7-yl}pyridine-3-carbonitrile
207 366.4 366 1-(4-{[7-(6-fluoropyridin-3-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
208 434.5 434 1- [4-({7-[2-(morpholin-4-yl)pyrimidin-5-yl]-5Hpyrrolo[2,3-b]pyrazin-2-yl}amino)piperidin-1-yl]prop- 2- en-1-one
209 347.42 347 1-{4-[(7-phenyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)amino]piperidin-1 -yl}prop-2-en-1 -one
210 379.42 379 1-(4-{[7-(2-methoxypyrimidin-5-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
211 366.4 366 1-(4-{[7-(2-fluoropyridin-4-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
212 366.4 366 1-(4-{[7-(5-fluoropyridin-3-yl)-5H-pyrrolo[2,3- b]pyrazin-2-yl]amino}piperidin-1 -yl)prop-2-en-1 -one
Examples 213-229 were prepared as detailed in the Scheme below.
TFA/ DCM/ 30 °CZ 8 hrs;
MeOH/ NH3.H2O/ 30 °C/ 2 hrs
O
DMF/ DlEA/ 0 °C/ 0.5 hr;
°C/2hrs
Step 1 : O-Displacement. t-BuOK (33.6 mg, 300 pmol, 2.0 eq.) was dispensed to 8 5 mL reaction vials, followed by 600 μΙ (150 μιτιοΙ, 1.0 eq.) of 2-bromo-7-iodo-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine solution (0.25 M in THF), 600 μΙ (600 μιτιοΙ, 4.0 eq.) of tert-butyl 4-hydroxy piperidine-1-solution (1.0 M in THF). Vials were capped and shaken at 30 °C for 0.5 hr and then shaken at 80 °C for 16 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated 10 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 intermediates of step 1.
Step 2: Suzuki Coupling. The step 1 intermediates (0.15 M in dioxane) were dispensed to 8 mL reaction vials, followed by Cs2CO3 (97.7 mg, 300 μιτιοΙ, 3.0 eq.), 1 15 mL (150 μιτιοΙ, 1.0 eq.) of boronic acids/ boronate solution, and Pd(dppf)CI2 (11 mg, μιτιοΙ, 0.1 eq.) under N2 atmosphère. Vials were capped and shaken at 100 °C for 16 hrs. After reactions were deemed complété by LC-MS, 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 re20 duced pressure to obtain intermediates of step 2.
Step 3 & 4: De-protection (De-Boc & De-SEM). One and one-half mL of TFA/ DCM (1:4, v/v) solution was dispensed to vials containing intermediates of step 2. Vials were capped and shaken at 30 °C for 8 hrs. Solvents were evaporated under reduced pressure. Two mL of NH3-H2O/ MeOH (1:3, v/v) solution were dispensed to • 175 each vial. Vials were capped and shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure. Solvents were evaporated to obtain intermediates of step 3.
Step 5: Acylation. 750 pl of DMF were dispensed to vials containing intermediates of step 3, followed by DIEA (58 mg, 450 pmol, 3.0 eq.) and acyloyl chloride (27 mg,
300 pmol, 2.0 eq.) at 0 °C. Vials were kept at 0 °C for 0.5 hr, and then shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure. The residue was purified by prep. HPLC to give final product.
Ex MW MW (obs) Name
213 367.38 367 1-(4-{[7-(5-fluoropyridin-3-yl)-5H- pyrrolo[2,3-b]pyrazin-2- yl]oxy}piperidin-1 -yl)prop-2-en-1 -one
214 363.42 363 1-(4-{[7-(6-methylpyridin-3-yl)-5Hpyrrolo[2,3-b]pyrazin-2- y l]oxy}piperidin-1 -yl)prop-2-en-1 -one
215 350.38 350 1 -(4-{[7-(pyrimidin-5-yl)-5Hpyrrolo[2,3-b]pyrazin-2- y l]oxy}pipe rid in-1 -yl)prop-2-en-1 -one
216 374.4 374 5-{2-[(1-acryloylpiperidin-4-yl)oxy]-5Hpyrrolo[2,3-b]pyrazin-7-yl}pyridine-2carbonitrile
217 367.38 367 1-(4-{[7-(2-fluoropyridin-3-yl)-5H- pyrrolo[2,3-b]pyrazin-2- yl]oxy}piperidin-1 -yl)prop-2-en-1 -one
218 352.4 352 1 -(4-{[7-(1 -methyl-1 H-pyrazol-4-yl)- 5H-pyrrolo[2,3-b]pyrazin-2- yl]oxy}piperidin-1 -yl)prop-2-en-1 -one
219 380.41 380 1-(4-{[7-(2-methoxypyrimidin-5-yl)-5H- pyrrolo[2,3-b]pyrazin-2-
• 176
y l]oxy}piperid in-1 -yl)prop-2-en-1 -one
220 363.42 363 1-(4-{[7-(2-methylpyridin-4-yl)-5Hpyrrolo[2,3-b]pyrazin-2yl]oxy}pipe rid in-1 -yl)prop-2-en-1 -one
221 380.45 380 1-(4-{[7-(1,3,5-trimethyl-1 H-pyrazol-4- yl)-5H-pyrrolo[2,3-b]pyrazin-2yl]oxy}piperidin-1 -yl)prop-2-en-1 -one
222 367.38 367 1-(4-{[7-(2-fluoropyridin-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2- y l]oxy}piperidin-1 -yl)prop-2-en-1 -one
223 435.49 435 1-[4-({7-[2-(morpholin-4-yl)pyrimidin-5- yl]-5H-pyrrolo[2,3-b]pyrazin-2yl}oxy)piperidin-1 -yl]prop-2-en-1 -one
224 367.41 367 1 -(4-{[7-(3,5-dimethyl-1,2-oxazol-4-yl)- 5H-pyrrolo[2,3-b]pyrazin-2yl]oxy}pipe rid in-1 -yl)prop-2-en-1 -one
225 374.4 374 5-{2-[(1-acryloylpiperidin-4-yl)oxy]-5Hpyrrolo[2,3-b]pyrazin-7-yl}pyridine-3carbonitrile
226 367.38 367 1-(4-{[7-(6-fluoropyridin-3-yl)-5Hpyrrolo[2,3-b]pyrazin-2- y l]oxy}piperidin-1 -yl)prop-2-en-1 -one
227 405.46 405 3-{2-[(1-acryloylpiperidin-4-yl)oxy]-5Hpyrrolo[2,3-b]pyrazin-7-y!}-Nmethylbenzamide
228 367.38 367 1-(4-{[7-(3-fluoropyridin-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2- y l]oxy}pipe rid in-1 -yl)prop-2-en-1 -one
229 426.5 426 1-[4-({7-[4-(methylsulfonyl)phenyl]-5Hpyrrolo[2,3-b]pyrazin-2- y l}oxy) piperidin-1 -yl]prop-2-en-1 -one
177
Examples 230 -291 were prepared as detailed in the Scheme below.
For general primary amines (Group 1), step 1 conditions are DMF/DIEA/HBTU/30 °C/16hrs.
For primary amines with an cyano group (Group 2, step 1 conditions are DMF/DIEA/HATU/60 °C/16 hrs.
Step 1 : Amide formation.
Group 1 : Amines (150 pmol, 1.5 eq.) were placed in 8 mL reaction vials, followed by 300 μΙ of DMF, 500 μΙ of 2-((1 -(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethylsilyl) ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.2 M in DMF; 100 pmol, 1.0 eq.), DIEA (70 pl, 400 pmol, 4.0 eq.), and HBTU (170 pmol, 1.7 eq.) to each vial. Vials were capped and shaken at 30 °C for 16 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure. One mL of saturated NaHCO3 solution to each vial. The resulting mixture was extracted with EtOAc (2 mLx3). Organic layers were combined and dried with anhydrous Na2SO4. Filtration and évaporation under reduced pressure afforded crude intermediates which were used directly in the next step.
Group 2: Amines (150 pmol, 1.5 eq.) were placed in 8 mL reaction vials, followed by 500 pl of 2-((1 -(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.2 M in • 178
DMF; 100 pmol, 1.0 eq.), DIEA (70 μΙ, 400 μιτιοΙ, 4.0 eq.) and 300 μΙ of HATU solution (0.67 M in DMF; 200 pmol, 2.0 eq.). Vials were capped and shaken at 30 °C for 16 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure. One mL of saturated NaHCO3 solution to each vial. The resulting mixture was extracted with EtOAc (2 mLx3). Organic layers were combined and dried with anhydrous Na2SO4. Filtration and évaporation under reduced pressure afforded crude intermediates which were used directly in the next step. Step 2 & 3: De-Boc & De-SEM. One and one-half mL of TFA/ DCM (1:4, v/v) were dispensed to vials containing intermediates of step 1. Vials were capped and shak10 en at 30 °C for 2 hrs. Solvents were evaporated under reduced pressure. One and two-tenths mL of NH3-H2O/ MeOH (1:2, v/v) were then dispensed to each vial. Vials were capped and shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to obtain intermediates of step 2/3, which were used directly for next step.
Step 4: Acylation: One mL of saturated NaHCO3 solution was dispensed to the vials containing intermediates of step 2/3, followed by 1 mL of EtOAc and acryloyl chloride (200 pmol, 2.0 eq.) to each vial. Vials were capped and shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to obtain residues which were purified by prep. HPLC to give final 20 product.
Ex MW MW (obs) Name
230 356.43 357 2-[(1-acryloylpiperidin-4-yl)amino]-N-(propan-2-yl)-5H- pyrrolo[2,3-b]pyrazine-7-carboxamide
231 398.47 399 2-[( 1 -acryloylpiperidin-4-yl)amino]-N-[(1 hydroxycyclobutyl)methyl]-5H-pyrroIo[2,3-b]pyrazine-7carboxamide
232 412.49 413 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 - hydroxycyclopentyl)methyl]-5H-pyrrolo[2,3-b]pyrazine- 7-carboxamide
233 422.41 423 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 R,2R)-2- (trifluoromethyl)cyclopropyl]-5H-pyrrolo[2,3-b]pyrazine-
Φ 179
7-carboxamide
234 418.45 419 2-[(1 -acryloylpiperidin-4-yl)amino]-N-(2,2difluorocyclopentyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
235 426.52 428 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 -hydroxy-3methylcyclopentyl)methyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
236 432.48 433 2-[(1-acryloylpiperidin-4-yl)amino]-N-(3,3difluorocyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
237 400.46 401 2-[( 1 -acryloylpiperidin-4-yl)amino]-N-[(1 R,2R)-2fluorocyclopentyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
238 418.45 419 2-[(1-acryloylpiperidin-4-yl)amino]-N-[(3,3- difluorocyclobutyl)methyl]-5H-pyrrolo[2,3-b]pyrazine-7- carboxamide
239 426.52 428 2- [(1 -acryloylpiperidin-4-yl)amino]-N-{[(3R)-1 -hydroxy- 3- methylcyclopentyl]methyl}-5H-pyrrolo[2,3-b]pyrazine- 7-carboxamide
240 424.43 425 2-[(1-acryloylpiperidin-4-yl)amino]-N-(4,4,4- trifluorobutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
241 438.45 439 2-[(1-acryloylpiperidin-4-yl)amino]-N-[(2R)-4,4,4trifluoro-2-methylbutyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
242 381.44 382 2-[(1-acryloylpiperidin-4-yl)amino]-N-(3-cyanopropyl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
243 386.43 387 2-[(1-acryloylpiperidin-4-yl)amino]-N-(3fluorocyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
244 400.46 401 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 S,3R)-3- fluorocyclopentyl]-5H-pyrrolo[2,3-b]pyrazine-7-
180
carboxamide
245 404.42 405 2-[(1-acryloylpiperidin-4-yl)amino]-N-(3,3difluorocyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
246 410.4 411 2-[(1-acryioylpiperidin-4-yl)amino]-N-(3,3,3trifluoropropyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
247 400.46 401 2-[( 1 -acryloylpiperidin-4-yl)amino]-N-[(1 S,3S)-3fluorocyclopentyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
248 468.48 469 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(2R,3R)-1,1,1trifluoro-2-hydroxy-4-methylpentan-3-yl]-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
249 462.5 463 2-[( 1 -acryloylpiperidin-4-yl)amino]-N-[(3,3-difluoro-1 hydroxycyclohexyl)methyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
250 444.51 446 2-[(1 -acryloylpiperidin-4-yl)amino]-N-{[(2R)-2-fluoro-1 hydroxycyclohexyl]methyl}-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
251 400.46 401 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 R,2S)-2fluorocyclopentyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
252 468.48 469 2-[(1-acryloylpiperidin-4-yl)amino]-N-[(2S,3S)-1,1,1trifluoro-2-hydroxy-4-methylpentan-3-yl]-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
251b 426.52 428 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[1 -(1 hydroxycyclobutyl)propyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
252b 462.5 463 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(4,4-difluoro-1 hydroxycyclohexyl)methyI]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
• 181
253 438.45 439 2-[(1 -acryloylpiperidin-4-yl)amino]-N-(4,4,4-trifluoro-2- methylbutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
254 444.51 446 2-[(1 -acryloylpiperidin-4-yl)amino]-N-{[(2S)-2-fluoro-1 hydroxycyclohexyl]methyl}-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
255 400.46 401 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 R,3S)-3fluorocyclopentyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
256 432.48 433 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2,2difluorocyclohexyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
257 506.61 508 2-[(1 -acryloylpiperidin-4-yl)amino]-N-{(2S)-1 -[(2S)-2cyanopyrrolidin-1 -yl]-3,3-dimethyl-1 -oxobutan-2-yl}-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide
258 492.58 494 2-[(1 -acryloylpiperidin-4-yI)amino]-N-{(2S)-1 -[(2S)-2cyanopyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide
259 418.45 419 2-[(1-acryloylpiperidin-4-yl)amino]-N-(3,3difluorocyclopentyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
260 451.58 453 2-[(1-acryloylpiperidin-4-yI)amino]-N-(8-cyanooctyl)-5H- pyrrolo[2,3-b]pyrazine-7-carboxamide
261 367.41 368 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2-cyanoethyl)-5H- pyrrolo[2,3-b]pyrazine-7-carboxamide
262 435.53 437 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(1 S,3S)-3(cyanomethyl)cyclohexyl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
263 395.47 396 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(2R)-1 cyanobutan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
264 438.49 439 2-[(1 -acryloylpiperidin-4-yl)amino]-N-{(2S)-1 -[(2-
182
cyanoethyl)amino]-1-oxopropan-2-yl}-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide
Examples 265 - 289 were prepared according to the scheme and procedure for Examples 230 -291. (Group 1 amines)
Ex Mw Mwobs Name
265 356.43 357 2-[(1-acryloylpiperidin-4-yl)amino]-N(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
266 370.46 371 2-[(1-acryloylpiperidin-4-yl)amino]-N-tertbutyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
267 384.48 385 2-[(1-acryloylpiperidin-4-yl)amino]-N-[(2S)pentan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
268 386.46 387 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(2R)-1 methoxypropan-2-yl]-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
269 370.46 371 2-[(1-acryloylpiperidin-4-yl)amino]-N-butyl- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
270 396.5 397 2-[(1-acryloylpiperidin-4-yl)amino]-N(cyclopentyImethyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
271 384.48 385 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2,2dimethylpropyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
272 370.46 371 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2methylpropyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
273 396.37 397 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2,2,2trifluoroethyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
183
274 384.48 385 2-[(1-acryloylpiperidin-4-yl)amino]-N-[(2R)pentan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
275 372.43 373 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2methoxyethyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
276 384.48 385 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2methylbutan-2-yl)-5H-pyrrolo[2,3-b]pyrazine7-carboxamide
277 386.46 387 2-[(1 -acryloylpiperidin-4-yl)amino]-N-[(2S)-1 methoxypropan-2-yl]-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
278 396.5 397 2-[(1-acryloylpiperidin-4-yl)amino]-Ncyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
279 370.46 371 2-[(1-acryloylpiperidin-4-yl)amino]-N-methylN-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
280 368.44 369 2-[(1-acryloylpiperidin-4-yl)amino]-Ncyclobutyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
281 380.45 381 2-[(1-acryloylpiperidin-4-yl)amino]-N(bicyclo[1.1.1 ]pent-1 -yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
282 392.41 393 2-[(1-acryloylpiperidin-4-yl)amino]-N-(2,2difluoropropyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
283 382.47 383 2-[(1-acryloylpiperidin-4-yl)amino]-Ncyclopentyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
284 354.41 355 1 -(4-{[7-(azetidin-1 -ylcarbonyl)-5H-
184
pyrrolo[2,3-b]pyrazin-2-yl]amino}piperidin-1- yl)prop-2-en-1-one
285 370.46 371 2-[(1-acryloylpiperidin-4-yl)amino]-N-[(2S)butan-2-yl]-5H-pyrroIo[2,3-b]pyrazine-7carboxamide
286 368.44 369 2-[(1-acryloylpiperidin-4-yl)amino]-Ncyclopropyl-N-methyl-5H-pyrrolo[2,3b]pyrazine-7-carboxamide
287 368.44 369 1 -(4-{[7-(pyrrolidin-1 -ylcarbonyl)-5Hpyrrolo[2,3-b]pyrazin-2-yl]amino}piperidin-1yl)prop-2-en-1-one
288 382.47 383 2-[(1 -acryloylpiperidin-4-yl)amino]-N-(1 cyclopropylethyl)-5H-pyrrolo[2,3-b]pyrazine7-carboxamide
289 370.46 371 2-[(1-acryloyIpiperidin-4-yl)amino]-N-[(2R)butan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
Examples 290 -328 were prepared as detailed in the Scheme below.
1. TFA/ DCM/ 30 °C/4hrs;
2. NH3.H2O/ MeOH/ 30 °C/ 2 hrs
0'
NH
EtOAc/ NaHCO3/ DIEA/ stir/ 30 °C/ 2 hrs
0' φ 185
Group 1 : For general amines, conditions for Step 1 are dioxane/Pd2(dba)3/Xphos/Cs2CO3/N2/120 °C/16 hrs. 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 : N-displacement. Group 1 : Amines (195 pmol, 1.5 eq.) were placed in 8 ml reaction vials. One thousand μΙ of 2-bromo-N-isopropyl-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.13 M in dioxane; 130 pmol, 1.0 eq.) solution was dispensed to each vial, followed by Cs2CO3 (81.9 mg, 260 pmol, 2.0 eq.), Pd2(dba)3 (11.9 mg, 13 μιτιοΙ, 0.1 eq.) and Xphos (6.2 10 mg, 13 μιτιοΙ, 0.1 eq.) under N2. Vials were capped and shaken at 120 °C for 16 hrs.
After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to obtain 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 give crude intermediates from 15 step 1, which were used directly for the next step.
Group 2: Amines (195 pmol, 1.5 eq.) were placed in 8 ml reaction vials. One thousand μΙ of 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide (0.1 M in toluene; 130 μιτιοΙ, 1.0 eq.) solution to each vial, followed by t-BuONa (24.9 mg, 260 pmol, 2.0 eq.) and Pd2(dba)3 (11.9 mg, 13 μιηοΙ, 20 0.1 eq.) and Ruphos (6.0 mg, 13 μιτιοΙ, 0.1 eq.) under N2. Vials were capped and shaken at 65 °C for 2 days. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to obtain 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 give 25 crude intermediates from step 1, which were used directly for the next step.
Step 2&3 : De-protection (De-Boc & De-SEM). One mL of TFA/ DCM (1:7, v/v) solution was dispensed to vials containing intermediates of step 1. Vials were capped and shaken at 30 °C for 4 hrs. Solvents were evaporated under reduced pressure. One and two-tenths mL of NH3-H2O/ MeOH (1:3, v/v) solution were dispensed to 30 each vial. Vials were capped and shaken at 30 °C for 2 hrs. After reactions were deemed complété by LC-MS, solvents were evaporated under reduced pressure to obtain the intermediates of step 2.
186
Step 4: Acylation. Five hundred (500) μΙ of EtOAc were dispensed to each vial containing intermediates of Step 2 (130 pmol, 1.0 eq.), followed by 500 μΙ of saturated NaHCO3 solution, acryloyl chloride (195 pmol, 1.5 eq.), and DIEA (390 pmol, 3.0 eq.). Vials were capped and stirred at 30 °C for 2 hrs. After reactions were deemed 5 complété by LC-MS, solvents were evaporated under reduced pressure to obtain residues which were purified by prep. HPLC to obtain final products.
Ex MW MW (obs) Name
290 342.4 343 2-(4-acryloylpiperazin-1-yl)-N-(propan-2-yl)-5H- pyrrolo[2,3-b]pyrazine-7-carboxamide
291 374.42 375 2-{[(3R,4R)-1-acryloyl-3-fluoropiperidin-4-yl]amino}-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
292 368.44 369 2-[(1 R,4R)-5-acryloyl-2,5-diazabicyclo[2.2.2]oct-2-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
293 370.46 371 2-(4-acryloyl-3,3-dimethylpiperazin-1-yl)-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
294 384.48 385 2-[(3R)-4-acryloyl-3-(propan-2-yl)piperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
295 356.43 357 2-[(3S)-4-acryloyl-3-methyIpiperazin-1-yl]-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
296 368.44 369 2-(2-acryloyl-2,6-diazaspiro[3.4]oct-6-yl)-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
297 356.43 357 2-[(2S)-4-acryloyl-2-methylpiperazin-1-yl]-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
298 370.46 371 2-[(2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
299 370.46 371 2-[(3S)-4-acryloyl-3-ethylpiperazin-1-yl]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
300 354.41 355 2-[(1 S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1 ]h ept-2-y I]- N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
187
301 368.44 369 2-[( 1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
302 386.46 387 2-{[(3S,4R)-1-acryloyl-3-methoxypiperidin-4-yl]amino}- N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
303 398.51 400 2-[(3S)-4-acryloyl-3-(2-methylpropyI)piperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
304 368.44 369 2-[(1S,4S)-5-acryloyl·2l5-diazabicyclo[2.2.2]oct-2-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
305 386.46 387 2-{[(3R,4R)-1-acryloyl-3-methoxypiperidin-4-yl]amino}- N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
306 370.46 371 2-[(3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
307 356.43 357 2-[(2R)-4-acryloyl-2-methylpiperazin-1-yl]-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
308 368.44 369 2-(5-acryloy[-2,5-diazabicyclo[2.2.2]oct-2-yl)-N-(propan- 2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
309 382.47 383 2-[(2R)-4-acryloyl-2-cyclopropylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
310 354.41 355 2-(6-acryloyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
311 370.46 371 2-[(3R)-4-acryloyl-3-ethylpiperazin-1-yl]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
312 370.46 371 2-(4-acryloyl-2,2-dimethylpiperazin-1-yl)-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
313 368.44 369 2-(7-acryloyl-4,7-diazaspiro[2.5]oct-4-yl)-N-(propan-2- yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
314 382.47 383 2-[(2S)-4-acryloyl-2-cyclopropylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
315 382.47 383 2-{[(3-endo)-8-acryloyl-8-azabicyclo[3.2.1 ]oct-3-
yl]amino}-N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7- carboxamide
316 370.46 371 2-[(2S,5S)-4-acryloyl-2,5-dimethylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
317 386.46 387 2-{[(3R,4S)-1-acryloyl-3-methoxypiperidin-4-yl]amino}- N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
318 370.46 371 2-[(1-acryloyl-4-methylpiperidin-4-yl)amino]-N-(propan- 2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
319 382.47 383 2-{[(3-exo)-8-acryloyl-8-azabicyclo[3.2.1]oct-3-yl]amino}- N-(propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide
320 374.42 375 2-{[(3S,4R)-1-acryloyl-3-fluoropiperidin-4-yl]amino}-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
321 370.46 371 2-[(2R)-4-acryloyl-2-ethylpiperazin-1-yl]-N-(propan-2-yl)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
322 368.44 369 2-(6-acryloyl-1-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N- (propan-2-yI)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
323 384.48 385 2-[(2S)-4-acryloyl-2-(propan-2-yl)piperazin-1 -yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
324 384.44 385 2-(7-acryloyl-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
325 370.46 371 2-[(2S)-4-acryloyl-2-ethylpiperazin-1-yl]-N-(propan-2-yI)- 5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
326 370.46 371 2-[(2R,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
327 370.46 371 2-[(2R,5S)-4-acryloyl-2,5-dimethylpiperazin-1-yl]-N- (propan-2-yI)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
328 370.46 371 2-[(2R,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl]-N- (propan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
189
Préparation 329: 2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3bjpyrazine.
Prepared as described in WO2010/063634.
Préparation 330: 2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide.
Prepared as described in Journal of Médicinal Chemistry, 56(4), 1677-1692 (2013). Préparation 331: 2-Bromo-N-(tert-butyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide.
Prepared as described in Journal of Médicinal Chemistry, 56(4), 1677-1692 (2013). Préparation 332: 2-ΒΐΌΓηο-5-((2-(ί:πιηθΙΐΊνΐ3ΪΙνΙ)βΙΗοχν)ΓηβΙΐΊνΙ)-5Η-ρνΐΎθΙο[2,3b]pyrazine-7-carboxylic acid.
Prepared as described in Journal of Médicinal Chemistry, 56(4), 1677-1692 (2013). Préparation 333: 2-Bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2,3-b]pyrazine.
Step 1.2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine. To a solution of 2-bromo-5Hpyrrolo[2,3-b]pyrazine (8 g, 40.4 mmol) in DMF (160 mL) was added Niodosuccinimide (11.8 g, 3.6 mmol) at room température, and stirred for 1 h. TLC (Petroleum ether; EtOAc, 2:1) indicated the reaction was completed. 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 give 2-bromo-7-iodo-5Hpyrrolo[2,3-b]pyrazine (26.1 g, 100 %) as brown solid (containing some DMF).
Step 2. 2-Bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3bjpyrazine. 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 dropwise, and stirred at this température for 20 min. Then, sem-CI (16.14 g, 96.67 mmol) was added dropwise at 0 oC, and warmed to room température for 1 hour. TLC (petroleum ether/EtOAc, 2:1) indicated the reaction was complété. 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 give product (13 g, 36 %) as a yellow solid. 1H NMR (400MHz, CDCI3) 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.
Préparation 334: Methyl 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H5 pyrrolo[2,3-b]pyrazine-7-carboxylate.
formaldéhyde NaOH/Dioxane-H20
NaOH
THF
Jones reagent/Acetone
sulphamic acid/dioxane
NaCIO2, KH2PO4/H2O
SOCI2
MeOH
NaH/DMF
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) 10 was added dropwise aqueous NaOH (590 mL, 1175 mmol, 2 M) at room température, then formaldéhyde (481 mL, 5884 mmol, 37% aqueous solution) was added to the mixture at room température. After that, the resulting mixture was stirred at room température for 18 hours. TLC (petroleum ether/EtOAc, 2:1) showed starting material was consumed completely. The three batches were combined for workup togeth15 er. The reaction mixture was evaporated to remove most of solvent. The residue was neutralized with 2 M HCl and extracted with EtOAc (1 L x 3), the combined organic layers were washed water (1 mL) and brine (1 mL), dried over Na2SO4 and concentrated to dryness, which was triturated with MTBE to give (2-bromo-5H-pyrrolo[2,3b]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 (2bromo-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 température. After the addition, the resulting mixture was stirred at room tem
191 perature for 18 hours. HNMR showed about 18% starting material was remained. The reaction mixture was stirred at room température for 48 hours. HNMR showed staring material was consumed completely. The three batches were combined for workup together. The reaction mixture was evaporated to remove most of THF. The aqueous residue was acidified to pH= 3~4 with 2M 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 give (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7yl)methanol (381 g, 96%) as s yellow solid, which was used for next step without purification
Step 3. 2-Bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. To a suspension of (2bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)methanol (127 g, 562 mmol) in acetone (2.5 L) was added dropwise Jones reagent (253 mL, 674 mol?2.67 M) below 10 °C. After the addition, the resulting mixture was stirred at room température for 50 min, which time suspension became clean and then brown solid was precipitated. The three batches were combined for workup together. The reaction mixture was quenched with i-PrOH (60 mL) and filtered, the filter cake was washed with acetone (1 L x2), the combined filtrate was evaporated to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7carbaldehyde (320 g, 84.4%) as a yellow solid. (A stock of Jones reagent (2.67 M) was prepared by carefully adding concentrated H2SO4 (184 mL) to CrO3 (213.6 g) then diluting to 800 mL with H2O.)
Step 4. 2-Bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (75 g, 333 mmol) and sulphamic acid (163 g, 1667 mmol) in dioxane-H2O (1.5 L, 4:1, v/v) was added dropwise a solution of NaCIO2 (36.4 g, 400 mmol) and KH2PO4 (227 g, 1667 mmol) in H2O (0.5 L) over a period of 40 min below 0 °C. After the addition, the resulting mixture was stirred at room température for 18 hours. TLC (petroleum ether/EtOAc, 1:1) showed the starting material was consumed completely. The two batches were combined for workup together. The reaction mixture was partitioned between EtOAc (2 L) and water (1 L), further 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 give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 g, 75%) as a yellow solid.
192
Step 5. Methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate. To a 0 C suspension of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (145 g, 602 mmol) in MeOH (1.5 L) was added dropwise SOCI2 (93 g, 781 mmol) over a period of 40 min. after the addition, the resulting mixture was heated to reflux for 4 hours, which time suspended solution became clear and then yellow solid was precipitated. TLC (petroleum ether/EtOAc, 1:1) showed starting material was consumed completely. The reaction mixture was evaporated to dryness, which was triturated with MTBE to give methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (109 g, 71%) as a yellow solid.
Step 6. Methyl 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxylate. To a 0 °C suspension of NaH (11.9 g, 297 mmol, 60% in oil) in DMF (500 mL) was added methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7carboxylate (55 g, 228 mmol) in portions. After the addition, the reaction mixture was stirred at 0 °C for 10 min. Then SEMCI (49.3 g, 251 mmol) was added dropwise to the mixture below 0 °C. After that, the resulting mixture was stirred at room température for 3 hours. TLC (petroleum ether/EtOAc, 1:1) showed starting material was consumed completely. The two batches were combined for workup together. The reaction mixture was poured into ice-water (1.5 L), then extracted with EtOAc (1.5 Lx3). 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 give methyl 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxylate (105 g, 59.7 %) as a white solid. 1H NMR (400 MHz, DMSO-de) 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-((5 W-Pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-1 yl)prop-2-en-1 -one.
193
Ύη - 2-bromo-5Hpyrrolo[2,3-ù]pyrazine TrCI, DMF CSCO3 khTN Tr Uh2 MePhos, Pd2(dba)3 sodium tert-butoxide V—ni dioxane £ o=Ko4 tr
2.0 M HCI/ether HN'7 Tr 0 Λ DIEA (5.0 Equiv) d-CHCI3 (0.036 M) 2°c - 22°C, 60 min H <ΖΎΝΎΝΎΛ TFA, 22°C, '[/'N 16 h ?
Step 1. 2-Bromo-5-trityl-5/7-pyrrolo[2,3-b]pyrazine. At 40 °C, a solution of 2-bromo5H-pyrrolo[2,3-b]pyrazine (725 mg, 3.66 mmol) and césium 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 ambient température and poured onto water (150 mL). The mixture was filtered and the filter cake was triturated with water (250 mL) for 1 hour. The solid was isolated and recrystallized from hot éthanol to afford 2-bromo-5-trityl-5A/-pyrrolo[2,3-b]pyrazine (750 mg, 52%) as a colorless crystalline solid. LC/MS (M+H) 440.16.
Step 2. (R)-tert-Butyl 3-((5-trityl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidine-1carboxylate. Under nitrogen, a solution of (R)-tert-butyl 3-aminopyrrolidine-1carboxylate (850 mg, 4.5 mmol), 2-bromo-5-trityl-5/7-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 back extracted with EtOAc (2 x 50 mL). Organic layers were combined, dried over sodium sulfate, filtered, concentrated in vacuo, and purified via column chromatography to afford (R)-tert-butyl 3-((5-trityl-5H-pyrrolo[2,3-b]pyrazin-2yl)amino)pyrrolidine-1-carboxylate (520 mg, 42%) as a colorless solid. LC/MS (M+H) 546.39.
Step 3. (R)-/V-(Pyrrolidin-3-yl)-5-trityl-5/7-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 • 194 (250 mg, 0.46 mmol) was treated with 2.0 M HCI/ether (10 mL) and sonicated for 15 minutes. The reaction mixture was then stirred for 3 hours at ambient température and the solvent was removed in vacuo to afford (R)-A/-(pyrrolidin-3-yl)-5-trityl-5Hpyrrolo[2,3-b]pyrazin-2-amine (221 mg, 100%) as the HCl sait. LC/MS (M - H)
446.33.
Step 4. (R)-1-(3-((5-Trityl-5/7-pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-1-yl)prop -2en-1-one. A solution of (R)-/V-(pyrrolidin-3-yl)-5-trityl-5/7-pyrrolo[2,3-b]pyrazin-2amine (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 a solu10 tion of acrylic chloride (0.38 mL, 0.47 mmol) in anhydrous chloroform (2.0 mL). After minutes, the reaction mixture was warmed to ambient température 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 back extracted with chloroform (2x10 mL). Organic layers were combined, dried over magnésium sulfate, filtered, concentrated in vacuo and purified via column chromatography to afford (R)-1-(3-((5-trityl-5/7-pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-1yl)prop -2-en-1-one (221 mg, 97%) as a colorless solid. LC/MS (M+H) 500.35.
Step 5. (R)-1 -(3-((5/7-Pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-1 -yl)prop-2-en-1 one. A solution of (R)-1-(3-((5-trityl-5/7-pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-120 yl)prop -2-en-1-one (221 mg, 0.5 mmol) in TFA (4.9 mL) was allowed to stir at ambient température for 22 hours. Concentrated in vacuo and purified via column chromatography to afford (R)-1-(3-((5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-1yl)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-((5 W-Pyrrolo[2,3-b]pyrazin-2-yl)amino)pyrrolidin-1 yl)prop-2-en-1 -one.
Prepared as in Example 173, except using (S)-tert-butyl 3-aminopyrrolidine-1carboxylate in step 2.
195
LC/MS (M+H) 258.3. Ή 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, 1 H), 1.19-1.14 (m, 1 H).
Example 337:1-(3-((5H-Pyrrolo[2,3-b]pyrazin-2-yl)amîno)azetidin-1-yl)prop-2en-1-one.
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-de) δ 11.47 (s,1H), 7.62 (s,1H), 7.46 (s,1 H), 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 -Acryloylpiperidîn-4-yl)oxy)-N-(tert-butyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide.
Boc
OH
Pd2(dba)3,dppf
Cs2CO3,toluene
TFA/DCM
acryl-CI, DIPEA
THF-H2O
Step 1. tert-Butyl 4-((7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2,3-b]pyrazin-2-yl)oxy)piperidine-1-carboxylate. To a solution of 2-bromo-N(tert-butyl)-5-((2-(trimethylsilyl)ethoxy) methyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide (200 mg, 0.468 mmol) in 10 mL of toluene was added tert-butyl 4hydroxypiperidine-1-carboxylate (188 mg, 0.935 mmol) and Cs2CO3 (305 mg, 0.935 mmol) at room température. 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) was added quickly and the flaks degassed and purged N2 several times as before. After addi • 196 tion, the mixture was heated to 100 °C overnight. TLC (petroleum ether: EtOAc, 4:1) showed 2-bromo-N-(tert-butyl)-5-((2-(trimethylsilyl) ethoxy)methyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide (was consumed completely. The resulting mixture was cooled to ambient température 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 from 10:1 to 1:2 ) to give tert-butyl 4-((7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[2,3-b]pyrazin-2-yl)oxy)piperidine-1-carboxylate ( 160 mg, 62.7%) as an oil.
Step 2. N-(tert-Butyl)-5-(hydroxymethyl)-2-(piperidin-4-yloxy)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide. tert-Butyl 4-((7-(tert-butylcarbamoyl)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)piperidine-1carboxylate (160 mg, 0.29 mmol) was dissolved in a mixed solution of TFA/DCM (1 mL/7 mL, 1:7, v/v) at room température. The mixture was stirred at room tempera15 ture overnight. LC-MS showed most of tert-butyl 4-((7-(tert-butylcarbamoyl)-5-((2(trimethylsilyI)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)piperidine-1carboxylate was consumed. The resulting mixture was concentrated in vacuo, and chased with DCM several times to give the crude TFA sait of N-(tert-butyl)-5(hydroxymethyl)-2-(piperidin-4-yloxy)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (200 mg, -0.29 mmol) as oil which was used to next step without further workup. LC/MS (M+H) 348.2.
Step 3. N-(tert-Butyl)-2-(piperidin-4-yloxy)-5H-pyrroIo[2,3-b]pyrazine-7-carboxamide. The TFA sait of N-(tert-butyl)-5-(hydroxymethyl)-2-(piperidin-4-yloxy)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide (200 mg, -0.29 mmol) was dissolved in a mixed solution of NH3«H2O/MeOH (1.8 mL/5.4 mL, 1:3, v/v) at room température. The mixture was stirred at room température for 2h. TLC (DCM/MeOH,10:1) showed starting material was consumed. The resulting mixture was evaporated in vacuo, and chased with DCM several times to give a crude N-(tert-butyl)-2-(piperidin-4-yloxy)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide (160 mg, -0.29 mmol) as an oil which was used to next step without further workup. LC/MS (M+H) 318.2.
Step 4. 2-((1 -Acryloylpiperidin-4-yl)oxy)-N-(tert-butyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide. To a solution of N-(tert-butyl)-2-(piperidin-4-yloxy)-5H-pyrrolo[2,3 ~ 197
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 température was added DI PEA (56 mg, 0.435 mmol) dropwise. The mixture was then cooled to 0 °C and acryloyl chloride (26 mg, 0.29 mmol) was added dropwise. After addition, the mixture was stirred at 0 °C for 2h.
TLC (DCM/MeOH, 10:1) showed the reaction was complété. To the mixture was added 10 mL of H2O, 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 via prepHPLC to give 2-((1 -acryloylpiperidin-4-yl)oxy)-N-(tert-butyl)-5H-pyrrolo[2,3-
b]pyrazine-7-carboxamide (overall 30 mg, 30% of 3 steps) as a white solid. LC/MS (M+H) 372.2. 1H NMR (400 MHz, DMSO-cfe) 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[2,3b]pyrazine-7-carboxamide.
Prepared as in Example 176:((1-acryloyIpiperidin-4-yl)oxy)-N-(tert-butyl)-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide, except using 2-bromo-N-isopropyl-5-((2(trimeth.yl-si)yl)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-c/6) 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-methylpïperidin-4-yl)amino)-N-(tertbutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Example 342: 2-(((2R,4R)-1 -Acryloyl-2-methylpiperidin-4-yl)amino)-N-(tertbutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Step 1. (2S,4S)-tert-Butyl 4-((7-(tert-butyIcarbamoyl)-5-((230 (trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yI)amino)-2methylpiperidine-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,
198
0,58 mmol) in 15 mL of toluene was added (2S,4S)-tert-butyl 4-amino-2methylpiperidine-1-carboxylate (250 mg, 1.17 mmol) and CS2CO3 (381 mg, 1.17 mmol) at room température. 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) was added and the flask degassed and purged N2 several times as before. The mixture was heated to 100 °C overnight. TLC (petroleum ether/EtOAc, 2:1) showed starting material was consumed completely. The resulting mixture was cooled to ambient température 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 were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by chromatography (silica, petroleum ether/EtOAc from 10:1 to 1:2) to give (2S,4S)-tert-butyl 4-((7-(tertbutylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2yl)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[2,3b]pyrazine-7-carboxamide. (2S,4S)-tert-Butyl 4-((7-(tert-butylcarbamoyl)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)-2methylpiperidine-1 -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 température. The mixture was .stirred at room température overnight. LC-MS indicated starting material consumed. The resulting mixture was evaporated in vacuo, and chased with DCM several times to give the crude TFA sait of N-(tert-butyl)-5-(hydroxymethyl)-2-(((2S,4S)-2methylpiperidin-4-yl)amino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (500 mg, -0.616 mmol) as an oil which was used to next step without further workup. LC/MS (M+H) 361.2.
The TFA sait of N-(tert-butyl)-5-(hydroxymethyl)-2-(((2S,4S)-2-methylpiperidin-4yl)amino)-5H-pyrrolo[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 température. The mixture was stirred at room température for 2h. LC-MS showed starting material was consumed. The resulting mixture was evaporated in vacuo, and chased with DCM several times to give a crude N-(tert-butyl)-2-(((2S,4S)-2methylpiperidin-4-yl)amino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (500 mg,
199
-0.616 mmol) as an oïl, which was used to next step without further workup. LC/MS (M+H) 331.2.
Step 3. rac- 2-(((2S,4S)-1-Acryloyl-2-methylpiperidin-4-yl)amino)-N-(tert-butyl)-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide. To a solution of N-(tert-butyl)-2-(((2S,4S)-2methylpiperidin-4-yl)amino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (500 mg, -0.616 mmol) in a mixed solution of THF/H2O (8 mL, 1:1, v/v) at room température was added DIPEA (232 mg, 1.8 mmol) dropwise. The mixture was then cooled to 0 °C and acryloyl chloride (108.6 mg, 1.2 mmol) was added dropwise at 0 °C. After addition, the mixture was warmed to ambient température and stirred for 2h. TLC (DCM/MeOH, 10:1) showed the reaction was complété. 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 via prep-HPLC to give rac- 2(((2S,4S)-1-acryloyl-2-methyl-piperidin-4-yl)amino)-N-(tert-butyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide (overall 32 mg, 14% of 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), 7.9997.991 (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)-5Hpyrrolo[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[2,3b]pyrazine-7-carboxamide was purified by chiral SFC (21x250 ChiralPak IA, CO2/EtOH) to give two peaks, arbitrarily assigned absolute stereochemistry.
Peak 1: 2-(((2S,4S)-1-AcryIoyl-2-methylpiperidin-4-yl)amino)-N-(tert-butyl)-5Hpyrrolo[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)-5Hpyrrolo[2,3-b]pyrazine-7-carboxamide. LC/MS (M+H) 385.2.
Example 343: 2-((1 -Acryloylpiperidin-4-yl)amino)-N-(prop-2-yn-1 -yl)-5Hpyrrolo[2,3-b]pyrazine-717901
200 carboxamide. Step 1. tert-Butyl 4-((7-(prop-2-yn-1 -ylcarbamoyl)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)piperidine-1carboxylate . To a stirred solution of compound 2-((1 -(tert-butoxycarbonyl)piperidin-
4-yl)amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7carboxylic acid (3 g, 6.1 mmol) in 50 mL of DMF was added HATU(2.78 g, 7.32 mmol) at 0 °C. After addition, the mixture was stirred at room température for 20 min. Then compound prop-2-yn-1-amine (0.67 g, 12.2 mmol) and Et3N (1.23 g, 12.2 mmol) was added separately. After addition, the mixture was stirred at room température for 3hrs. LC-MS indicated acid was consumed completely. 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 solvent removed in vacuo. The crude product was purified by column chromatography (silica, EtOAc/Hep) to give tert-butyl 4-((7-(prop-2-yn-1-ylcarbamoyl)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)piperidine-1carboxylate (2.7 g, 83%) as a yellow solid.
1H NMR (400 MHz, CHCI3-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-yn-1 -yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide. To a solution of tert-butyl 4-((7-(prop-2-yn-1ylcarbamoyl)-5-((2-(trimethylsilyl)ethox-y)methyl)-5H-pyrroio[2,3-b]pyrazin-2yl)amino)piperidine-1 -carboxylate (2.2 g, 4.16 mmol) in anhydrous DCM (10 mL) was cooled to -5 oC in ice-methanol bath. Then TFA (20 mL) was added dropwise. After addition, the cooled bath was removed and the resulting solution was stirred at room température for 2hrs. LC-MS indicated the reaction was complété. 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 give the TFA sait of 5-(hydroxymethyl)-2-(piperidin-4-ylamino)-N-(prop-2yn-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.
201
Step 3. 2-(piperidin-4-ylamino)-N-(prop-2-yn-1 -yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide. To a stirred solution of TFA sait of 5-(hydroxymethyl)-2-(piperidin-4ylamino)-N-(prop-2-yn-1 -yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (3.57 g, crude) in anhydrous MeOH (20 mL) was added K2CO3 (5.7 g, 41.6 mmol) in portions at room température. After addition, the resulting mixture was stirred at room température for 2hrs. LC-MS indicated the reaction was complété. The reaction suspension was filtered, and the filtrate was concentrated to give crude 2-(piperidin-4-ylamino)N-(prop-2-yn-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (4.47 g, >100%). LC/MS (M+H) = 299.2
Step 4. 2-((1 -acryloylpiperidin-4-yl)amino)-N-(prop-2-yn-1 -yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide.
To a solution of 2-(piperidin-4-ylamino)-N-(prop-2-yn-1-yl)-5H-pyrrolo[2,3-b]pyrazine7-carboxamide (4.49 g, crude, 4.16 mmol) in THF/H2O (20 mL/20 mL, V/V=1:1) was added DIPEA (2.7mL, 20.8 mmol) dropwise. The resulting mixture was cooled to 0 °C and acryloyl chloride (376 mg, 4.16 mmol) was added dropwise at 0 °C. After addition, the mixture was stirred at 0 oC for 1h. LC-MS indicated -20% of starting material was remaining. Additional acryloyl chloride (376 mg) was added at 0-5 °C and then stirred at the température for 0.5h. LC-MS indicated most of 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 via prep-HPLC to give 2-((1-acryloylpiperidin-4-yl)amino)-N-(prop-2-yn-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7carboxamide (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). Préparation 344: 2-((1 -(tert-Butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trîmethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Step 1. methyl 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3b]pyrazine-7-carboxylate. A mixture of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ( 50g, 134.8mmol), K2CO3 (28g,
202
202.2mmol) and iodomethane( 34.5g, 242.9mmol) in DMF( 1200mL) was heated at 35 °C for 2h. The mixture was cooled to room température, diluted with water (500mL) and the mixture extracted with ethyl acetate( 800mL x 3). The combined organic phases were washed with water (2000mL x 1) and brine (1000mL x 1), dried over anhydrous Na2SO4 and concentrated to give methyl 2-bromo-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (49g, 94.4%) as a yellow solid. LC/MS (M+H)= 387.9.
Step 2. Methyl 2-((1 -(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate. To a solution of methyl 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrroIo[2,3-b]pyrazine-7carboxylate (39g, 101.3 mmol) in 780 mL of toluene was added tert-butyl 4aminopiperidine-1 -carboxylate (30.4g, 151.9 mmol) and Cs2CO3 (66 g, 202.6 mmol) at room température. The mixture was degassed and purged with N2 several times, followed by addition of Pd2(dba)3 (9.3g, 10.13 mmol) and dppf (7.3g, 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 température overnight under N2. TLC (Petroleum ether: EtOAc =4:1) indicated methyl 2-bromo-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate was consumed completely. The resulting mixture was cooled to ambient température 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 chromatography column (silica, petroleum ether: EtOAc from 10:0 to 10:3) to give methyl 2-((1 -(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethyIsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxyIate ( 50 g, 78%) as a yellow solid.
1H NMR (400 MHz, DMSO-ofe) 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. 2-((1 -(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. To a solution of methyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate ( 50g,
203
99mmol) in THF (1000mL) was added aqueous 1M NaOH (396mL). The reaction mixture was stirred at room température overnight. TLC (PE/EA=2:1) showed most of the methyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate remained. The 5 reaction mixture was heated to 45 °C for 3h. TLC (PE/EA=2:1 ) still showed ester remained. The reaction mixture was heated to 60 °C overnight. LC-MS indicated about 15% of ester remained. A solution of NaOH (7.9g, 198 mmol) in H2O (200mL) was added to the reaction mixture. The reaction mixture was heated to reflux. LC-MS indicated about 8% of ester remained. After cooling to rt, a majority of the THF was 10 removed and during this time a green solid formed. The mixture was filtered and 45g of light green solid was obtained. This solid was acidified to pH=4~5 with HCl (2M in H2O) and extracted with ethyl acetate (400mLx3). The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-((215 (trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (overall
29.1 g, 44% of 3 steps) as a yellow solid.
1H NMR (400 MHz, CDCIg) 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. s., 1 H) 4.08 (br. s., 2 H) 4.71 (br. s., 1 H) 5.58 (s, 2 H) 7.72 (s, 1 H) 8.05 (s, 1 H)
Biological Evaluation
JAK Caliper Enzyme Assay at 4 μΜ or 1mM ATP
Test article was solubilized in dimethyl sulfoxide (DMSO) to a stock concentration of 30 mM. An 11-point half log dilution sériés was created in DMSO with a 25 top concentration of 600 μΜ. The test compound plate also contained positive control wells containing a known inhibitor to define 100% inhibition and négative control wells containing DMSO to define no inhibition. The compound plates were diluted 1 to 60 resulting in a top final assay compound concentration of 10 μΜ and a 2% DMSO concentration.
Test article and assay controls were added to a 384-well plate. Reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mM magnésium chloride, 0.01% bovine » 204 sérum albumin (BSA), 0.0005% Tween 20, 4 μΜ or 1 mM ATP and 1 μΜ peptide substrate. The JAK3 assays contained 1 μΜ of the JAKtide peptide (FITCKGGEEEEYFELVKK). The assays were initiated by the addition 1 nM JAK3 enzyme and were incubated at room température 75 minutes for JAK3. Enzyme concentra5 tions and incubation times were optimized for each new enzyme preps and were modified slightly over time to ensure 20%-30% phosphorylation. The assays were stopped 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 séparation conditions to measure the unphosphorylated and phosphorylated peptide.
Stability of JAK3 Covalent Inhibitors in Rat and Human Whole Blood
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 one male and one female healthy subjects at the Occupational Health & Wellness Center at
Pfizer, Groton, CT and pooled for each study. Both rat and human blood was collected freshly into K2-EDTA tubes and kept on ice. An aliquot of the blood was transferred to microtubes and pre-warmed for 10 min at 37°C using a heat block. The test compound was then added (1 μΜ final concentration) and the incubation was continued for 180 min 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 internai standard,vortexed and centrifuged. The resulting supernatants were removed and subjected to LC-MS/MS analyses to détermine parent compound concentrations. Peak area ratios of the parent compound vs the internai standard were used to détermine the % of parent compound remaining vs incubation time.
HWB IL-15 induced STAT5 phosphorylation Assay
After serial dilution of the test compounds 1:2 in DMSO at desired concentration (500X of final), the compounds were further diluted in PBS (by adding 4 μΙ_ compound/DMSO in 96 μΙ_ PBS, [DMSO]=4%, 20X final). To 96-well polypropylene plates were added 90 μΙ HWB (heparin treated Human Whole Blood)/well, followed by 5 μΙ/well 4% DMSO in D-PBS or various concentrations of 20X inhibitor in 4%
205
DMSO in D-PBS (w/o Ca+2 or Mg+2) to give 1X in 0.2% DMSO. After mixing and incubating for 45 minutes at 37°C, 5 μΙ D-PBS (unstimulated control) or 20X stocks of 5μΙ human IL-15 (final concentration is 50 ng/ml) were added, and mixed three times. After incubating 15 minutes at 37°C, 1X Lyse/Fix Buffer (BD Phosflow 5x Lyse/Fix
Buffer) was added to ali wells at 1000 μΙ/well, then incubated for 20 minutes at 37 °C and spun 5 mins at 1200 rpm. After washing in 1000 μΙ FACS buffer 1X and spinning for 5mins at 1200 rpm, 400 μΙ ice cold Perm Buffer III were added to each well. After mixing gently (1-2X) and incubating on ice for 30 minutes, spinning for 5 mins at 1200 rpm without interruption, and washing 1X in cold 1000 ml FACS buffer (D10 PBS containing 0.1 % BSA and 0.1% sodium azide) 250 μΙ/well of the desired AlexaFluor647-conjugated anti-phospho STAT5 antibody at 1:125 dilution in FACS buffer was added. Following incubating at 4 °C over night, ail the samples were transferred to 96-well polypropylene U-bottom plate, and checked by flow cytometry gated on total lymphocytes. IC50 values obtained are listed in the Table.
PBMC IL-15 Induced P-STAT5
Test compounds were serially diluted in DMSO, with further 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 (by adding 5 pL 20 compound/DMSO in 120 pL Dulbecco's Phosphate-Buffered Saline (D-PBS, 1X), [DMSO]=4%, and mixing the solution by repeated pipetting, 6X). IL-15 was diluted to the concentration at 820 ng/mL in RPMI 1640 medium.
Frozen human PBMC (200-250 million cells/vial) was thawed at 37 °C. The cells were transferred to 10 mL warm medium in a 50-mL conical tube, and centrifuged at 25 1,200 RPM at room température for 5 min. The supernatant was aspirated. Cells were suspended in 3 mL warm human plasma and incubated at 37 °C in a tissue culture incubator for 1.5 to 2 h. After adding 47 ml D-PBS (37 °C) to PBMC/FBS suspension, centrifuging at 1,200 RPM at room température for 5 min, and aspirating the supernatant, the cells were resuspended in 20 mL warm RPMI medium. Ninety 30 pL of cell suspension were pipetted per well in a 96-well, deep-well, V-bottom plate, and the plate was incubated at 37 °C for 30 min. Five pL of compound were transferred to each well (final 0.2% DMSO), vortex gently and incubate at 37°C for 15 min;
206 μΙ_ 4%DMSO/PBS were added to the control wells. After adding 5 μΙ_ 820 ng/mL of human IL-15 (final 41 ng/mL) to each well (5 pL PBS to the control wells), vortexing gently and incubating at 37 °C for 15 min, followed by 0.3 mL 1% paraformaldehyde/PBS (37 °C) to each well, and incubating the plate at room température for 15 min, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room température for 5 min, and the supernatant was aspirated using a 8-channel or 12-channel manifold. After adding 0.8 mL staining buffer per well, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room température for 5 min, and again the supernatant was aspirated using a 8channel or 12-channel manifold. The plate was vortexed, and 0.35 mL 90% methanol/10% H2O (-20°C) was added per well, and the plate incubated on ice for 20 min. After again adding 0.8 mL staining buffer per well, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room température for 5 min, and again the supernatant was aspirated using a 8-channel or 12-channel manifold, and then 0.8 mL Staining buffer was added per well. After once again adding 0.8 mL staining buffer per well, the plates were centrifuged at 1,200 RPM (Beckman GS-6R or Sorvall Legend) at room température for 5 min, and again the supernatant was aspirated using a 8-channel or 12-channel manifold. Then the plate was vortexed, and 250 pL/well of Alexa Fluor® 647 conjugated anti-STAT5 antibody (1 to 125 dilution; 1 pL antibody per 250 pL staining buffer) was added, and the plate was incubated at 4 °C overnight in the dark. Samples of 250 pL/well were transferred to a 96-well U-bottom plate, and the FACS analysis was performed gating on total lymphocytes. Samples were analyzed using a BD Calibur™ or BD FACSCanto™ flow cytometer equipped with the BD High Throughput Sampler.
Table 1. Enzyme Assay and Blood Stability Data.
207
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
1 OXt fQ_> N 0.2 16.8 50.8 494.1 209.9
2 Tl^Y^n cr 0.2 18.9 30.4 220.2 >360.0
3 Τθγ P1 νό <0.1 22 35.2 152.7 191.8
4 O*F ° ^N^-N 0.5 32.1 19.7 115.1 139.7
5 Chiral r5r> 0.3 33.1 51.7 197.2 >331.0
6 N il· ^YrCZXNH ° ÙQ 0.3 40 45.8 870.5 253
208
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (ηΜ) JAK3 (1mM ΑΤΡ) IC5o (ηΜ) PBMC IL15pSTAT5 IC50 (ηΜ) HWBIL15pSTAT5 ic50 (ηΜ) Human blood stability t-l/2 (min)
7 ° ύο <Ν H 0.3 45.3 76.9 455.3 >333.5
8 dÇ-r w Ν Η <0.4 47.7 115.9 399.2 192
9 j-vj ΝΗ ό Η 0.4 53.9 35.5 578 >360.0
10 F 5 °<5^|CA-NH Ô3 0.6 54.8 133.1 461.1 163
209
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 Ιθ50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
11 rr ηγ^-γΐΗ γ An H 0.4 55.9 97.9 362.6 >295.8
12 ΓΊ ° N irn nQ 0.7 56.8 107.1 392.1 >331.5
13 Y> ” MM H 0.4 60.6 113.5 548.8 305
14 Chira o ,<L _ N H 0.5 60.5 114.4 538.3 >250.7
210
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (ηΜ) JAK3 (1mM ΑΤΡ) IC50 (ηΜ) PBMC IL15pSTAT5 ICso (ηΜ) HWBIL15pSTAT5 IC50 (ηΜ) Human blood stability t-l/2 (min)
15 Λ ° 03 0.9 82.7 128.1 399.7 232
16 Ν Η 0.8 89.2 61.5 498.9 >358.5
17 ΟΗ Λ ^ΝΗ ° Ù3 Η 1.7 92.2 71.8 209.9 >310.0
18 \/χ Chiral 0 05 <Ν Η 0.2 16.1 31.5 555.4 >318.5
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
19 CK JJ Chiral Ύ H N J-a’ 0.6 67.6 139.3 505.2 210.5
20 0 ν^ΝΗ A < NZ<V< vA H lirai 1 76.5 361.6
21 E3-c N · 0 ^NX< 1.4 106 235.7
22 ,„0 '’ il ~^N ôo 1.2 81.6 216 712 347
212
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 lC50 (nM) HWB1L15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
23 M 0 ιγλϊ An^-'nh A Il k J 1.3 86.6 187.8 >360.0
24 A _N o m? ίΥΥ 1.2 98.1 319.9 >360.0
25 M H AyN n «-Ja 0 · | \ OF ^|\θΝΗ 1 2·9 149.1 84
26 Y o nAQ Aj‘ b 1.6 153 254.4 >360.0
Ex Structure JAK3 (4μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability lt/2 (min)
27 rM o /'0' Q 0 \ 2.8 293.6 1866.4 46
28 M H i TN> ° Lcr a 48.2 358.5 >10000. 0 >360.0
29 ô XV N w H ‘ 6.6 664.9 463.7
30 ô3 0 Ν·Λ( ân^...-nh /x i Ο ιγ 14.6 1536.1 >360.0
214
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) Ιθ50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stabil>ty tl/2 (min)
31 Chiral Y N \-:O w 24.1 1859 >360.0
32 M H rV> O NyU iô<jNH O/ 26.2 2114.8
33 G ô XM là 0 N-V 49.5 3809.1 >360.0
34 Cz ΖΎ^Ν ° w H ,N 54.4 4822 >360.0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ICso (nM) PBMC IL15pSTAT5 ICS0 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
35 K ,=U «Η \Λ 0 -4 K N\ 83.4
36 H zN^N\ îJj. M' Q 64.4 >360.0
37 J. HN.......\ / \ \=( ην~Λ ,n >- O 295.1 /
38 rV> o nyW ιάΟ'” \ 3254
Ex Structure JAK3 (4μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stabil>ty t-1/2 (min)
39 m H m Il o ΛθΝΗ 1 >10000.0
40 1 HN.......( ) i '—N // y N-^ 0 >10000.0
41 F Chiral 0 H 1 T» 1 92.5 446.4 2.8
42 Chiral !γθχ J ° Ôri 0.9 94.4 292.8 818.6 >360.0
217
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC5o (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
43 Chiral FF F 1.2 99.5 116.3 463 274.1
44 J HN.......( ) hn4Jn H N-^ 0 0.3 167.8 320.2 1181.1 165.9
45 Chiral lil cD 1 168.5 347.7 1010.6 >360.0
46 Λ H Z N.......O HNX > h 0 2.8 305.4 278.8 359 >344.3
218
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
47 Chiral 0,¾ 4 608.1 1076 315.8
48 0.8 101.1 65.2 149.8
49 0 N 1 111 354.9
50 [Rac] ry ° nS^ d N H 2 115.7 202.4 925.6 >360.0
219
Ex Structure JAK3 (4 μΜ ATP) ICS0 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB1L15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
52 0 Vy S 03 10.6 >180.1 >354.3 234.7 >358.0
53 // ΓΛ Chira Vn^a ,oh 0 NH nAJ W 4 191.5
54 Chiral rŸïÇ O N^N N ό 1.7 192.2 222 366.4 210
55 n __ Chiral va ο» 0 NH N^vAx W 2 203 430.5
220
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB - IL15pSTAT5 IC50 (nM) Human blood stability t-I/2 (min)
56 ^Ν^ΝΗ ° lV> v n 2.5 242.3 158.4 2099.5 >360.0
57 Chiral Λ ° 03 \ί^Ν 1.4 360.6 1227.7 2610.3 81.2
58 N Chiral <^γΝ^'^>ΝΗ 0 N'Z^A w 2.5 360.7 2785.4 7837.9 35
59 vQ 3.2 402.9 >2553.1 184.2
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB- IL15pSTAT5 IC5o (nM) Human blood stability t-1/2 (min)
60 Chiral O NÔO 4.2 603 2472.7 2784.1 >360.0
61 Chiral 00 7.5 608.7 1029.5 1873.4
62 Chiral va. j 0 / w 9 649.8
63 ^v’V-Xh ° 1¼ ™ΛΠ A 9.1 671.7 1376 >360.0
222
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
64 q° w 5.3 996.1 4638.6
65 ,J3. ^γ 03 17.9 1495.5 3742.1 >10000. 0 267
66 HyO C-J rt »H \=3 05 kN'AN 14.6 1536.1 >360.0
67 ° 0? 30 1682.6 6895.2 >360.0
223
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
68 'Ό V^N^'Z/''NH ° rir» ’-Ά 144.8 >2477.8 >360.0
69 OH Va ° ÔO 33.7 1852.4
70 ° ôo 19.5 1868.3 5527.1 343.2
71 ° V 57.9 3423.4 >10000. 0 229.2
224
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
72 o ° Αλ k JL > H 828.2 >10000. 0 >10000. 0
73 Chiral d)ï N iJ-l N N 48.4 1959.2 195
74 Chiral ° 03 22.8 202Î.2 103
75 Chiral ° 715.6 >10000. 0 >360.0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15 pSTAT5 IC50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability t-1/2 (min)
76 N 0 w 42.4 2038.2 >6077.4
77 Chiral q' 1 15.5 2065.3 3972.7 252
78 Chiral A ’io 386.6 >10000. 0 >10000. 0
79 Chiral <^γθ-Ν vO 26.6 2379.3 2365.5 230
Ex Structure JAK3 (4μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stabil>ty t-l/2 (min)
80 H en > <5 M 22.7 2944.1
81 H t f 35.3 3753.6 >4000.0 16.9
82 H en n ;N J y N z/ 1 57.2 5292.6 >7295.1 >360.0
84 Chiral 0 N 727 >10000. 0
227
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
85 Chiral 2181.8 >10000. 0 >360.0
86 Chiral yQ) lO 'f/N 149.1 >10000. 0 >360.0
87 H HNS N 0 F N·- 138.9 >10000. 0
88 Chiral ''N·''' ° Ce 18.2 3388.5 74
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) Ιθ50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB1L15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
89 A-Cb r A< 35.2 3943.9 >6156.8
90 ^C0 il ï %> 49.3 4435.8 >10000. 0 168.2
91 Chiral jCnQ F' 0 ùo 56.5 4650.7
92 ητθ + ™Ό H 4750.2 >10000. 0 >10000. 0
Ex Structure JAK3 (4 pM ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-J/2 (min)
93 K <A 703 >10000. 0 >10000. 0
94 h/n.......0 / I Μ X r° HNO H 801.5 >10000. 0 >10000. 0
95 Chiral \a. A? 2477 >1000.0 0 >360.0
96 N \ P 2741.7 >10000. 0
230
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
97 M 0 o γΟνγΫ*1 0 904.4 >10000. 0
98 oA......Q Sa Sa 2632.1 >10000. 0
99 n, J <° <Vnh 254.7 >10000. 0
100 Chiral Of 1 653.9 >10000. 0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ICso (nM) PBMC IL15pSTAT5 IC5o (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability t-1/2 (min)
101 Chiral A? h JL / 881 >10000. 0
102 Chiral °γΆΝ 352.7 >10000. 0
103 4.7
104 HN—/ ) HNJJN H ΐΆ o 64.5
232
Ex Structure JAK3 (4 μΜ ATP) lC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
105 Chiral \.Q. 2477 >10000. 0 >360.0
106 M H I θ I k/ 49.1
107 otQ HNVN o^VT 1160.2
108 „ 05 527.9 >10000. 0 >360.0
Ex Structure JAK3 (4 μΜ ATP) 1C5O (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 Ιθ50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
109 M - 2818.7
110 aA î T V-, yVjNH 1431.5
111 Chiral VNCb°x Ô3 39.2 4738.5
112 Chiral Ô3 188.7 7569.7 142
234
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- 1L15pSTAT5 IC50 (nM) Human blood stabil>ty tl/2 (min)
113 B® ..OH O ° Ô3 ΙΊ H 42.4 8478.1 >10000. 0
114 ÎAbsj . rl ° llA^ LA' 143.7 >9514.4 >360.0
115 ÎAbs] . *>, s \ ^•ANH ° ô:> N N 462.6 >10000. 0 185
116 ηΤςτ (pA \'Ά/Α I z fY\ AA,/ 417.6 >10000. 0 >10000. 0 >10000. 0 281
Ex Structure JAK3 (4 μΜ ATP) 1C5O (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
117 (Ab s) ho^-Q N H ° 03 416.5 >10000. 0 >10000. 0 >10000. 0 >360.0
118 OH Va 0 ” H 323.4 >10000. 0 >10000. 0 >333.5
119 α œ 95.9 >10000. 0 >10000. 0
236
Ex Structure JAK3 (4 μΜ ATP) lC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 icso (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability t-f/2 (min)
120 (Âbs) Λ3 N H 692.1 >10000. 0 >10000. 0
121 Chiral Xi 647.9 >10000. 0 >360.0
122 >-0/ 03 AO 75.6 >10000. 0
123 Chiral X, X 2112.4 >10000. 0
237
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (ηΜ) JAK3 (1mM ΑΤΡ) IC50 (ηΜ) PBMC IL15pSTAT5 IC50 (ηΜ) HWBIL15pSTAT5 IC50 (ηΜ) Human blood stability tl/2 (min)
124 'Ό °γΝΆΝΗ N03 IJ H 264.6 >10000. 0
125 ΟγΝ^'ΫΝΗ Ύμ 1424 >10000. 0
126 π ^ΥΝΎ'ΝΗ ° 03 <Ν Η 602.5 >10000. 0
127 π 0 ύο 'Ν ΙΝ Η 190.2 >10000. 0
238
Ex Structure JAK3 (4 μΜ ATP) lC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC5o (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
128 L A xi 443.6 >10000. 0 304
129 ÎRac] ° 03 113.8 797.3
130 Chiral ov Jx 0 Û3 75.2
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stabil>ty t-l/2 (min)
131 Chiral ύο 988.1
132 (Rac| Q' ''νη 0 ΝΛ3 2076.6
133 Chiral vÛ'iP A 0 n ΡΆ w 18
134 Chiral 0? 71.2
240
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 Ιθ50 (nM) HWB- IL15pSTAT5 IC50 (nM) Humain blood stability tl/2 (min)
135 (Àbs) ° 05 >10000.0
136 ® n 0 Ad IN H 238.3
137 [Ab s) O. ry°H ΐ. xS h 0.3
138 Chiral Ory° f /AVa νΆΑ vX> 110.5
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
139 ÎAbsJ I À Y- rœ· Y H 83.1
142 I I NH œNMe2 0 m h 225.3
143 - ^n^-nh ΛΤ OH 144.5
144 M o v? ^qnh <rNx 139.4
242
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
145 H — A H,N.....< > hnO N— O 112.1
146 m H M o nya ^Αθ-ΝΗ OA0 957.3
147 o ÇQ /xAnqnh ao >10000.0
148 M H 0 ÇQ Ah U Λ OH 6957.2
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) lC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
149 oz hÎL° cô ° H IN >10000.0
151 // /^\ (Âbs) PH o nh w 3490.6
152 _/ /Λ (δ3 rA j™ ο NH γ w 4242.8
153 [Racl Jy'O'N'Y 0 9444.6
244
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stabil>ty t-1/2 (min)
154 (Rac) w 4936.8
156 V1 7.2
157 (Âb£ i. Y « 1 0 K JL > 1470.4
158 ÎAbs) _ HO-^x ΓΛ N 1 su S Ά rJ .1 j N' vi tl aJ N H >10000.0
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
159 [Abs] rO, oh O NH ^4— nÀH w >10000.0
160 E3 [''·'γ0Η '^ÿ7'N'^>NH ° Ù3 IN H >10000.0
161 [Abs] o Y.. - <N H 0.3 45.3 76.9 455.3 >323.5
162 OH Δ '^Ύ '·Ύη ci 0 ôn 1.2 169 361.3 1003.2 >360.0
246
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stabil>ty tl/2 (min)
163 lÂbs) Ύ1 n ΑγΝΑ>ΝΗ 11! 0 03 VA 0.6 47.1 108.9 521.8 290.1
164 °v-nh2 w H 4.1 314.4 1653.3
165 (Âbs) ' ^'ySXkjh » ° 3d> 0.5 22.7 40.6 380.3 >349.4
166 ,α ° Ô3 SA 369.6 >10000. 0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stabil•ty t-1/2 (min)
167 Aï 2410.5
168 ! ο hH JH> Çw H 0.2 7.5 37.1 135.7 >349.6
169 .. H AK-N cA^ 42.8 4732.3
170 \ H Γ )=N <Kp H 3.3 392.5 1369
248
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 «c50 (nM) Human blood stability t-1/2 (min)
171 ' J ' ï: 0.4 32.7 726 2951.1 >360.0
172 0 25.5 2230.8
173 M H ιί VNs  y? N y 8.1 692.1
174 M H /N^N I Vn^J 0Anh o 0.4 34.8 58.4 622.7 249.3
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) lC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability t-l/2 (min)
175 o 1610.8
176 àbAx“ H 7.2 910.3 >360.0
177 ΗΆ h ΓΛ çv 0.7 44.4 107.6 804.3 >321.0
178 j. AT H 1.1 102 208.2 2556.7 143
250
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stabil>ty t-I/2 (min)
179 HO ? ? 4-Àj N H 2.3 308.6 >10000. 0 >10000. 0
180 A3 H kAA/V ÇA a 12.4 1498.5
181 ·—/ hnA H 10.3 1016.9
182 O HM-^ H K'-C,!, 11.4 975.3
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ICso (nM) PBMC IL15pSTAT5 IC5o (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
183 w ° 9.6 793.9
184 'V hL·0 h 1.5 210.3 3407.1 >10000. 0 >360.0
185 M H 20.4 1457
186 ~0 A1 2347.6
252
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
187 AA 0Λνη A 0.6 27.2 709.5 >360.0
188 / 0 h,n3/n'A H 0.3 8.8 154.6 245.5 96
189 z?—N hn—/ y~NH M N=V V......H oAA O=(^_ H 1.1 197.9 1735.1 >10000. 0 >360.0
190 aA χΆνΆ VJ J^NH 4 0 \ y 13.9 1014.7
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stabil>ty tl/2 (min)
191 /γ T H N 1.5 137.6 2647.9 9582.3 >360.0
192 0 3maçVnh 271.6
193 / r^'N'^O fi Ν-^ϊγ^Ν Cr r t 29 2294.2
194 Chiral fi fiN N I '-ArV O 1 12.7 1659.3
254
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ICso (nM) PBMC IL15pSTAT5 IC5o (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t|/2 (min)
195 o N—f O 1 12.1 970
196 N— S^C-N^'N-· 3^ O=X O 0.3 30.6 1491.8 3290.9 >360.0
197 û'( nÔ. V# 3486
198 d N—Λ O=n 1 77.6 1170.4 >360.0
255
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
199 V# Ύ” 1.2 101 734.9 >10000. 0 >360.0
200 \ U>) 1 H 0.8 88.9 818.6
201 P yTpT 0.5 28 262 3478.4 >360.0
202 P tO’î» 0.9 99.1 669.9 3739.3
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability t-1/2 (min)
203 H N \ Xy X V 2 147.8 1182.6
204 H χ y—N >—NH \X € oX. iX H 0.5 49.3 854.9
205 O XntnX 0.5 14.8 218.7 1884.9
206 N f y N / N-Z '—' 0 ArO Il >=N 9 0.1 19.6 163 >10000. 0
Ex Structure JAK3 (4 μΜ ATP) 1C5O (nM) JAK3 (1mM ATP) ICso (nM) PBMC IL15pSTAT5 IC50 (nM) HWB IL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
207 Fy\ < / nY >—' 0 ίγΌ Il )=n 1 0.3 28.9 185.4 2824.3 >360.0
208 0 » ϊΎ'° ^NH 5.9 575.8
209 yY Y 0.2 14.3 152.4 6685.8
210 Ta , ?ό4 Y T H 0.4 45.4 462.5 2679.5 >360.0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
211 J _) HN—( IW 0 Ï>=N Ή H 0.2 34.2 205.6 4330.1
212 ή jO4 fAA_7) iM M 0.3 16 154.5 2083.3
213 _A 4^^ 1/ II 0.8 69.4 317.9 >10000. 0
214 N=X V αϊ'τΓ °yY JA/ 2.3 308 1110.4
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stabil'ty tl/2 (min)
215 AA 2.9 386 1263.3
216 Q A4 AO Il )=N H 12.5 1029.4
217 fVF A0-CX MO 0 A7 H 0.7 42.4 129.3 >10000. 0
218 N 3 -Λ A4 AO H 0.6 81.1 345.3 6189.6 >360.0
260
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability t-l/2 (min)
219 X p 6 yW) 1.7 153.3 986.7
220 O- 0.8 70.4 464.5 >10000. 0 >360.0
221 -(T .-Pl Y ΊΊ H 15.5 1484.7
222 i y F /=H ιΊ H 1.1 125.4 756.6
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
223 ΥΊ =-Ο'Λ Ύ N A Ah 30 3358.9
224 aq/ΌΧ Ί\ 1- 17.6 1544
225 N Ψ \ n J Ά x—7 0 ArO ff )=N H 1.4 120 2906.2
226 'n -A rw A' H 1 91 699
Ex Structure JAK3 (4 μΜ ATP) lC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB - IL15pSTAT5 ic50 (nM) Human blood stability t-f/2 (min)
227 _IL 0 Vn)-C) K 0.9 71.8 642.9
229 H FL P” 7 7.1 744.6
231 HO o J N-{ l-Y 0 0 h rt / A N H 0.6 52.6 3616.4
232 HO o H,N-C/NV γΫΆ-Α /A 0 _N H 0.3 25 1636.3
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
233 ΛΑ ? ΑΧ - Ά N H 0.2 20.6 212.8 532.3
234 HA ” A H <0.3 4.9 65.2 296
235 , jÂA W_Jhi/h 0 OH 0.3 22.5 1703.8
236 F'Z'Z 0 HN-Z^N-( Min 0 H (W H 0.1 8.3 141.5 437.6
264
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 Ιθ50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
223 7 A η HN-T^Νγ A ° Y H 0.2 7.8 80.1 243
238 0 HN-CNY mvv 0 F H (Vn7 N H 0.2 9.3 181.3 615.1 260
239 . A W_J-NH 0 OH 0.5 38.1 1899.3
224 0 Kj .-Y ' ! rP SN H 0.1 9.1 83.8 442.5 235
Ex Structure JAK3 (4 μΜ ΑΤΡ) lC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
241 /-Λ j Fyj 4 ' I tTM ) V H QA H 0.2 7.3 87.9 656.8 >310.5
242 N f X b° .tv-% Au TJ H 0.1 10.7 1097.2
243 Fll 0 η/νΌπ Va - Vf H <0.1 9 155.4 617 >360.0
244 f-A o ηνΥΛι-{ Va 0 H 0.2 7.3 126.7 403.1 284
266
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB1L15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
245 7 H 0.2 17.9 228.2 901.2
246 y o , «n 0 ( H IM VN H 0.3 6.4 43 186.2 >360.0
247 MA 0 Ί\Ι H 0.2 8.2 141.4 651 272
248 X MÀ y-vA H 0.4 40.2 892.9
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
249 H F A NL VA ^2/·^ ° °h 0.6 47 2105.7
250 HO ° tCK dV H 0.6 76.7 4118.7
251 0 o hyOh va H 0.2 8.1 73.9 809.5 201
252 V° T A b v H 0.5 37.2 673.1
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-t/2 (min)
251 b no ) o H 0.4 54.1 1512.1
252 b HO o H/N~0^ W F H 0.5 40.6 2467.9
253 ry _ i N—( — 0 F\ / NA> Fy « w F V H 0.2 6.9 77.5 429.3 >360.0
254 ,LLx j n J ν_/’Λ G^ ΓΚ H 0.5 41.5 836.5
Ex Structure JAK3 (4μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB - IL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
255 ψ ” 0.3 9.7 130.2 817.8
256 0 o h/n~Ch M-a 0 fl H 0.2 7.9 48.6 550.4 239
257 nærQ 0 /-y ΓΗγΑ Wj-X 0 0 108
258 N /—l n=An=..Ç1 ο „ ΜΓΑ 4.6 547.6
270
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-I/2 (min)
259 ΗζΗ 0 H V H . 0.2 11.1 117 668.2 >360.0
260 A \ _ NV v vM YMh 0.2 14.7 574.7 >10000. 0
261 Y H 0.2 7.4 214.4 215.2 >360.0
262 Vy A 0.2 30.8 1331 >10000. 0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
263 , ' r\ } H 0.2 8.7 74.3 431.4
264 u/A VnQh/i 0 / u 2.6 225.8 4483
266 A#3 H 0.3 13.6 71 386.4 336.1
267 λλ) f 0 H,N-\ zNA Ai A H 0.3 9 36 242.4 224
272
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
268 Z ‘ N H 0.3 7.9 43.4 263.1 288
269 / 0 n vrt 0 H 0.2 7.3 47.9 364.1 256
270 ο HN—( '\|—/ o-A4 A H <0.1 8.6 53.6 1223.1 232
271 \ o j 0 W ’ ΊΜ H 0.4 14.9 134.6 790.3 137
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB1L15pSTAT5 ic50 (nM) Human blood stabil•ty tl/2 (min)
272 λ HN—( N—/ w Y H 0.2 8.8 72.3 258.9 217
273 '-h Y ’ Y H 0.4 11.4 56.7 214.1 218
274 / λ HN—( 'Ί—/ Y Y Y H 0.2 8.2 57.9 475.7 >360.0
275 ) 0 2/N_O^ M H 0.4 13.1 148.8 389.2 >360.0
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
276 yj .ΑΧ X H <0.3 11.1 57.8 486.6 225
277 Λ F n HN~( \( 'N H 0.3 6.6 102.8 83.2 >360.0
278 - 0- H 0.2 6.3 57.4 362.3 236
279 X.X À H Zf 9.7 591.9
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
280 π ° h/nhTh W n H 0.2 4 39.4 376.3 >360.0
281 H Ν--Λ WA .H HNp 0.4 5.2 31.5 489.4 346
282 , 0 HN-(W A H 0.2 12.9 71.7 432 243
283 Cl 0 ην-ΓΗ A ° H 0.3 7.6 58.4 700.3 >360.0
276
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWB - IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
284 An Λα OA A? H A3 1.9 176.2 2789
285 f o A ° Ή H 0.3 8.5 31.4 373.2 345
286 AA 15.9 813.6
287 OuA H Aû 4.2 345.8 7366.3
277
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stabil•ty tl/2 (min)
288 I 0 Η,Ν-Οη ΊΊ . H 0.2 7.8 44.4 357.8 220
289 i ° h/nX7h Αγ ” H 0.3 7.1 37.5 106 >360.0
291 / \ / ; r. N—\ -Aajya 0 Γ)=K ^N’ H 0.2 9.2 168.1 196
292 V? .A 31 3038.4
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-l/2 (min)
293 /A AP Ah Y?\ 0 Λ 0.6 107.1 300.3 4488.4 >360.0
294 W A. 0 / 1.9 234.6 1003.2
295 rM. W «% 0 5 / 1.1 89.8 334.5 2674 189
296 y \ 0 λ ΗΝγ rv\, > Ρνυν·Α/νΥ Cf T o jrV 56.6 4200.8
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15 pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
297 Il r-A 0Anh o / 1.5 181.4 752
298 AyN I N } 0 / 4.6 728.5
299 . χΑΑ γΥ A o X 0.7 55.6 224.8 1377.4 199
300 Yx> O f k vv YN-h / T 0 x H 0 / 0.9 84.4 714.2 3401.1 117
280
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC5o (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
301 o=z 3e -...... \__ /A / == 0.6 89 408.3 4896.4 84
302 X -Γ'Κ XJ < Tl H 1.2 49.4 263.6 1306.3 >360.0
303 rNy\ l X k w A 0 XpX z 0.4 47.2 294 2730.9 341
304 r Y> iG^N'Sr Ύ LU zMs'H OV N^ 0X z 7.1 624.4
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 ic50 (nM) Human blood stabil>ty t-l/2 (min)
305 / o H..N'......CA τ V J W H 0 H rw x 'N H 0.8 65 744.4 2644.2 357
306 il 3r N n \ ο * 3.9 325.5 1086.8
307 » vAA yvA cAT · o 1.1 128.1 456.8 122
308 V° γΆ° a <τΎΝ^ 5.2 430.8 2236.6
309 v° Av A 6.6 813.9
282
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
310 s H \^N „ i 7° f\=N Z- -8 '/ hHJ<XHo 117 >10000. 0
311 ΓΝτ^·> i ΟΛνυ çy 1.2 200 695.9
312 rAx X o>y 4.5 592.1
313 Ίιύζ0 Γ^νΑ1 mNxJ nAt H IN 1.4 182.8 706.4
314 Κγ° ΑχΑ <<r H 5 661.6
283
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
315 xA- 60.5 5192.6
316 M H /γΝ· η oYnh o 18.7 1530.7
317 λχα H 0.5 44.6 242.6 420 >360.0
318 A 0 \ /Ύ t/vJ 0 χνΑν> H lN 0.3 21.3 260.5 2081.7 352
319 AK/H FF Il \ OH 0.5 26.7 325.3 278
284
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 IC50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability tl/2 (min)
320 / o H,N....... A II n-A W o Au ' A H 0.4 10.7 61.1 343.3 190
321 l AZ 0 I / 0.9 144.3 414.7
322 0 jj A ' <A ΝΎ H N 29.4 3440.9
323 ΑγΝ> Il PA VA A 11.9 885.8
324 H Ma A A VÎA T O 37.5 3097.1
285
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 Ιθ50 (nM) HWB- IL15pSTAT5 ic50 (nM) Human blood stability t-l/2 (min)
325 .. H Il |^ΝΛΝ^~ί YŸ 0 x 5 479.8 1555.1
326 fNYIl 'γγΛιΧY ΙλΛ /γ o 4.9 506.1
327 _ A) Il y N N Λ V-A 0Anh o / 6 569.4
328 , ifY. , ρΛιΛ/ Y^.8 0 / 1.6 221.9 891.4
335 WYn =7 a γ 621.5 >10000. 0 >10000. 0
286
Ex Structure JAK3 (4 μΜ ATP) IC50 (nM) JAK3 (1mM ATP) IC50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability t-1/2 (min)
336 30.6 3398.9 >10000. 0
337 H LA 1.1 95.6 237 631 81
338 V ^nl , CD o XA nh Os ΐ x> 0.4 114.6 479.9 >10000. 0 328
339 o^ J V Q vr ,N, _/ l χχ Α'Ά 0.2 17.5 80.6 502.1 227
340 °U rac rr Y V< hVtv 21.1 1394.1 >360.0
287
Ex Structure JAK3 (4 μΜ ΑΤΡ) IC50 (nM) JAK3 (1mM ATP) ic50 (nM) PBMC IL15pSTAT5 ic50 (nM) HWBIL15pSTAT5 IC50 (nM) Human blood stability tl/2 (min)
341 Chîral 7 U HNvM H 15.6 1093.3 >360.0
342 Chîral O °« J/ HVrV va 81.1 5970.9 >360.0
343 A •y A-nhT HA JA J 1 XX 0.1 3.4 36.8 105.3 >351.0
288

Claims (17)

  1. 5 or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic 10 heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-Ce linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)CrC6 linear or branched chain alkyl, (Ο-ι-Οβ linear or branched chain alkyl)aryl, (C-|-C6 linear or branched chain alkyl)heteroaryl, (Οι-Οθ linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, Ci-C6 linear or branched chain alkoxy, 15 CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ο-ι-Οβ linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SORi2, -SO2Ri2, NR-|3SO2Ri2, -SO2NRi3Ri4, and -NR13SO2NRuRi5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents se20 lected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Cj-Ce linear or branched chain alkyl)aminocarbonyl, and Ο3-Οβ cycloalkyl;
    289
    Ra is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C-|-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    A is --(CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, CrC6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, C-|-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C-|-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, Ri, R4, R5, R6, R7, Rs, R9 and R10 are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or Ri, and/or R6 or R7, respectively together with either of R4, R5, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R4 or R5, respectively together with either of Ra, Rb, Rc or Rb, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternatively, R3 and Rg may together form a 3-
    6-membered ring optionally containing one or two O or N atoms;
    Rn is hydrogen or deuterium;
    R12, R13, R14 and R15 are independently selected from hydrogen, C1-C6 linear
    5 or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-C10 aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
    Y is O or N, where when Y is O, n is 0;
    10 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 CRi6; 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)Ci-C6 linear or branched chain alkyl,
    15 (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ο-ι-Οβ linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, or (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino,
    20 CF3, and C3-C6 cycloalkyl;
    X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, 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, CrC6 linear or
    25 branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)CrC6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is
    30 bonded to H, and said dotted bond between X and — (CH2)n— is absent, and when X is —(CReRf)s—, and X is bonded 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 substi17901
    291 tuted by H, (ii) Z is C, Z’ is C or N, the dotted bond to Z is a single bond, the dotted bond to Z’ being absent, or (iii) Z is C or N, Z’ is C, the dotted bond to Z’ is a single bond, the dotted bond to Z being absent, where said Y being an N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring op5 tionally substituted by C1-C6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
  2. 2. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, C-|-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic 15 heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, (C1-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, CrC6 linear or branched chain alkoxy, 20 CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (CrC6 linear or branched chain alkyl)aminocarbonylamino, (C1-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR-|3SO2Ri2, -SO2NR13Ru, and -NR13SO2NRi4Ri5; where said alkyl, aryl and
    292 heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkyiamino, dialkylamino, CF3, aminocarbonyl, (Οι-Οθ linear or branched chain alkyl)aminocarbonyl, and 03-0θ cycloalkyl;
    R3 is seiected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C-|-C6 linear or branched chain perfluoroalkyl, haiogen, and cyano;
    10 A is —(CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rj are independently seiected from hydrogen, C1-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, Οβ-Ο-ιο aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)C-|-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, haiogen, cyano, hydroxyl, Ci-C6
    15 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, .
    20 alkyiamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, Ri, R4, R6i Re, R9 and R-|0 are independently selected from hydrogen, Cr C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, 25 (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, haiogen, cyano, hydroxyl, C-|-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-Ce linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Οι-Ο6 linear or branched chain alkyl)heterocyclic, where said al30 kyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkyiamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1( and/or R6, respectively together
    293 with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, altematively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or 5 two O or N atoms;
    R11 is hydrogen or deuterium;
    R12, R13, Ru and R15 are independently selected from hydrogen, C1-C6 linear 10 or branched chain alkyl, C-i-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, alkylaryl, and (aryl)CrC6 linear or branched chain alkyl;
    Y is O or N, where when Y is O, n is 0;
    15 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 CR-|6; or, Z is CR16 or N when the dotted bond to Z’ is a single bond, and Z’ is C; where R16 is CrC4 alkyl, C6-C1o aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-|-C6 linear or branched chain alkyl,
    20 (heteroaryl)C-|-C6 linear or branched chain alkyl, (heterocyclicJCrCe linear or branched chain alkyl, (C-i-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, or (Οι-Οβ linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino,
    25 CF3, and C3-C6 cycloalkyl;
    X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, Y is N, and X is O or —(CReRf)s--, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, CrC4 alkoxy, amino, CF3, CrC6 linear or
    30 branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)C-|-C6 linear or branched
    294 chain alkyl, or (heterocyclic)Ci-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and --(CH2)n— is absent, and when X is — (CReRf)s—·, and X is bonded 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 substituted by H, (ii) Z is C, Z’ is C or N, the dotted bond to Z is a single bond, the dotted bond to Z’ being absent, or (iii) Z is C or N, Z’ is C, the dotted bond to Z’ is a single bond, the dotted bond to Z being absent, where said Y being an N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by CrC6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, r and s are independently 0, 1 or 2.
  3. 3. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, Ο6-Ο10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (C-i-C6 linear or branched chain alkyl)heteroaryl, (Ci-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, C-|-C6 linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, φ 295 carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR-13SO2R12, -SO2NR13RU, and -NR13SO2NR14R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents se5 lected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, C-i-Ce linear 10 or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    A is — (CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Ra are independently selected from hydrogen, CrC6 linear or branched chain alkyl, CrC6 linear or branched 15 chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (C1-C6 line20 ar or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and 03-0β cycloalkyl;
    25 Ro, Ri, R4, R6, Rs, R9 and R10 are independently selected from hydrogen, C-r
    C6 linear or branched chain alkyl, C-|-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-Ce linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy,
    30 amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said al ~ 296 kyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1( and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear
    5 alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, Rg and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
    10 R11 is hydrogen or deuterium;
    R12, R13, R14 and R15 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, alkylaryl, and (aryl)Ci-Ce linear or branched chain alkyl;
    Z is CR-te or N, where R16 is C1-C4 alkyl, Οβ-Ο-ιο aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)CrC6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or
    20 branched chain alkyl)heteroaryl, or (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
    25 X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, X is O or —(CReRf)s—, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, CrC4 alkoxy, amino, CF3, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or
    30 branched chain alkyl)heteroaryl, (heteroaryl)CrC6 linear or branched chain alkyl, or (heterocyclic)Ci-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and
    297 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 (i) the adjacent N atom is substituted by H, or (ii) said N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by C-|-C6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
  4. 4. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)CrC6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (Ci-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, Οι-Οθ linear or branched chain alkoxy, C1-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C-|-C6 linear or branched chain alkyl)aminocarbonylamino, (CrCe linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NRi3SO2R12, -SO2NR13Ru, and -NR13SO2NR14Ri5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents se
    298 lected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    A is —(CRaRb)g-(CRcRd)r-> wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-i-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, Ri, R4, R6> Rs, R9 and R10 are independently selected from hydrogen, Cr C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-|-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R-i, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear
    299 alkyl chain; and/or, alternative^, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
    Z is CR16 or N, where R-|6 is Ci-C4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ο-ι-Οθ linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, or (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
    Ru is hydrogen or deuterium;
    Ri2, R13, Ru and R-|5 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, Ci-Cô linear or branched chain perfluoroalkyl, C6-Ci0 aryl, alkylaryl, and (aryl)C-|-C6 linear or branched chain alkyl; and, p, q, and rare independently 0, 1 or 2.
  5. 5. The compound of claim 1 having the structure:
    300 or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrCe linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, (C1-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, CrC6 linear or branched chain alkoxy, C1-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR-|2, -SO2Ri2, NRi3SO2R12, -SO2NRi3Ru, and -NRi3SO2NRuRis; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, C1-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    301
    Ra> Rb, Rc and Rd are independently selected from hydrogen, Ο-ι-Οβ linear or branched chain alkyl, Ο-ι-Οθ linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-|-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, Ri, R4, R6, Rs, R9 and R-io are independently selected from hydrogen, C1C6 linear or branched chain alkyl, Ο-ι-Οθ linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternative^, Ro or R-i, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternative^, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
    Z is CR-ie or N, where R16 is CrC4 alkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-Ce linear or branched chain alkyl, (heteroaryl)C-i-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or
    302 branched chain alkyljheteroaryl, or (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;
    Ru is hydrogen or deuterium; and,
    Ri2, R13, Ru and R-i5 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-C10 aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl.
  6. 6. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ο-ι-Οβ linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, CrC6 linear or branched chain alkoxy, Ci-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino,
    303 carboxy, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonylamino, (Cf-C6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR13SO2R12, -SO2NR13R14, and -NR-13SO2NR14R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents se5 lected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Οι-Οθ linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, CrC6 linear 10 or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    Ra, Rb, Rc and Rd are independently selected from hydrogen, CrC6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, 15 (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said al20 kyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, Ri, R4, Re, Rs, R9 and R10 are independently selected from hydrogen, Cr 25 C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrCe linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)^-C6 linear or branched chain alkyl, 30 (Cf-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (Ci-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the
    304 group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1( and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or 5 Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
    R-ι-ι is hydrogen or deuterium; and,
    Ri2, R13, Ru and R15 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-C10 aryl, alkylaryl, and (aryl)Ci-Ce linear or branched chain alkyl.
  7. 7. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 line25 ar or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C-|-C6 linear or
    305 branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, Ο-ι-Οθ linear or branched chain alkoxy, Ci-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Οι-Οθ linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2R12, NR13SO2Ri2, -SO2NR13Ri4, and -NRi3SO2NRi4R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonyl, and Ο3-Οθ cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, C-|-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    Ra, Rb, Rc and Rd are independently selected from hydrogen, CrC6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ο-ι-Οβ linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, R-t, R4, R6, Rs, R9 and R10 are independently selected from hydrogen, C1C6 linear or branched chain alkyl, Ci-Ce linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C-i-C6 linear or branched chain alkyl, (heteroaryl)C-|-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl,
    306 (Ci-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (C-rC6 linear or branched chain alkyl)heterocyclic, where said al· kyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkyiamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or Ri, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a Ci-C6 linear alkyl chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Ci-Οβ linear alkyl chain; and/or, alternatively, R3 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
    Rn is hydrogen ordeuterium; and,
    R12, R13, Ru and R15 are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, C6-C-io aryl, alkylaryl, and (aryl)Ci-Ce linear or branched chain alkyl.
  8. 8. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, C-i-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Ci0 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)C-i-C6 line
    307 ar or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, (Ci-C6 linear or branched chain alkyl)heterocyclic, CrCe linear or branched chain perfluoroalkyl, CrC6 linear or branched chain alkoxy, CrC6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (Ci-C6 linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SOR12, -SO2Ri2, NRi3SO2Ri2, -SO2NR13Ru, and -NRi3SO2NRuRi5; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    A is —(CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rd are independently selected from hydrogen, Οι-Οθ linear or branched chain alkyl, C-i-C6 linear or branched chain perfluoroalkyl, Οθ-Οιο aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-i-C6 linear or branched chain alkyl, (C-i-Ce linear or branched chain alkyl)aryl, (C-|-C6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with 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, CrC6 linear or branched chain alkyl, Ο-ι-Οβ linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, CrC6 linear or branched chain alkoxy,
    308 amino, carboxy, aminocarbonyl, (heterocyclic)CrC6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (Οι-Οθ linear or branched chain alkyl)heterocyclic, wherein said alkyl is further optionally substituted with one or more substituents selected from the
    5 group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    10 Ro, Ri, R4, Rô! Rs> R9 and Rw are independently selected from hydrogen, Cr
    C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy,
    15 amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3,
    20 and C3-C6 cycloalkyl; where, alternative^, Ro or Ri, and/or R6, respectively together with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl chain; and/or, alternative^, R4, respectively together with either of Ra, Rb> Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternatively, R3 and Rg may together form a 3-6-membered ring optionally containing one or
    25 two O or N atoms; and,
    Ru is hydrogen or deuterium;
    Y is O or N, where when Y is O, n is 0;
    309
    R-i 2, Ri3, Ru and R15 are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, Οβ-Ο-ιο aryl, alkylaryl, and (aryl)Ci-Ce linear or branched chain alkyl;
    X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is présent, 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, Ci-C6 linear or branched chain alkyl, Ο3-Οθ cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)CrC6 linear or branched chain alkyl, or (heterocyclic)CrC6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is bonded to H, and said dotted bond between X and —(CH2)„— is absent, and when X is --(CReRf)s—, and X is bonded 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 substituted by H, or (ii) said N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by Ci-C6 linear or branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
  9. 9. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait thereof, and wherein
    310
    R2 is selected from the group consisting of hydrogen, deuterium, Ci-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Οι-Οθ linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, (CrC6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, Ο-ι-Οβ linear or branched chain alkoxy, CrCe linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C1-C6 linear or branched chain alkyl)aminocarbonylamino, (Ci-C6 linear or branched chain alky))aminocarbonyl, -SORi2, -SO2R12, NR-i3SO2R12, -SO2NR13Ri4, and -NRi3SO2NRuR15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (CrC6 linear or branched chain alkyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, CrC6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    Ro, Ri, R6, Rs, R9 and R10 are independently selected from hydrogen, CrC6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C-i-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternatively, Ro or R1; and/or R6, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C1-C6 linear alkyl
    311 chain; and/or, alternatively, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a Ο-ι-Οθ linear alkyl chain; and/or, alternatively, Rg and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms;
    Ru is hydrogen or deuterium; and,
    R12, R13, Ru and R-|5 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, CrCg linear or branched chain perfluoroalkyl, C6-Cio aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl.
  10. 10. The compound of claim 1 having the structure:
    or a pharmaceutically acceptable sait or solvaté thereof, or an enantiomer or diastereomer thereof, and wherein
    R2 is selected from the group consisting of hydrogen, deuterium, CrC6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)Ci-C6 linear or branched chain alkyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (C1-C6 linear or branched chain alkyl)aryl, (C-|-C6 linear or branched chain alkyl)heteroaryl, (Ci-C6 linear or branched chain alkyl)heterocyclic, CrC6 linear or branched chain perfluoroalkyl, CrC6 linear or branched chain alkoxy, Ci-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, (C-i-Cg linear or branched chain alkyl)aminocarbonylamino, (CrC6 linear or branched chain alkyl)aminocarbonyl, -SORi2, -SO2Ri2,
    312
    NR13SO2Ri2, -SO2NR13R14, and -NRi3SO2NR-i4R15; where said alkyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, cyano, alkylamino, dialkylamino, CF3, aminocarbonyl, (Ci-C6 linear or branched chain al5 kyl)aminocarbonyl, and C3-C6 cycloalkyl;
    R3 is selected from the group consisting of hydrogen, deuterium, Οι-Οβ linear or branched chain alkyl, C-i-C6 linear or branched chain perfluoroalkyl, halogen, and cyano;
    A is — (CRaRb)q-(CRcRd)r-, wherein Ra, Rb, Rc and Rj are independently selected from hydrogen, Ci-C6 linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, monocyclic or bicyclic heteroaryl, comprising 5and/or 6-membered rings, alkylaryl, (aryl)CrC6 linear or branched chain alkyl,
    15 (heteroaryl)Ci-C6 linear or branched chain alkyl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (Ci-C6 linear or branched chain alkyl)aryl, (CrC6 linear or branched chain alkyl)heteroaryl, and (C1-C6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more
    20 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, Οι-Οθ linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, 25 (aryl)C-|-C6 linear or branched chain alkyl, (heteroaryl)Ci-Ce linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C1-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)aryl, (Ci-C6 linear or branched chain alkyl)heteroaryl, and (C-i-C6 linear or branched chain alkyl)heterocyclic, wherein said 30 alkyl is further optionally substituted with 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 further optionally substituted with one or
    313 more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl;
    Ro, Ri, R4, Rô, Rs, R9 and R10 are independently selected from hydrogen, C-r
    5 Οθ linear or branched chain alkyl, Ci-C6 linear or branched chain perfluoroalkyl, C6C10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)CrC6 linear or branched chain alkyl, (heteroaryl)CrC6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, Ci-C6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)Ci-C6 linear or branched chain alkyl, 10 (C1-C6 linear or branched chain alkyl)aryl, (C1-C6 linear or branched chain alkyl)heteroaryl, and (CrC6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF3, and C3-C6 cycloalkyl; where, alternative^, Ro or R^ and/or R6, respectively together 15 with either of R4, Ra, Rb, Rc or Rd, may independently form a bond or a CrC6 linear alkyl chain; and/or, alternative^, R4, respectively together with either of Ra, Rb, Rc or Rd, may independently form a bond or a C-|-C6 linear alkyl chain; and/or, alternatively, R8 and Rg may together form a 3-6-membered ring optionally containing one or two O or N atoms; and,
    Ru is hydrogen or deuterium;
    Y is O or N, where when Y is O, n is 0;
    25 R12, R13, Ri4 and R15 are independently selected from hydrogen, C1-C6 linear or branched chain alkyl, C-i-C6 linear or branched chain perfluoroalkyl, C6-Cio aryl, alkylaryl, and (aryl)Ci-C6 linear or branched chain alkyl;
    X and the dotted bonds thereto may be présent or absent, whereby, (a) if X is 30 présent, Y is N, and X is O or — (CReRf)s~, where Re and Rf are independently hydrogen, deuterium, halo, hydroxy, Ci-C4 alkoxy, amino, CF3, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C6-Cw aryl, monocyclic or bicyclic heteroaryl,
    314 comprising 5- and/or 6-membered rings, (aryl)Ci-C6 linear or branched chain alkyl, (CrC6 linear or branched chain alkyl)heteroaryl, (heteroaryl)Ci-C6 linear or branched chain alkyl, or (heterocyclic)Ci-C6 linear or branched chain alkyl, and said dotted bonds are présent and are single bonds, whereby when n is 0, and X is O, said O is
    5 bonded to H, and said dotted bond between X and — (CH2)n-- is absent, and when X is — (CReRf)s—, and X is bonded 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 substituted by H, or (ii) said N atom may together with R2 and the atoms intervening therebetween form a 6-membered ring optionally substituted by Ci-C6 linear or
    10 branched chain alkyl or C3-C6 cycloalkyl; and, n, p, q, rand s are independently 0, 1 or 2.
  11. 11. The compound of claim 1 selected from the group consisting of:
    15 2-(1-acryloylpiperidin-4-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
    N-isopropyl-2-(3-(N-methylacrylamido)azetidin-1-yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide;
    2-((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-ylamino)-N-isopropyl-5H20 pyrrolo[2,3-b]pyrazine-7-carboxamide; (S)-2-(1-acryloylpyrroIidin-3-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
    (S)-2-((1-acryloylpyrrolidin-2-yl)methyIamino)-N-isopropyl-5H-pyrrolo[2,3b]pyrazine-7-carboxamide;
    25 2-((1R,3R)-3-acrylamidocyclobutylamino)-N-isopropyl-5H-pyrrolo[2,3b]pyrazine-7-carboxamide; and, (S)-2-((1-acryloylpyrrolidin-3-yl)methylamino)-N-isopropyl-5H-pyrrolo[2,3b]pyrazine-7-carboxamide;
    (R)-4-(1-acryloylpiperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 30 (R)-4-(1 -acryloylpiperidin-3-ylamino)-1 H-pyrrolo[2,3-b]pyridine-3-carbonitrile;
    (R)-1-(3-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
    315
    1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methy[piperidin-1yl)prop-2-en-1-one;
    1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-hydroxypiperidin-1yl)prop-2-en-1-one;
    5 (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-1yl)prop-2-en-1-one;
    1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-110 yl)prop-2-en-1-one;
    1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1yl)prop-2-en-1-one;
    1-((3S,4R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-fluoropiperidin-1yl)prop-2-en-1-one;
    15 1 -((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-ethylpiperidin-1 -yl)prop2-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-yI)tetrahydro-1 H-pyrrolo[2,3-
    c]pyridin-6(2H,7H,7aH)-yl)prop-2-en-1-one;
    20 (R)-1 -(3-(3-chloro-1 H-pyrrolo[2,3-b]pyridin-4-ylamino)piperidin-1 -yl)prop-2-en1-one;
    1 -((1 R,2R,5R)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-8azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one;
    1-((2R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-225 (hydroxymethyl)piperidin-l -yl)prop-2-en-1 -one;
    1-((3R,5R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1yl)prop-2-en-1-one;
    (R)-1-(3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
    30 1 -((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1 yl)prop-2-en-1-one;
    316
    1-((2S,5R)-5-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2methylpiperidin-1 -yl)prop-2-en-1 -one;
    1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1yl)prop-2-en-1-one;
    5 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-2en-1-one;
    1- ((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1-
    10 yl)prop-2-en-1-one;
    (R)-1-(3-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2en-1-one;
    (R) -4-(1-acryloylpiperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5carbonitrile; and,
    15 (3R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-acryloylpiperidine-3carbonitrile; or, a pharmaceutically acceptable sait thereof.
  12. 12. A compound of claim 1 wherein the compound is selected from the group consisting of:
    20 2-(1-acryIoylpiperidin-4-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
    N-isopropyl-2-(3-(N-methylacrylamido)azetidin-1-yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxamide;
    2- ((3R,4R)-1-acryloyl-3-hydroxypiperidin-4-ylamino)-N-isopropyl-5H-
    25 pyrrolo[2,3-b]pyrazine-7-carboxamide;
    (S) -2-(1-acryloylpyrrolidin-3-ylamino)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7carboxamide;
    (S)-2-((1-acryloylpyrrolidin-2-yl)methylamino)-N-isopropyl-5H-pyrrolo[2,3-
    b] pyrazine-7-carboxamide;
    30 1 -((3aS,7aS)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydro-1 H-pyrrolo[2,3-
    c] pyridin-6(2H,7H,7aH)-yl)prop-2-en-1-one;
    317
    1 -((1 R,2R,5R)-2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8azabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1 -one;
    1-((3R,4S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-methylpiperidin-1yl)prop-2-en-1-one;
    1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1yl)prop-2-en-1-one; and, (R)-4-(1-acryloylpiperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; or, a pharmaceutically acceptable sait thereof.
  13. 13. A pharmaceutical or a veterinary composition comprising a compound of claim 1, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.
  14. 14. A treating or preventing a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigoid, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, celiac diseases, proctitis, éosinophilie 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 dépréssion disorder, allergy, asthma, Sjogren’s disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anémia, autoimmune atrophie gastritis of pernicious anémia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, 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, intervertébral dise, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancréas, skin, small intestine, or trachea, or xeno transplantation, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvénile onset diabètes, and complications from diabètes, or thyroiditis, chronic pulmonary obstructive disorder, acute respiratory disease, cachexia, cancer,
    318 including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, leukemia, adult T cell leukemia activated B-cell like, diffuse large B cell lymphoma, kidney cancer, lung cancer, muscle 5 cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma septic shock, cardiopulmonary dysfunction, acute myeloid leukemia, T cell acute lymphoblastic leukemia, multiple myeloma, myeloproliferative disorders, proliférative diabetic retinopathy, or angiogenicassociated disorders including solid tumors, pancreatic cancer, brain tumors,
    10 gliomas including astrocytoma, oligodendroglioma, and glioblastoma, acute CNS trauma including traumatic brain injury, encephalitis, stroke, and spinal cord injury, epilepsy, seizures, chronic neuroinflammation associated with neurodegeneration including Alzheimer’s disease, Parkinson’s disease, Amyotropic Latéral Sclerosis, Huntington's disease, cérébral ischemia, fronto-temporal lobe dementia, and with
  15. 15 neuropsychiatrie disorders including schizophrenia, bipolar disorder, treatment résistant dépréssion, Post Traumatic Stress Disorder, anxiety, and auto-antibodies mediated encéphalopathies, Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, her20 petic keratitis, conical keratitis, corneal épithélial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-KoyanagiHarada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergie conjunctivitis, and ocular neovascularization. Use of a compound of claim 1, or a pharmaceu25 tically acceptable sait thereof, in the manufacture of a pharmaceutical or veterinary composition for A.
    15. Use of a compound of claim 1, or a pharmaceutically acceptable sait thereof, in the manufacture of a pharmaceutical or veterinary composition for treating 30 or preventing inflammatory bowel disease.
    319
  16. 16. A coumpond of claim 1, or a pharmaceutically acceptable sait thereof, for use in a method of A.
  17. 17. A compound of claiml, or a pharmaceutically acceptable sait thereof,
    5 for use in a method of treating or preventing inflammatory bowel disease in a mammal.
OA1201600205 2013-12-05 2014-11-20 Pyrrolo[2,3-D]Pyrimidinyl, Pyrrolo[2,3B]Pyrazinyl and Pyrrolo[2,3-D]Pyridinyl Acrylamides. OA17901A (en)

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