 pyrrolo [2,3-d] pyrimidine derivatives as janus kinase (jak) inhibitors
专利摘要:
abstract “pyrrolo[2,3-d]pyrimidine derivatives as janus kinase (jak) inhibitors” are described herein pyrrolo{2,3-d}pyrimidine derivatives, their use as janus kinase (jak) inhibitors, and pharmaceutical compositions containing them. 公开号:BR112015019634A2 申请号:R112015019634 申请日:2014-02-11 公开日:2019-12-17 发明作者:Gonzales Andrea；Edward Fenwick Ashley；Parikh Mihir D；David Trzupek John；Walter Strohbach Joseph；Edward Flanagan Mark；J Mitton-Fry Mark；Frank Brown Mathew；L Vazquez Michael；Kaila Neelu；Jal Unwalla Rayomand；E Tenbrink Ruth；Allan Johnson Timothy 申请人:Pfizer； IPC主号:
专利说明:
“PIRROLEUM DERIVATIVES [2,3-D] PYRIMIDINE AS INHIBITORS OF JANUS KINASE (JAK)” FIELD OF THE INVENTION [001] The present invention provides pharmaceutically active pyrrolo [2,3-d] pyrimidine compounds and the like. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention is also directed to compositions comprising methods for making such compounds, and methods for treating and preventing JAK-mediated conditions. BACKGROUND OF THE INVENTION [002] Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified as tyrosine and serine / threonine kinase. Inappropriate kinase activity, appearing from mutation, overexpression, or inappropriate regulation, disregulation or deregulation, as well as over or under production of growth factors or cytokines has 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, neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cell responses related to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases. [003] Thus, protein kinase has 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 role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004 , 5, 253)). When connecting to your receivers 2/111 cytokines activate JAK which then phosphorylates the cytokine receptor, thus creating anchorage sites for signaling molecules, notably the members of signal transducers and activators of the transcription family (STAT) that ultimately lead to expression of gene. Several 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), the gamma C family (IL-2, IL-7 , TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), the single chain family (EPO , GH, PRL, TPO), the tyrosine kinase receptor (EGF, PDGF, CSF-1, HGF), and the coupled protein G receptors, (AT1). [004] There remains a need for new compounds that selectively and effectively inhibit JAK enzymes, and in particular JAK1, vs. JAK2. JAK1 is a member of the Janus family of the protein kinase composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed at various levels in all tissues. Many tyrosine kinase receptors signal through pairs of JAK kinases in the following combinations: JAK1 / JAK2, JAK1 / JAK3, JAK1 / TYK2, JAK2 / TYK2 or JAK2 / JAK2. JAK1 is the most widely paired JAK kinase in this context and is required for signaling by γ-common (IL-2Ry) cytokine receptors, the IL-6 receptor family, Type I, II and III receptor families and receptor family IL-10. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity may prove useful in the treatment of various immune disorders (Murray, PJJ Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al „Gene, 285, 1-24 (2002); O'Shea, J. J „et al., Cell, 109, (suppl.) S121-S131 (2002)) while avoiding thrombopoietin (EPO) and (EPO) dependent erythropoietin signaling de JAK2 (Neubauer H., et al., Cell, 93 (3), 397-409 (1998); Parganas E „et al., Cell, 93 (3), 385-95 (1998)). 3/111 SUMMARY OF THE INVENTION [005] The present invention provides a compound of formula I having the or a pharmaceutically acceptable salt thereof, where R 1 is hydrogen or C 1 -C 4 alkyl, such alkyl being optionally further substituted by one or more substituents selected from a group consisting of halo, hydroxy, methoxy, amino, CF3 , and C3-C6 cycloalkyl; R 2 and R 3 are each independently hydrogen, deuterium, C 1 -C 6 alkyl branched or linear, C 3- C 6 cycloalkyl, C 1 -C 6 perfluoroalkyl branched or linear, CrC 6 alkoxy branched or linear, Ci-C 6 branched or linear chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, aryl, heteroaryl, (aryl) Ci-C 6 branched or linear chain alkyl, (heteroaryl) Ci-C 6 alkyl de straight or branched chain, (heterocyclic) C 1 -C 6 straight or branched chain alkyl, (CrC 6 straight or branched chain alkyl) aryl, heteroaryl (CrC 6 straight or branched chain alkyl), (branched 6 -chain alkyl) or linear) heterocyclic, (branched or linear chain CrC 6 alkoxy) carbonyl, (branched or linear chain CrC 6 alkyl) amino-carbonylamino, or (branched or linear chain CrC 6 alkyl) aminocarbonyl; R 4 is selected from hydrogen, deuterium, Ci-C 6 alkyl branched or straight chain Ci-C6 perfluoroalkyl branched or straight chain alkyl , aryl, and alkylaryl; X is selected from -NH- and - CR to R b -, where (a) R a and R b are independently hydrogen, deuterium, C r C 6 alkyl branched or linear, C 3 -C 6 cycloalkyl, aryl, (aryl) C 1 -C 6 branched or straight chain alkyl, heteroaryl, (CrC 6 6-branched or linear chain) heteroaryl, (heteroaryl) C 1 -C 6 branched or straight chain alkyl, (heterocyclic) Ci-C 6 branched or straight chain alkyl, or (b) R a and R b together 4/111 form a chain comprising - (CR c Rd) / -, where R c and Rd are independently hydrogen, deuterium, CrC 6 straight or branched chain aryl, aryl, (CrC 6 straight or branched chain alkyl) aryl , heteroaryl, (CrC 6 branched or straight chain alkyl) heteroaryl, halo, CN, CF 3 , hydroxyl, CONH 2 , or SO 2 CH 3 ; Y is -AR 5 , where A is a bond, - (CH2) k- or - (CD2) k-- and R 5 is branched or linear C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl , or -NR to R b , or is a partially saturated, saturated or unsaturated dicyclic or monocyclic ring structure containing a total of five to eleven atoms having one to three hetero atoms independently selected from a group consisting of oxygen, nitrogen, and sulfur, such alkyl, C 3 -C 6 cycloalkyl, aryl, or dicyclic or monocyclic ring structure being optionally further substituted by one or more substituents selected from a group consisting of deuterium, halo, C 1 -C 6 alkyl branched or straight chain, CN, hydroxyl, CF 3 , --OR e , -NR and R f , S (O) p R e and C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by a or more substituents selected from a group consisting of halo, CN, hydroxyl, CONH 2 , and SO 2 CH 3 , where (a) R a · and R b · Are independently hydrogen, deuterium, C 1 -C 6 alkyl branched or linear, C 3 -C 6 cycloalkyl, aryl, (CrC 6 alkyl branched or linear) aryl, heteroaryl, or (CrC 6 alkyl branched or linear) heteroaryl, where such alkyl and cycloalkyl can be replaced by one or more R C ', or (b) R a ' and R b 'together form a chain comprising - (CR C ' Rd ') /> where Rc' θ Rj are independently hydrogen, deuterium, Ci-C6 branched chain alkyl or straight, aryl (C r C6 branched chain alkyl or straight) aryl, heteroaryl, (-C 6 branched alkyl or linear) heteroaryl, halo, CN, hydroxyl, CF 3 , CONH 2 , -OR e , -NR and R f , or -S (O) p R e ; where R e and R f are independently hydrogen, deuterium, C 1 -C 6 branched or straight chain alkyl, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH 2 ; j is 2, 3, 4 or 5; k is 1.2; 3, or 4; p is 0.1 or 2; and, n is 1 or 2. 5/111 [006] In other respects, the present invention also provides: pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula I; methods to treat conditions or disorders including myositis, vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depression, allergy, asthma, Sjogren's disease, dry eye syndrome, transplant rejection, cancer, inflammatory disease intestinal, septic shock, cardiopulmonary dysfunction, acute respiratory disease, or cachexia by administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; methods to treat conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritic conditions, allergic reactions including allergic dermatitis in mammals, allergic diseases in horses including bite hypersensitivity, summer eczema, mild itching in horses, gasps, inflammatory airway disease, recurrent airway obstruction, airway hyperresponsiveness, and chronic obstructive pulmonary disease by administering to a mammal in need of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof ; and, methods for the preparation of compounds of the present invention. The present invention will be further understood from the following description given by way of examples only. The present invention is directed to a class of pyrrole [2,3-d] pyrimidine derivatives. In particular, the present invention is directed to pyrrolo [2,3-d] pyrimidine compounds useful as JAK inhibitors, and particularly JAK1. While the present invention is not so limited, an appreciation of various aspects of the invention will be obtained through the following discussion and examples. [007] The term "alkyl", alone or in combination, means a saturated acyclic hydrocarbon group of the formula C n H 2n + i which can be linear or branched. 6/111 Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl and hexyl. Unless otherwise specified, an alkyl group comprises 1 to 6 carbon atoms. The alkyl carbon atom content of several other hydrocarbon-containing halves is indicated by a prefix designating a higher and lower number of carbon atoms in half, that is, the prefix C, -Cj indicates one half of the integer i for the whole number j of carbon atoms, inclusive. Thus, for example, C 1 -C 6 alkyl refers to the alkyl of one to six carbon atoms, inclusive. [008] The term "hydroxy," as used here, means a radical OH. The term "heterocyclic" refers to a partially saturated or saturated heterocycle (i.e., non-aromatic) that can be attached via a ring nitrogen atom (when the heterocycle is attached to a carbon atom) or an atom ring carbon (in all cases). Likewise, when substituted, the substituent can be located on a ring nitrogen atom (if the substituent is joined via a carbon atom) or a ring carbon atom (in all cases). Specific examples include oxiranyl, aziridinyl, oxetanil, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanil, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanil and diazepinil. [009] The term "aryl" refers to a monocyclic or dicyclic aromatic hydrocarbon that can be attached via a ring carbon atom. Likewise, when substituted, the substituent can be located on a ring carbon atom. Specific examples include phenyl, toluyl, xylyl, trimethylphenyl, and naphthyl. Examples of aryl substituents include alkyl, hydroxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO 2 Me, benzyl, and substituted benzyl. [010] The term "heteroaryl" refers to an aromatic heterocycle that can be attached via a ring carbon atom (in all cases) or a ring nitrogen atom with an appropriate valence (when the heterocycle is attached The 7/111 a carbon atom). Likewise, when substituted, the substituent can be located on a ring carbon atom (in all cases) or a ring nitrogen atom with an appropriate valence (if the substituent is joined via a carbon atom). Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyriminyl. The term cycloalkyl means a saturated, monocyclic hydrocarbon group of the formula C n H 2n -i. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, a cycloalkyl group comprises 3 to 8 carbon atoms. [011] The terms "halo" and "halogen" refer to fluorine (F), chlorine (Cl), bromide (Br) or iodine (I). [012] The term mammal refers to a human, livestock or pet. [013] The term "pet" or "pets" refers to animals kept as pets or domestic animals. Examples of pets include dogs, cats, and rodents including ramisters, guinea pigs, gerbils and the like, rabbits, ferrets and birds. [014] The term “cattle” refers to animals raised or raised in an agricultural setting to make products such as food or fiber, or for their work. In some embodiments, cattle are compatible for consumption by mammals, for example, humans. Examples of farm animals include cattle, goats, horses, pigs, sheep including lambs and rabbits, as well as birds, such as chickens, ducks and turkeys. [015] The term "treating" or "treatment" means a relief from the symptoms associated with a disease, disorder or condition, or even a pause in the progression or worsening of those symptoms. Depending on the patient's illness and condition, the term “treatment” as used here may include one or more dressings, palliative, and 8/111 prophylactic treatment. Treatment may also include administering a pharmaceutical formulation of the present invention in combination with other therapies. [016] The term therapeutically effective indicates the ability of an agent to prevent, or improve the severity of, the disorder, while avoiding the side effects typically associated with alternative therapies. The phrase therapeutically effective is to be understood as being equivalent to the phrase “effective for treatment, prevention or improvement, and both intend to qualify the amount of each agent for use in the combination and therapy that will achieve the goal of improving the severity of the cancer, cardiovascular disease, or pain and inflammation and the frequency of incidence on the treatment of each agent by itself, while avoiding the side effects typically associated with alternative therapies. [017] "Pharmaceutically acceptable" means compatible for use in mammals, pets or livestock. [018] If the substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Each substituent, therefore, can be identical to or different from another substituent (s). DETAILED DESCRIPTION OF THE INVENTION [019] The present invention is related to new compounds that are selective JAK1 modulators useful for the treatment of diseases and conditions associated with JAK1 dysregulation. The present invention further provides pharmaceutical compositions comprising such JAK1 modulators as well as methods of treating and / or preventing such diseases and conditions. Therefore, the present invention provides a compound of formula I having the structure: 9/111 or a pharmaceutically acceptable salt thereof, where R 1 is hydrogen or C1-C4 alkyl, and that alkyl is optionally further substituted by one or more substituents selected from a group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl; R 2 and R 3 are each independently hydrogen, deuterium, C 1 -C 6 alkyl branched or linear, C 3- C 6 cycloalkyl, C 1 -C 6 perfluoroalkyl branched or linear, CrC 6 alkoxy branched or linear, Ci-C 6 branched or linear chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, aryl, heteroaryl, (aryl) Ci-C 6 branched or linear chain alkyl, (heteroaryl) Ci-C 6 alkyl de straight or branched chain, (heterocyclic) C 1 -C 6 straight or branched chain alkyl, (CrC 6 straight or branched chain alkyl) aryl, heteroaryl (CrC 6 straight or branched chain alkyl), (branched 6 -chain alkyl) or linear) heterocyclic, (branched or linear chain CrC 6 alkoxy) carbonyl, (branched or linear chain CrC 6 alkyl) amino-carbonylamino, or (branched or linear chain CrC 6 alkyl) aminocarbonyl; R 4 is selected from hydrogen, deuterium, straight or branched chain C1-6 alkyl, straight or branched chain C1-6 perfluoroalkyl, aryl, and alkylaryl; X is selected from -NH- and - CRaRb-, where (a) Ra and Rb are independently hydrogen, deuterium, branched or linear chain CrC6 alkyl, C3-C6 cycloalkyl, aryl, (aryl) Ci-C6 alkyl of branched or linear, heteroaryl, (CrC6 alkyl, branched or linear) heteroaryl, (heteroaryl) C1-6 alkyl, branched or linear, (heterocyclic) C1-6 alkyl, branched or linear, or (b) Ra e Rb together form a chain comprising - (CRcRd) / -, where Rc and Rd are independently hydrogen, deuterium, C 1 -C 6 branched or linear alkyl, aryl, (CrC 6 straight or branched alkyl) aryl, heteroaryl, ( Straight or branched chain alkyl CrC6) heteroaryl, halo, CN, CF3, hydroxyl, CONH2, or SO2CH3; -AR 5 Y is where A is a bond, - (CH2) k - or - (CD 2) k - , and R is C 5 -C 6 branched or straight chain alkyl, C 3 -C 6 cycloalkyl, aryl, or -NR to 'R b ', or is a partially saturated, saturated or unsaturated dicyclic or monocyclic ring structure containing a total of five to eleven atoms of 10/111 carbon having one to three heteroatoms independently selected from a group consisting of oxygen, nitrogen, and sulfur, such alkyl, C 3 -C 6 cycloalkyl, aryl, or dicyclic or monocyclic ring structure is still optionally substituted by one or more substituents selected from a group consisting of deuterium, halo, CrC 6 branched or straight chain alkyl, CN, hydroxyl, CF 3 , --OR e , NR and R f , -S (O) p R e and C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CONH 2 , and SO 2 CH 3 , where (a ) R a · and R b are independently hydrogen, deuterium, C 1 -C 6 alkyl branched or linear, C 3 -C 6 cycloalkyl, aryl, (C r C 6 alkyl branched or linear) aryl, heteroaryl, or (CrC 6 straight or branched chain alkyl) heteroaryl, where such alkyl and cycloalkyl may be sub substituted by one or more R C ', or (b) R a · and R b together form a chain comprising - (CR c Rd') r-, where R C 'and Rd' are independently hydrogen, deuterium, C r C 6 branched or linear chain alkyl, aryl, (CrC 6 branched or linear chain alkyl, heteroaryl, (CrC 6 branched or linear chain alkyljeteroaryl, halo, CN, hydroxyl, CF 3 , CONH 2 , -OR and , -NR and R f , or -S (O) p R e ; where R and and Rf are independently hydrogen, deuterium, C 1 -C 6 branched or straight chain alkyl, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH 2 ; j is 2, 3, 4 or 5; k is 1.2; 3, or 4; p is 0, 1 or 2; and, n is 1 or 2. In one embodiment, the invention provides a compound of formula IA having the structure: N N ' IA or a pharmaceutically acceptable salt thereof, where Y is -AR 5 , where 11/111 A is a bond, - (CH 2 ) k- or - (CD2) k- and R5 is branched or straight chain C1-C6 alkyl, C 3 -C 6 cycloalkyl, aryl, or -NR to R b ', or is a partially saturated, saturated or unsaturated dicyclic or monocyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from a group consisting of oxygen, nitrogen, and sulfur, with such alkyl, C 3- C 6 cycloalkyl, aryl, or dicyclic or monocyclic ring structure is further optionally substituted by one or more substituents selected from a group consisting of deuterium, halo, C r C 6 alkyl of branched or linear chain, CN, hydroxyl , CF 3 , --OR e , NR and R f , -S (O) pR e and C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CONH 2 , and SO 2 CH 3 , where (a) R a · and R b are independently and hydrogen, deuterium, C 1 -C 6 branched or linear chain, C 3 -C 6 cycloalkyl, aryl, (C r C 6 alkyl, branched or linear) aryl, heteroaryl, or (CrC 6 alkyl, branched chain or linear) heteroaryl, where such alkyl and cycloalkyl can be replaced by one or more R C ', or (b) R a · and R b together form a chain comprising - (CR c Rd) j--, where R C ' e Rd 'are independently hydrogen, deuterium, C r C 6 straight or branched alkyl, aryl, (Cree straight or branched chain alkyl) aryl, heteroaryl, (CrC 6 straight or branched chain alkyl) heteroaryl, halo, CN, hydroxyl, CF 3 , CONH 2 , -OR e , -NR and R f , or -S (O) pR e ; where R and and Rf are independently hydrogen, deuterium, C1-C6 branched or straight chain alkyl, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH2; j is 2, 3, 4 or 5; k is 1.2; 3, or 4; and, p is 0, 1 or 2. [020] In one embodiment, the invention provides a compound of formula IA wherein A is a bond and R is a C 5 -C 6 branched or straight chain alkyl, C 3 -C 6 cycloalkyl or aryl. In another embodiment, the invention provides a compound of the formula IA where A is a bond or - (CH 2 ) k--, and R 5 is C 3 -C 6 cycloalkyl sen 12/111 that such C 3 -C 6 cycloalkyl is optionally further substituted by one or more substituents selected from a group consisting of halo, C 1 -C 6 branched or straight chain alkyl, and CN where such alkyl and cycloalkyl may optionally be substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CONH 2 , and SO 2 CH 3 ; where k is 1,2, or 3. In yet another embodiment, the invention provides a compound of the formula IA with A being a bond or - (CH2) k--, and R5 being a partially dicyclic or monocyclic ring structure saturated, saturated or unsaturated containing a total of five to eleven atoms having from one to three heteroatoms independently selected from a group consisting of oxygen, nitrogen, and sulfur, with such alkyl, C 3 -C 6 cycloalkyl, aryl, or dicyclic or monocyclic ring structure is further optionally substituted by one or more substituents selected from a group consisting of deuterium, halo, C1-C6 straight or branched chain alkyl, CN, hydroxyl, CF 3 , --NR to R b ', -OR and , --S (O) pR e and C 3 -C 6 cycloalkyl; where k is 1,2, or 3. [021] In another embodiment, the invention provides the compound of the formula IB having the structure: or a pharmaceutically acceptable salt thereof, where (a) R a 'and R b · are independently hydrogen, deuterium, C 1 -C branched or straight chain alkyl, C 3 -Ce cycloalkyl, aryl, (C 1 -C alkyl of straight or branched chain) aryl, heteroaryl, or heteroaryl (C1-Ce straight or branched chain alkyl), where such alkyl and cycle 13/111 alkyl can be substituted by one or more R c , or (b) R a · and R b · together form a chain comprising - (CR c Rd) j--, where R c · and Rd 'are independently hydrogen , deuterium, Ci-C6 branched chain alkyl or straight, aryl (-C 6 branched alkyl or linearjaril, heteroaryl, (C1-C6 chain alkyl branched or linearjheteroaril, halo, CN, hydroxyl, CF 3, CONH 2 , --OR e , --NR and R f , or --S (O) pR e ; where R e and Rf are independently hydrogen, deuterium, C 1 -C 6 straight or branched chain alkyl, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH 2 ; or, (c) R a · and R b together form a partially saturated, saturated or unsaturated dicyclic or monocyclic ring structure containing a total of five to eleven atoms having from one to three independently selected heteroatoms from a group consisting of oxygen, nitrogen, and sulfur, with such a dicyclic or monocyclic ring structure still optionally being substituted by one or more substituents selected from a group consisting of deuterium, halo, C1-C6 alkyl chain branched or linear, CN, hydroxyl, CF3, --NR to R b ', --OR and , --S (O) pR e and C 3 -C 6 cycloalkyl; j is 2, 3, 4 or 5; and, p is 0, 1 or 2. [022] In another embodiment, the invention provides the compound of the formula IC having the structure: or a pharmaceutically acceptable salt thereof, where (a) R a · and R b 14/111 are independently hydrogen, deuterium, Ci-C 6 alkyl branched or straight chain, C 3 -C 6 cycloalkyl, aryl (-C 6 branched or straight chain alkyl) aryl, heteroaryl, or (Ci-C 6 alkyl straight or branched chain) heteroaryl, where such alkyl and cycloalkyl can be replaced by one or more R c , or (b) R a · and R b · together form a chain comprising - (CR C 'Rd') /> where Rc 'θ Rd' are independently hydrogen, deuterium, C 1 -C 6 alkyl branched or linear, aryl, (CrC 6 alkyl branched or linear) aryl, heteroaryl, (CrC 6 alkyl branched or linear) heteroaryl, halo, CN, hydroxyl, CF 3 , CONH 2 , --OR e , --NR and R f , or -S (O) p R e ; where R and and Rf are independently deuterium, C 1 -C 6 alkyl branched or straight chain, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH 2 ; or, (c) R a · and R b together form a partially saturated, saturated or unsaturated dicyclic or monocyclic ring structure containing a total of five to eleven atoms having one to three hetero atoms independently selected from a group consisting of oxygen , nitrogen, and sulfur, with such a dicyclic or monocyclic ring structure still optionally substituted by one or more substituents selected from a group consisting of deuterium, halo, C 1 -C 6 branched or straight chain alkyl, CN, hydroxyl , CF 3 , -NR to Rb ', --OR and , --S (O) p R e and C 3 -Ce cycloalkyl; is 2, 3, 4 or 5; and, p is 0, 1 or 2. [023] In another embodiment, the invention provides the compound of the formula ID having the structure: or a pharmaceutically acceptable salt thereof, where Y is -AR 5 , where A is a bond or - (CH 2 ) k-, and R 5 is C 1 -C branched or straight chain alkyl, C 3 -Ce 15/111 cycloalkyl, aryl, or is a partially saturated, saturated or unsaturated dicyclic or monocyclic ring structure containing a total of five to eleven atoms having one to three hetero atoms independently selected from a group consisting of oxygen, nitrogen, and sulfur, such alkyl, C 3 -C 6 cycloalkyl, aryl, or a dicyclic or monocyclic ring structure is optionally further substituted by one or more substituents selected from a group consisting of deuterium, halo, Cr C 6 alkyl of branched or straight chain, CN, hydroxyl, CF 3 , -NR to R b ', --OR and , -S (O) p R e and C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CONH 2 , and SO 2 CH 3 , where (a) R a · and R b · are independently hydrogen, deuterium, C r C 6 alkyl of branched or straight chain, C 3 -C 6 cycloalkyl, aryl, ( aryl) C 1 -C 6 alkyl branched or linear, heteroaryl, (CrC 6 alkyl, branched or linear chain) heteroaryl, (heteroaryl) C 1 -C 6 alkyl, branched or linear chain, (heterocyclic) C 1 -C 6 alkyl branched or linear chain, where such alkyl and cycloalkyl can be replaced by one or more R b , or (b) R a · and R b · together form a chain comprising - (CRc'Rd ') / -, where R b and R are independently hydrogen, deuterium, Ci-Ce alkyl branched or straight chain, aryl (-C 6 branched alkyl or linear) aryl, heteroaryl, (Ci-C 6 alkyl branched or straight chain) heteroaryl, halo, CN, hydroxyl, CF 3 , CONH 2 , -OR e , -NR and Rf, or -S (O) p R e ; where R e and Rf where they are independently hydrogen, deuterium, C 1 -C 6 alkyl branched or straight chain, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH 2 ; j is 2, 3, 4 or 5; k is 1,2, or 3; and, p is 0, 1 or 2. In one embodiment, the invention provides the compound of the formula ID wherein R 5 is C r C 6 alkyl of branched or straight chain or C 3 -C 6 cycloalkyl. [024] In another embodiment, the invention provides the compound of the formula ID where A is a bond or - (CH 2 ) k -, and R 5 is a dicyclic ring structure or 16/111 monocyclic partially saturated, saturated or unsaturated containing a total of five to eleven atoms having from one to three heteroatoms independently selected from a group consisting of oxygen, nitrogen, and sulfur, with such alkyl being C 3 -C 6 cycloalkyl, aryl, or dicyclic or monocyclic ring structure is further optionally substituted by one or more substituents selected from a group consisting of deuterium, halo, C 1 -C 6 branched or straight chain alkyl, CN, hydroxyl, CF 3 , -NR to 'R b ', --OR and , -S (O) p R e and C 3 -C 6 cycloalkyl; where R and and Rf are independently hydrogen, deuterium, C 1 -C 6 branched or straight chain alkyl, or C 3 -C 6 cycloalkyl, where such alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 , and CONH 2 ; k is 1,2, or 3; and, p is 0, 1 or 2. In another embodiment, the invention provides the compound of formula I with R 5 being an unsaturated ring structure containing a total of five to eleven atoms having one or two heteroatoms independently selected from a group consisting of oxygen, nitrogen, and sulfur. In other embodiments, the invention provides the compound of formula I with R 5 being furyl, thiofuryl, pyrrolyl, pyrazolyl, oxazolyl, azetidinyl, piperidinyl or thiazolyl, optionally substituted by one or two methyl. [025] In another embodiment, the invention provides the compound selected from a group consisting of: 4-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyridine2-sulfonamide; 2,2,2-trifluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} ethanesulfonamide; 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1-sulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1sulfonamide; 11/171 -cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methanesulfonamide; N- {cis-3 - [(butylsulfonyl) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4amine; -cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} azetidine-3-sulfonamide; 3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} azetidine-1-sulfonamide; (1 R, 5S) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -6-oxa3-azabicyclo [3.1.1] heptane- 3-sulfonamide; (3R) -3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyrrolidine-1-sulfonamide; (3S) -3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyrrolidine-1-sulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1- (oxetan-3yl) methanesulfonamide; - (3,3-difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methanesulfonamide; trans-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutylcyclo-butanesulfonamide; cis-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutylcyclobutane-sulfonamide; N- [cis-3 - ({[(3,3-difluorocyclobutyl) methyl] sulfonyl} methyl) cyclobutyl] -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4-amine; (1 S, 5S) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -3-azabicyclo [3.1.0] hexane- 3-sulfonamide; (1 R, 5R) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4 18/111 il) amino] cyclobutyl} -3-azabicyclo [3.1.0] hexane-3-sulfonamide; (3R) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile; - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] -4 (trifluoromethyl) piperidin-4-ol; N- (cis-3 - {[(4,4-difluoropiperidin-1-yl) sulfonyl] methyl} cyclobutyl) -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4-amine; (3S) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile; N- (cis-3 - {[(3-chloro-4-fluorophenyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7H-pyrrolo [2,3d] pyrimidin-4-amine; N- (cis-3 - {[(2-cyclopropylethyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7H-pyrrolo [2,3d] pyrimidin-4-amine; N-methyl-N- [cis-3 - ({[1 - (propan-2-yl) pyrrolidin-3-yl] sulfonyl} methyl) cyclobutyl] -7Hpyrrolo [2,3-d] pyrimidin-4-amine; 3,3-difluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutane-sulfonamide; 1- [3- (cyanomethyl) oxetan-3-yl] -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -methanesulfonamide; cis-3- (cyanomethyl) -3-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -cyclobutanesulfonamide; trans-3- (cyanomethyl) -3-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} cyclobutanesulfonamide; N- (2-cyanoethyl) -N-methyl-N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} sulfuric diamide; N - {(1S, 3R) -3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclopentyl} propane- 1-sulfonamide; 11/191 3- (2-hydroxypropan-2-yl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutylbenzene-sulfonamide; N- (cyclopropylmethyl) -N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] sulfuric cyclobutyldiamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -4- (1 H-pyrazol-3i) pi peridine-1-sulfonamide; 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -2,6 dihydropyrrolo [3,4-c] pyrazole-5 (4H ) -sulfonamide; 2- [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyridine-4-carbonitrile; (1 S, 3S) -3 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclopentanecarbonitrile; (1 R, 3R) -3 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclopentanecarbonitrile; -cyclopropyl-N- {trans-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methane sulfonamide; 3-cyano-N- {trans-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -pyrrolidine-1-sulfonamide; N-methyl-N- {trans-3 - [(propylsulfonyl) methyl] cyclobutyl} -7H-pyrrolo [2,3-d] pyrimidin-4amine; and, 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1,3thiazolo-5-sulfonamide; or, a pharmaceutically acceptable salt thereof. [026] In another embodiment, the invention provides the compound selected from the group consisting of: - (3,3-difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclo-butylmethanesulfonamide; trans-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] 20/111 cyclobutylcyclo-butanesulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1sulfonamide; 3,3-difluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutane-sulfonamide; and, N - {(1S, 3R) -3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclopentyl} propane1-sulfonamide; or, a pharmaceutically acceptable salt thereof. [027] In other embodiments, the invention provides the compound selected from the group consisting of: (3R) -3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} pyrrolidine-1-sulfonamide; (1 R, 5S) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -6-oxa- 3-azabicyclo [3.1.1] heptane-3-sulfonamide; (1 S, 5S) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -3-azabicyclo [3.1.0] hexane- 3-sulfonamide; N- (2-cyanoethyl) -N-methyl-N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} sulfuric diamide; and, 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -2,6 dihydropyrrolo [3,4-c] pyrazole-5 (4H ) -sulfonamide; or, a pharmaceutically acceptable salt thereof. [028] In another embodiment, the invention provides the compound selected from the group consisting of: (3R) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile; - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] -4 (trifluoromethyl) piperidin-4-ol; N- (cis-3 - {[(4,4-difluoropiperidin-1-yl) sulfonyl] methyl} cyclobutyl) -N-methyl-7H21 / 111 pyrrolo [2,3-d] pyrimidin-4-amine; (3S) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile; and, or, a pharmaceutically acceptable salt thereof. [029] In yet another embodiment, the invention provides the compound selected from the group consisting of: (1 R, 3R) -3 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclo-pentanocarbonitrile; (1 S, 3S) -3 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclo-pentanocarbonitrile; 2 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyridine-4-carbonitrile; N- [cis-3 - ({[(3,3-difluorocyclobutyl) methyl] sulfonyl} methyl) cyclobutyl] -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4-amine; and, N- {cis-3 - [(butylsulfonyl) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4amine; or, a pharmaceutically acceptable salt thereof. [030] Particularly preferred embodiments include 2-methyl-N- {cis-3 [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1,3-thiazol-5- sulfonamide, N {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -propane-1-sulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1-oxetan-3ylmethanesulfonamide; 1- (3,3-difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} -methanesulfonamide; 3,3-difluoro-N- {cis-3- [methyl (7Hpyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutanesulfonamide; trans-3 (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutanesulfonamide; (1 S, 5S) -1-cyano-N- {cis-3- [methyl I (7H-pyrrolo [2,3-d] pyramidi-n-4yl) amino] cyclobutyl} -3-azabi-cycle [3.1.0] hexane-3-sulfonamide; and, (3S) -1 - [({cis-3 [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3 22/111 carbonitrile; or, a pharmaceutically acceptable salt thereof. [031] The present invention also provides a veterinary or pharmaceutical composition comprising a compound of the formula I, IA, IB, IC or ID, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [032] The present invention also provides a method for treating a disorder or condition related to dysregulation of JAK, and particularly JAK1, in a subject, comprising administering to the subject a therapeutically effective amount of the compound having the structure of formula I, IA , IB, IC or ID, or a pharmaceutically acceptable salt thereof. In certain modalities, the disorder or condition treated by the method is selected from among rheumatoid arthritis, myositis, vasculitis, pemphigus, Crohn's disease, ulcerative oolitis, Alzheimer's disease, lupus, nephritis, psoriasis, atopic dermatitis, autoimmune thyroid disorders , multiple sclerosis, major depression, allergy, asthma, Sjogren's disease, dry eye syndrome, organ transplant rejection, xeno transplantation, Type I diabetes and complications of diabetes, cancer, leukemia, acute T-cell lymphoblastic leukemia, leukemia adult B cell-activated T-cell disease, diffuse large B-cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic obstructive pulmonary disorder, acute respiratory disease, and cachexia comprising the step of administering to a subject an effective amount of a composition comprising a compound of the formula I, IA, IB, IC or ID. In certain embodiments, the therapeutically effective amount used according to the method is 0.01 mg / kg of body weight / day to 100 mg / kg of body weight / day. In other embodiments, the therapeutically effective amount used according to the method is a therapeutically effective amount is 0.1 mg / kg body weight / day to 10 mg / kg body weight / day. In the practice of the method, the compound of formula I is preferably selected from N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -propane-1-sulfonamide , N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin23 / 111 4-i 1) amino] cyclobutyl} -1-oxetan-3-ylmethanesulfonamide; 1 - (3,3-difluorocyclobutyl) -N- {cis3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -methanesulfonamide; 3,3difluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} cyclobutanesulfonamide; trans-3- (cyanomethyl) -N- {cis-3- [methyl (7Hpyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -cyclobutanesulfonamide; (1 S, 5S) -1-cyanoN- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -3-azabi- cycle [3.1.0] hexane-3-sulfonamide; and, (3S) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile ;, or a salt pharmaceutically acceptable. [033] The present invention further provides a method for treating or preventing a disorder or condition selected from atopic dermatitis, eczema, scleroderma, pruritus, other pruritic conditions, allergic reactions including allergic dermatitis in mammals, allergic diseases in horses including hypersensitivity to bite, summer eczema, mild itching in horses, sighs, inflammatory airway disease, recurrent airway obstruction, and airway hyperresponsiveness by administering to a mammal in need of a therapeutically effective amount of a compound of formula I, IA, IB, IC or ID, or a pharmaceutically acceptable salt thereof. [034] In certain embodiments, the therapeutically effective amount used according to the method is 0.01 mg / kg body weight / day to 100 mg / kg body weight / day. In other embodiments, the therapeutically effective amount used according to the method is where the therapeutically effective amount is 0.1 mg / kg of body weight / day to 10 mg / kg of body weight / day. According to the method, the mammal treated with the compound of the invention is selected from domestic animals, dogs, and livestock. In certain embodiments, the compound of the formula I, IA, IB, IC or ID, or a pharmaceutically acceptable salt thereof, can be administered according to the method orally, parenterally or topically. 24/111 [035] In the practice of the method, the compound of formula I is preferably selected from N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1-sulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4i) amino] cyclobutyl I} -1 -oxetan-3-ylmethanesulfonamide; 1 - (3,3-difluorocyclobutyl) -N- {cis-3 [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methanesulfonamide; 3,3-difluoroN- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutanesulfonamide; trans-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutanesulfonamide; (1 S, 5S) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -3-azabi-cycle [3.1.0] hexane-3-sulfonamide; and, (3S) -1 - [({cis-3 [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3carbonitrile; or, a pharmaceutically acceptable salt thereof. [036] The compounds that have the same molecular formula, but differ in the nature or binding sequence of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers" will be appreciated by those skilled in the art that the compound of formula I, IA, IB, IC or ID can exist as cis- and trans- achiral diastereomers. [037] Included in the scope of the described compounds are all (e.g., cis-, trans-, or diastereomers) of the compounds described here alone as well as any mixtures. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are included in the compounds described. Stereomeric mixtures, for example, mixtures of diastomers, can be separated into their corresponding isomers in a known manner by means of compatible separation methods. Diastomeric mixtures, for example, can be separated into their individual diastereomers by means of fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can happen both in the 25/111 level of one of the initial compounds or in a compound of the formula I, IA, IB, IC or ID itself. Enantiomers can be separated from the formation of diastereomeric salts, for example by the formation of salt with a pure enantiomer chiral acid, or by means of chromatography, for example, by HPLC, using chromatographic substrates with chiral ligands. [038] In therapeutic use to treat disorders in a mammal, a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections into the afflicted area. Topical administrations include treatment of skin or organs readily accessible by local application, for example, eyes and ears. It also includes transdermal delivery to generate a systemic effect. Rectal administration includes the suppository form. Preferred routes of administration are oral and parenteral. [039] The pharmaceutically acceptable salts of the compounds of the formula I, IA, IB, IC or ID include the addition of acid and base salts thereof. Compatible acid addition salts formed from acids that form non-toxic salts. Examples include salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsilate, citrate, cyclamate, edisylate, esilate, format, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrate / chlorine, hydrobromide / bromide, hydroiodine / iodine, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrate , pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. [040] Compatible base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olami 26/111 na, potassium, sodium, tromethamine and zinc. [041] Hemisals of acids and bases can also be formed, for example, hemisulfate and hemicalcio salts. For a review of compatible salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). [042] The pharmaceutically acceptable salts of the compounds of the formula I, IA, IB, IC or ID can be prepared, respectively, by one or more of the three methods: (i) the compound of the formula I, IA, IB, IC or ID with the desired acid or base; (ii) removing a labile or acid labile protecting group from a compatible precursor of the compound of formula I, IA, IB, IC or ID or by a ring opening compatible cyclic precursor, for example, a lactone or lactams , using the desired base or acid; or (iii) converting a salt of the compound of the formula I, IA, IB, IC or ID to another by reacting it with an appropriate base or acid through a compatible ion exchange column. All three reactions are typically performed in the solution. The resulting salt can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized. [043] The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee, levigation, emulsifier, encapsulation, trapping, lyophilization or drying processes. pulverization. [044] Pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate the processing of the active compound into preparations, which can be used pharmaceutically. The formulation itself is dependent on the chosen route of administration. Pharmaceutically acceptable carriers and excipients are generally co 27/111 known to those skilled in the art and are then included in the present 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 short acting, quick release, long acting, and sustained release. In this way, pharmaceutical formulations can also be formulated for a control release or for a slow release. [045] Pharmaceutical compositions compatible for use in the present invention include compositions where the active ingredients are contained in an amount sufficient to achieve the intended purpose, that is, the control or treatment of disorders or diseases. More specifically, a therapeutically effective amount means an effective amount of the compound to prevent, alleviate or ameliorate the symptoms / signs of the disease or prolong the survival of the subject being treated. [046] The amount of active component, which is the compound of this invention, in the pharmaceutical composition and the unit dosage form thereof, can vary to be adjusted widely depending on the mode of administration, the potency of the particular compound and the desired concentration. The determination of a therapeutically effective amount is well within the skill of those skilled in the art. Generally, the amount of active component will vary between 0.01% to 99% by weight of the composition. [047] Generally, a therapeutically effective amount of the active component dosage 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 the 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 understood that the dosages may vary depending on the requirements of each subject and the severity of the disorders or diseases being treated. [048] The desired dose can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example 11/28, such as two, three, four or more sub-doses per day. The sub-dose itself can be further divided, for example, into a number of administrations that are vaguely discreetly spaced; such as multiple inhalations from an insufflator or by applying a plurality of drops to the eye. [049] Also, it is understood that the initial dosage administered can be increased to the upper level in order to quickly reach the desired plasma concentration. On the other hand, the initial dosage may be less than optimal and the daily dosage may be increased progressively during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two or four times a day. [050] The compounds of the present invention are directed to pyrrole [2,3-d] pyrimidine compounds useful as inhibitors of Janus Kinase (JAK-i). They are useful as therapeutic agents in connection with the treatment or prevention of a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, Crohn's disease, ulcerative oolitis, Alzheimer's disease, lupus, nephritis, psoriasis, dermatitis atopic, autoimmune thyroid disease, multiple sclerosis, major depression, allergy, asthma, Sjogren's disease, dry eye syndrome, organ transplant rejection, xeno transplantation, Type I diabetes, and complications of diabetes, cancer, leukemia, leukemia acute T-cell lymphoblasts, adult B-cell activated T-cell leukemia, diffuse large B-cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic obstructive pulmonary disorder, acute respiratory disease, cachexia, and other indications where immunosuppression / immunomodulation could be desirable, comprising the step of administering to a subject a effective use of a compound of the invention. [051] There are substantial needs for effective and safe agents to control JAK-related disorders, such as atopic dermatitis, in both humans and animals. The market for treating atopic dermatitis in animals is current 29/111 dominated by corticosteroids, which cause undesirable and painful side effects in animals, specifically in pets such as dogs. Antihistamines are also used, but they are not very effective. A formulation for cyclosporine canines (ATOPICA ™) is currently being marketed for atopic dermatitis, but it is expensive and has a slow start of effectiveness. In addition, there are Gl tolerance fabrics with ATOPICA ™. The compounds of the present invention are JAK inhibitors with selective efficacy against JAK1. These compounds are expected to provide an alternative to steroid use and provide a resolution for chronic itching and inflammation that could either persist in atopic dermatitis or regress slowly followed by removal of the allergenic or causative agent, such as fleas in allergic dermatitis for fleas. [052] The compounds of the present invention can be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents that modulate a mammalian immune system or anti-inflammatory agents. These agents may include, but are not limited to, cyclosporin A (eg Sandimmune ™ or Neoral ™, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (eg Cellcept ™, azathioprine (eg Imuran ™ ), daclizumab (for example, Zenapax ™), OKT3 (for example, Orthocolone ™), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (for example, prednisolone or dexamethasone). administered as part of the same or separate dosage forms, through the same or a different route of administration, and in the same or different administration schedules according to standard pharmaceutical practice known to a person skilled in the art. [053] Therefore, the invention provides methods for 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 30/111 more compounds described here to the subject. Compatible subjects that can be treated include wild or domestic animals, pets, such as dogs, cats, horses and the like; farmed animals including cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhesus monkeys and cinomolgos (also known as crab eaters or long tail) monkeys, marmosets, monkeys, chimpanzees, simians and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier. [054] Conditions in which selective targeting of the JAK pathway or modulation of JAK kinase, particularly JAK1, are contemplated to be therapeutically useful include, arthritis, asthma, autoimmune diseases, cancers or tumors, diabetes, certain eye diseases, disorders or conditions, inflammation, intestinal inflammation, allergies or conditions, neurodegenerative diseases, psoriasis, and transplant rejection. The conditions that can benefit from selective JAK1 inhibitors are discussed in more detail below. [055] Therefore, the compound of formula I, IA, IB, IC or ID, or its pharmaceutically acceptable salts, and their pharmaceutical compositions can be used to treat a variety of conditions or diseases such as the following: [056] Arthritis, including rheumatoid arthritis, junven arthritis, and psoriatic arthritis; [057] Autoimmune diseases or disorders, including those designated as single cell or single organ type autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease , autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, aggressive chronic hepatitis, ulcerative oolitis and membranous glomerulopathy, those designated to involve systemic autoimmune disorders, for example lupus 11/311 systemic erythematosus, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which may be based on O (humoral) cells or with T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, juvenile Type I early diabetes or thyroiditis; [058] Cancers or tumors, including cancers of the gastrointestinal / alimentary tract, colon cancer, liver cancer, skin cancer including mast cell tumors and squamous cell carcinoma, breast or breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, including acute myeloid leukemia and chronic myeloid leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myelomas, including multiple myeloma, rheumatic diseases, diabetic proliferative retinopathy, or angiogenic-associated disorders including solid tumors; [059] Diabetes, including Type I diabetes or diabetes complications; [060] Eye disorders, disorders or conditions including autoimmune eye diseases, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with the disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, epithelial corneal dystrophy, keratoleukoma, keratoleukoma ocular, ulcer, scleritis, Graves' ophthalmopathy, Mooren's Vogt-Koyanagi-Harada syndrome, dry keratoconjunctivitis (dry eye), flictenula, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, or neovascular; [061] intestinal inflammation, allergies or conditions including Crohn's disease and / or ulcerative oolitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis; [062] Neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Hunting's disease 32/111 ton, cerebral ischemia, neurodegenerative disease or caused by traumatic injury, attack, glutamate neurotoxicity or hypoxia; ischemic / reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or platelet aggregation; [063] Skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other pruritic conditions; [064] Allergic reactions including allergic dermatitis in mammals (including allergic diseases in horses such as hypersensitivity to bite), summer eczema, mild itching in horses, sighs, inflammatory airway disease, recurrent airway obstruction, airway hyperresponsiveness , or chronic obstructive pulmonary disease; [065] Asthma and other obstructive airway diseases, including chronic or confirmed asthma, late asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, or dust asthma; [066] Transplant rejection, including pancreatic islet transplant rejection, bone marrow transplant rejection, host versus graft disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc , islet, kidney, limbs, liver, lung, muscle, myoblasts, nerve, pancreas, skin, small intestine, or trachea, xeno transplant; and [067] Another embodiment provides a method for selectively inhibiting a JAK1 enzyme, which includes contacting the JAK enzyme with either a non-therapeutic amount or a therapeutically effective amount of one or more compounds currently taught. Such methods can occur in vivo or in vitro. In vitro contact may involve a screening assay to determine the effectiveness of one or more compounds against the selected enzyme in varying amounts or concentrations. In vivo contact with a therapeutically effective amount of one or more compounds can en 33/111 return to the treatment of a disease, disorder or condition described or prophylaxis of organ transplant rejection in the animal in which the contact occurs. The effect of one or more compounds on the JAK enzyme and / or the host animal can also be determined or measured. Methods for determining JAK activity include those described in the Examples as well as those described in WO99 / 65908, WO 99/65909, WO01 / 42246, W002 / 00661, W002 / 096909, W02004 / 046112 and W02007 / 012953. CHEMICAL SYNTHESIS [068] The following schemes and written descriptions provide general details regarding the preparation of the compounds of the invention. SULPHONAMIDES [069] The compounds of formula I, where p is 2, X is NH, Y is AR 5 , and A is a bond, can be prepared according to Scheme 1. Layout 1 Step 5 I (p = 2, X = NH, Y = AR 5 ; A = bond) [070] It will be apparent to those skilled in the art that sensitive functional groups 34/111 levels (PG) may need to be protected or unprotected during the synthesis of a compound of the invention. Protection and deprotection can be achieved by conventional methods, as described, for example, in “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc. (1999), and references there. Thus, in Scheme 1, in Step 1, a compound of formula II, where Q 1 is halogen, is treated with a protective agent for a compound of formula III, with PG 1 being an arylsulfonyl protecting group such as benzenesulfonyl, or preferably para-toluenesulfonyl ("tosyl"). The protecting group can be installed by reacting the compound of formula II with an arylchloro sulfonyl, preferably tosyl chloro, in the presence of a base such as an aqueous sodium hydroxide solution and an organic solvent such as acetone. The reaction is typically carried out at 0 ° C to about 50 ° C, preferably at about 23 ° C (room temperature). Alternatively, bases such as sodium hydride and potassium tertbutoxide can be used, employing a compatible solvent such as Ν, Ν-dimethylformamide or tetrahydrofuran. Various compounds of formula II are known in the literature and have been prepared by the above methods. For example, the synthesis of the compound of formula II, where Q 1 is Cl and R 2 and R 3 are hydrogen have been reported previously, for example in WO 2007 012953. [071] In Scheme 1, step 2 the protective compound of formula III is combined with 1-2 equivalents of an amine of formula IV in the presence of 1-3 equivalents of a base and a protic solvent to provide a compound of the formula V. compatible bases include triethylamine, diisopropylethylamine, and potassium carbonate while compatible solvents include methanol, ethanol, diisopropyl alcohol and water or mixtures thereof. The reaction is typically carried out at about 23 ° C to about 150 ° C, preferably about 75 ° C. It will be noted that the amine of formula IV contains a second amino group that is protected with a PG 2 protecting group that can be removed under conditions that do not lead to 35/111 of that of PG 1 . The PG 2 compatible protection groups include t-butoxycarbonyl (“Boc”) and (“Cbz”), preferably benzyloxycarbonyl. [072] In Scheme 1, step 3, the protecting group PG 2 is removed from the compound of formula V under conditions that do not lead to the loss of PG 1 to give a primary amine (or a salt thereof) of formula VI. When PG 2 is benzyloxycarbonyl, the benzyloxycarbonyl protecting group can be removed by hydrogenolysis with the compound of formula V being exposed to the hydrogen transfer reagent or hydrogen such as cyclohexene in the presence of a hydrogenation catalyst such as palladium hydroxide using a solvent such as methanol, acetic acid or, preferably, ethanol. Alternatively, when PG 2 is benzyloxycarbonyl, the benzyloxycarbonyl protecting group can be removed by treating the compound of formula V with a solution of hydrogen bromide (about 6 equivalents) in acetic acid optionally in the presence of a compatible solvent such as acetate ethyl at an ambient temperature of about minus 20 ° C to about 40 ° C, preferably less than 25 O. The latter deprotection method is preferred with n being 1, R 2 , R 3 and R 4 being hydrogen, R 1 is methyl, PG 1 is tosyl and PG 2 is benzyloxycarbonyl and provides the amine of formula VI as the dihydrobromide salt. When PG 2 is t-butoxycarbonyl, the t-butoxycarbonyl protecting group can be removed by treating with an excess of an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as dichloromethane or 1,4-dioxane. [073] In Scheme 1, Step 4, the primary amine formula VI (or salt thereof) is converted to a sulfonamide derivative of formula VII by treating with an activated sulfonic acid derivative of formula VIII, where Q 2 is halogen, O-alkyl or O-aryl in the presence of a base. Most commonly, VIII is a chlorine derivative with Q 2 being Cl. Various sulfonyl chlorines can be obtained from commercial sources. Also, several methods exist for the preparation of chloron sulfonyl, which are known to those skilled in the art and have been described in texts such as "Advanced Organic Chemistry" by J. March, John Wiley & Sons (1985). Typically, the amine of formula VI is treated with 36/111 is a sulfonyl chlorine derived from formula VIII where Q 2 is Cl in the presence of at least one equivalent of a base such as triethylamine or diisopropylamine in a compatible solvent such as dichloromethane, tetrahydrofuran or acetonitrile. When a salt form of the amine is used, an additional equivalent of the base is used for each equivalent of acid forming the salt. For example, using a dihydrobromide salt, two extra equivalents of base are used. The reaction can be carried out from about 20 ° C to about 50 ° C menus, preferably starting the reaction at about 0 ° C and then allowing it to warm up to about 23 ° C (room temperature). [074] Finally, in Scheme 1, Step 5, the sulfonamide derived from formula VII is deprotected to provide a compound of formula 1, where p is 2, X is NH, Y is AR 5 and A is a bond. Two methods are typically employed, the choice of which is determined by the compatibility of conditions with other functional groups in the molecule. The first method involves exposing the compound of formula VII to an excess (about 4 equivalents) of a base such as lithium hydroxide or sodium hydroxide. The reaction is carried out in a solvent mixture containing water and an alcohol such as methanol or ethanol. It can also be carried out in a mixture of water and tetrahydrofuran, and optionally an alcohol such as methanol or ethanol. The reaction can be carried out at a temperature of about 23 a to about 100 Ό, typically about 60 Ό. The second method, which is preferred in cases where there is a hydroxide-sensitive functionality such as nitrile present in the molecule, involves reacting the compound of formula VII with an excess of tetrabutylammonium fluoride (4-25 equivalents) in a solvent such as 1 , 2-dimethoxyethane or, preferably tetrahydrofuran. Deprotection is carried out at a temperature of about 0 ° to about 60 ° C, preferably about 23 ° C. [075] The compounds of formula II, where Q 1 is halogen, are either commercially available or known in the chemical literature. For example, 4-chloro7 / - / - pyrrolo [2,3-d] pyrimidine, where Q 1 is Cl and R 2 and R 3 are both hydrogen, is a commercially available compound. 37/111 [076] The compounds of formula IV are known in the chemical literature or can be prepared by standard chemical reactions well known to those skilled in the art. [077] An alternative method for preparing the compounds of the invention where p is 2, X is NH, Y is AR 5 , A is a s bond and shown in Scheme 2. Layout 2 I (p = 2, X = NH, Y = AR 5 , A = bond) [078] In Scheme 2, Step 1, a compound of formula IX is combined with a benzyloxycarbamate derived from formula X in the presence of a base (1 -5 equivalents) to provide a benzyloxycarbamate derived from formula XI. The reaction is carried out in a solvent such as water or an alcohol such as ethanol, optionally with the addition of a miscible co-solvent such as tetrahydrofuran. Compatible bases include potassium carbonate, cesium carbonate, triethylamine and diisopropylethylamine. The reaction is carried out at about 23 ° C to about 100 ° C. When n is 1, R 2 , R 3 and R 4 are hydrogen, and R 1 is methyl, the preferred conditions are to carry out the reaction in water, using a potassium carbonate (3 equivalents) as the base, starting the reaction in about 23 ° C and then heating to about 95 ° C. [079] In Scheme 2, Step 2, the benzyloxycarbamate derived from formula XI is deprotected by exposing the hydrogen transfer reagent or a hydrogen such as cyclohexene in the presence of a hydrogenation catalyst such as palladium hydroxide. At the same time, under deprotection conditions, the chlorine atom in the 2H ring position of 7H-pyrrole [2,3-d] pyrimidine is replaced with hydrogen to propose 38/111 add a hydrochlorine amine salt of formula XII. The reaction is carried out in a solvent such as methanol or ethanol at a temperature of about 50 Ό to about 80 O. When R 2 , R 3 and R 4 are hydrogen, and R 1 is methyl, the preferred conditions are to perform the reaction in ethanol at about 78 Ό using palladium hydroxide as a catalyst, and cyclohexene (about 20 equivalents) as a hydrogen transfer reagent. [080] Finally, in Scheme 2, Step 3, the hydrochlorine amine of formula XII is converted to a sulfonamide of formula I, where p is 2, X is NH, Y is AR 5 , A is a reaction bond with a sulfonic acid derived from formula VIII, where Q 2 is halogen, O-alkyl or O-aryl in the presence of at least two equivalents of a base. Most commonly, VIII is a chloron sulfonyl derivative with Q 2 being Cl. Compatible bases include triethylamine, diisopropylethylamine and potassium carbonate. Compatible solvents include Ν, Ν-dimethylformamide, and a mixture of tetrahydrofuran and water. The reaction can be carried out at a temperature of about 20 ° C to about 50 ° C, preferably at about 23 ° C. Alternatively, the hydrochlorine amine of formula XII is treated first with about 2 equivalents of trimethylchlorosilane in the presence of about 2-3 equivalents of a base such as lithium bis (dimethylsilyl) amide or sodium bis (dimethylsilyl) amide in a compatible aprotic solvent such as tetrahydrofuran. Then, after about 1 hour, about 1.2 equivalents of sulfonyl chlorine of formula VIII, Q 2 is Cl is added to provide, after processing, the sulfonamide of formula I, where p is 2, X is NH, Y is AR 5 , A is a bond. The reaction can be carried out at a temperature of about 20 ° C to about 50 ° C, preferably about 23 ° C. [081] The compounds of the formula IX, are commercially available or are known in the chemical literature. For example, 2,4-dichloro-7 / - / - pyrrole [2,3c /] pyrimidine, where R 2 and R 3 are both hydrogen, is commercially available. Its synthesis is described in PCT International Publication No. WQ2007 / 012953. SULFAMIDES [082] Qs compounds of formula I, where p is 2, X is NH, and Y is NR to R b , po 39/111 to be prepared according to Scheme 3. Layout 3 χιι [083] In Scheme 3, Step 1, an amine of formula VI (or salt thereof), PG 1 being an arylsulfonyl protecting group such as benzenesulfonyl, or preferably tosyl, is converted to oxazolidinone derived from formula XIII. First, a solution of N-chlorosulfonylisocyanate (1 equivalent) is added slowly to a solution of 2-bromoethanol (1 equivalent) at a temperature of about -40 ° C to about 10 ° C, preferably about 0 ° C. Subsequently, after 0.5 to 2 hours, an amine solution of formula VI (1 equivalent) and a base such as triethylamine or diisopropylethylamine (about 3 equivalents, plus one equivalent for each mole of acid forming a salt) is added slowly and the reaction is slowly heated to about 23 ° C over a period of about 10 to 24 hours. Compatible solvents for the reaction include chloroform or preferably dichloromethane. 40/111 [084] In Scheme 3, Step 2, the oxazolidinone derived from formula XIII is reacted with 1-3 equivalents of an amine of the formula HNR to R b , in the presence of a base (2-5 equivalents), to provide a sulfamide derived from formula XIV. Compatible bases include triethylamine and diisopropylethylamine. The reaction is preferably carried out by heating to about 90 ° C to about 150 ° in a pressure vessel using a compatible solvent such as Ν, Ν-dimethylformamide or acetonitrile. [085] In Scheme 3, Step 3, the compound of formula XIV is deprotected, removing the arylsulfonyl protecting group PG 1 to provide a sulfamide derived from formula 1, where p is 2, X is NH, and Y is NR a R b . The reaction can be carried out by one or more general methods described in Scheme 1, Step 5. Again, the choice of the deprotection method is determined by the compatibility of conditions with other functional groups in the molecule. Alternatively, the sulfamides of the formula XIV can be obtained directly from an amine of the formula VI (or salt thereof). Thus, in Scheme 3, Step 4, the amine of formula VI (or salt thereof) is treated with a sulfamoyl chloride of the formula CI-SO 2 NR to R b and a base such as triethylamine or diisopropylethylamine as described in Scheme 1, Step 4. The sulfamoyl chlorides of the formula ClSO 2 NR to R b can be prepared, in part, from the amines of the formula HNR to R b according to the procedures reviewed by WR Bowman and RJ Marmon in “Comprehensive Organic Functional Group Transformations, Volume 2 ”, Pergamon (1995). [086] The compounds of the formula I, where p is 2, X is NH, and Y is NR to R b can also be obtained directly from an amine of the formula XII (or salt thereof). Thus, in Scheme 3, Step 5, the amine of formula XII (or salt thereof) is treated with a sulfamoyl chlorine of the formula CI-SO 2 NR to R b and a base such as triethylamine or diisopropylethylamine as described in Scheme 1 , Step 4. The amines of formula XII are obtained as described in Scheme 2. The amines of formula XII (or salts thereof) can be obtained by removing the arylsulfonyl protecting group PG 1 from a compound of formula VI (referring to the Scheme 1). The lack of protection 41/111 to be carried out by one or more general deprotection methods described in Scheme 1, Step 5. The choice of deprotection method is determined by the compatibility of conditions with other functional groups in the molecule. REVERSE SULPHONAMIDES [087] The compounds of formula I, where p is 2, X is CH 2 , and Y is NR to R b , can be prepared according to Scheme 4. Layout 4 [088] In Scheme 4, Step 1, a compound of formula III (referring to the 42/111 Scheme 1), is combined with an amino alcohol of formula XV in the presence of a base and a polar solvent to provide a compound of formula XVI. Compatible bases include triethylamine and diisopropylethylamine while compatible solvents include methanol, diisopropyl alcohol and acetone. The reaction is typically carried out at about 23 ° C to about 70 ° C. Preferably, a catalytic amount (about 1 mole%) of potassium iodide is added to the reaction. [089] In Scheme 4, Step 2, the compound of formula XVI is converted to a compound of formula XVII, where LG is a leaving group such as bromine, iodine, methanesulfonate or, preferably, para-toluenesulfonate. Methods for installing such leaving groups are well known to those skilled in the art and have been described in the texts as "Advanced Organic Chemistry" by J. March, John Wiley & Sons (1985). In the case where LG is para-toluenesulfonate, the compound of formula XVI is treated with para-toluenochloride sulfonyl in the presence of a base such as triethylamine, diisopropylethylamine or Ν, Ν-dimethylaminopyridine in an aprotic solvent such as dichloromethane or tetrahydrofuran. The reaction is carried out at a temperature of about -10 ° C to about 40 ° C, preferably starting at around 0 ° C and allowing the reaction to warm up to about 23 ° C. [090] In Scheme 4, Step 3, the compound of formula XVII is combined with an acetic thioacid salt, preferably potassium thioacetate to yield an uncle ester derived from formula XVIII. The reaction is carried out in a polar solvent such as Ν, Ν-dimethylformamide or N-methylpyrrolidine, at a temperature of about 23 ° C to about 80 ° C, preferably at about 55 O. [091] In Scheme 4, Step 4, the thioester derived from formula XVIII is converted to a sulfonic acid derived from formula XIX by reaction with an aqueous solution of hydrogen peroxide, typically 30% by weight. The reaction is carried out in an acidic solvent such as acetic or formic acid at a temperature of about 0 ° C to about 40 ° C, preferably about 23 ° C. 43/111 [092] In Scheme 4, Step 5, sulfonic acid derived from formula XIX is converted to a sulfonyl chlorine derived from formula XX. Various methods for carrying out this functional group transformation are known in the literature. The preferred method is to treat the compound of formula XIX with an excess (3-15 equivalents) of thionyl chlorine in the presence of a catalytic amount of Ν, Ν-dimethylformamide in an aprotic solvent such as dichloromethane or chloroform. The reaction can be carried out from about minus 20 ° C to about 100 ° C, preferably starting the reaction at about 0 ° C, and then heating to about 75 ° C. [093] Alternatively, in Scheme 4, Step 6, the thioester derived from formula XVIII can be directly converted to a sulfonyl chlorine derived from formula XX by treatment with a chlorinating agent. Various methods for carrying out this functional group transformation are known in the literature. Chlorinating agents include chlorine gas and N-chlorosuccinimide, and a reaction is commonly carried out in the presence of an acid such as hydrochloric acid or acetic acid. Aqueous solvent systems are generally used, such as water and dichloromethane and water and acetonitrile. [094] In Scheme 4, Step 7, the sulfonyl chlorine derived from formula XX is combined with 1-3 equivalents of an amine of the formula HNR to R b to form a sulfonamide derived from formula XXI. The reaction is carried out in the presence of at least one equivalent of a base such as triethylamine or diiosopropylethylamine at a temperature from about minus 20 ° C to about 50 ° C, preferably starting the reaction at about 0 ° C and allowing the reaction to heat to about 23 ° C. The reaction is carried out in an aprotic solvent such as tetrahydrofuran or dichloromethane. [095] Finally in Scheme 4, Step 8, the arylsulfonyl protecting group PG 1 is removed to provide a compound of formula I, where p is 2, X is CH 2 , and Y is NR to R b . The reaction can be carried out by one of the two methods of deprotection 44/111 general described in Scheme 1, Step 5. The choice of deprotection method is determined by the compatibility of the conditions with the other functional groups in the molecule. The amino alcohols of formula XV are known in the chemical literature or can be prepared by methods well known to a person skilled in the art. SULPHONES, Sulfoxides and Thioethers [096] The compounds of formula I, where p is 0, 1, or 2, X is CH 2 , Y is AR 5 and A is a bond, can be prepared according to Scheme 5. Layout 5 [097] In Scheme 5, Step 1, a compound of formula XVII (referring to Scheme 4) is treated with 1-2 equivalents of a thiol of formula R 5 SH in the presence of 1-2 equivalents of a base to give a sulfide of the formula XXIII. Compatible bases include sodium hydride, sodium bis (trimethylsilyl) amide, 1.5 45/111 diazabiciclo [4.3.0] non-5-eno (DBN) and preferably 1.8 diazabiciclo [5.4.0] undec-7-eno (DBU). The reaction is carried out in a solvent such as Ν, Ν-dimethylformamide or N-methylpyrrolidinone at a temperature from about 0 ° C to about 50 ° C, preferably at about 23 ° C. [098] In Scheme 5, Step 2, the compound of formula XXIII is deprotected, removing the arylsulfonyl protecting group PG 1 to provide a compound of formula XXIV. The reaction can be carried out by one of the two general deprotection methods described in Scheme 1, Step 5. The choice of deprotection method is determined by the compatibility of conditions with other functional groups in the molecule. [099] In Scheme 5, Step 3, a sulfide of formula XXIV is oxidized to yield a sulfone of formula I, where p is 2, X is CH 2 , Y is AR 5 and A is a bond. Several methods are known in the literature and all involve the use of an oxidant such as metachloroperbenzoic acid, hydrogen peroxide, or potassium peroxymonosulfate (Oxone®). A preferred method is to treat the compound of formula XXIV with 2 equivalents of potassium peroxymonosulfate (Oxone®) in a mixture of tetrahydrofuran, ethanol and water at a temperature of about 23 ° C. The sulfide of formula XXIV can also be oxidized under milder conditions, for example, using 1 equivalent of meta-chlorobenzoic acid in a solvent such as dichloromethane at about 0 ° C to produce a sulfoxide of formula I, where p is 1 , X is CH 2 , Y and AR 5 and A are a bond. [0100] Note that the order of Steps 2 and 3 in Scheme 5, can optionally be reversed so that the oxidation step is carried out before the deprotection step. [0101] The compounds of the formula I, where p is 0, X is CH 2 , Y is AR 5 and A is a bond are prepared in Scheme 5, Step 4 removing the arylsulfonyl protecting group PG 1 from a compound of the formula XXIII. The reaction can be carried out 46/111 by one of the two general deprotection methods described in Scheme 1, Step 5. Again, the choice of deprotection method is determined by the compatibility of conditions with other functional groups in the molecule. [0102] In Scheme 5, Step 5, compounds of formula XXIII are alternatively prepared from a thioacetate derived from formula XVIII. First, the thioacetate of formula XVIII is dissolved in a solvent such as ethanol, methanol, or water (or a mixture thereof) A compatible base such as potassium carbonate or cesium carbonate (about 2 equivalents) is added and nitrogen is bubbled through through the solution to remove oxygen An alkylating agent of the formula R 5 -LG is then added, with LG being a leaving group such as bromine, iodine, methanesulfonate or para-toluene sulfonate.The reaction is conducted at a temperature from about minus 20 ° C to about 30 ° C. Preferably, the reaction is started at about 0 ° C and then allowed to warm to about 23 ° C. [0103] Many thiols of the formula R 5 SH and alkylating agents of the formula R 5 -LG can be obtained from commercial sources. Also, several methods exist for the preparation of such compounds, which are well known to those skilled in the art and have been described in the texts such as "Advanced Organic Chemistry" by J. March, John Wiley & Sons (1985). [0104] It is noted that certain compounds of the invention can be obtained by transformations of functional groups in a last stage of the synthesis, for example, by chemical modification of the groups R 4 or R 5 after performing Steps 4 or 5 in Scheme 1, Step 3 in Scheme 2, Steps 2, 3 or 4 in Scheme 3, Steps 7 or 8 Scheme 4 and Steps 2, 3, 4 or 5 in Scheme 5. Such transformations in functional groups can include a step or multiple steps, for example , the reduction of an ester to an alcohol, the reoxidation to an aldehyde, the addition of an organomagnesium reagent to form a secondary alcohol, the reoxidation to a ketone, and 47/111 finally the addition of an organomagnesium reagent to yield a tertiary alcohol. [0105] In performing the synthesis of the compounds of the invention, a person skilled in the art will recognize the need to sample and test the reaction mixtures before processing in order to monitor the progress of the reactions and decide whether the reaction should be continued or if it is ready to be processed to obtain the desired product. Common methods for testing reaction mixtures include thin layer chromatography (TLC), liquid chromatography / mass spectrometry (LCMS), and nuclear magnetic resonance (NMR). [0106] A person skilled in the art will also recognize that the compounds of the invention can be prepared as mixtures of diastereomers or geometric isomers (for example, substitution of cis and trans in a cycloalkane ring). These isomers can be separated by standard chromatography techniques, such as normal phase chromatography on silica gel, preparative reverse pressure 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 can be prepared as racemic or scalemic mixtures of enantiomers. Several methods are available for the enantiomer separation routine. A preferred method for the enantiomer separation routine is supercritical liquid chromatography employing a chiral stationary phase. EXPERIMENTAL SECTION [0107] Except where otherwise noted, reactions were carried out under a nitrogen atmosphere. Chromatography on silica gel was performed using a 250-400 mesh silica gel using pressurized nitrogen (-10-15 psi) to drive the solvent through the column ("flash chromatography"). Where indicated, mixtures of reactions and solutions were concentrated by rotary evaporation under vacuum. 48/111 Example 1: 2 ! 2 ! 2-Trifluoro-N- {cis-3- [metH (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} ethanesulfonamide Step 1: Benzyl [cis-3- (methylamino) cyclobutyl] carbamate and benzyl [trans-3 (methylamino) cyclobutyl] carbamate [0108] A 33% solution of methylamine (1000 mL, 9.13 mol) in absolute ethanol was added to a mixture of benzyl (3-oxocyclobutyl) carbamate (WO2012 / 75381 A1 and WO2012 / 09678 A1) (200 g, 0.913 mol) and acetic acid (88 ml) while stirring in ethanol (1000 ml) at 0 ° C. The reaction mixture stirred at 0 ° C for 1.5 hours and then stirred at room temperature for 2 hours. Lithium borohydride (41 g, 2.05 mol) was added in parts to a reaction mixture at -70 ° C. After the addition was complete, the reaction mixture was stirred at -70 ° C for 1 hour and then allowed to warm to room temperature for 12 hours. The reaction mixture was quenched with water (400 ml), and concentrated in vacuo to remove ethanol. The aqueous layer was acidified with concentrated hydrochloric acid at pH 2, washed with ethyl acetate (2 x 1000 ml), basified with 10% sodium hydroxide at pH 9-10 and then extracted with dichloromethane (3 x 1000 ml). The combined organic layers were washed with brine (1000 ml), dried over sodium sulfate, and concentrated to obtain the crude product as a light brown to light brown liquid. This was dissolved in dichloromethane (400 ml) and cooled to 0 ° C. The resulting resolution was added a solution of 4M HCI in dioxane (300 ml). The mixture was stirred at 0 ° C for 30 minutes, and then at room temperature for 12 hours. The reaction mixture was filtered and the remaining solid was recrystallized from a mixture of methanol and methyl tert-butyl ether to provide the cis-isomer as a white solid (111.09 g, 52%). 1 H NMR: (400 MHz, D 2 O): δ 7.33-7.38 (m, 5H); 5.02 (s, 2H), 3,833.87 (m, 1H), 3.89-3.41 (m, 1H), 2.66-2.70 (m, 2H), 2.56 (s, 3H), 2.03-2.05 (m, 2H), LC / MS (exact mass) calculated for Ci 3 H 18 N 2 O 2 ; 234,137, found (M + H + ); 235.1. 49/111 [0109] The trans isomer was isolated from the mother liquor using a supercritical fluid chromatography. Step 2: Benzyl {cis-3 - [(2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) (methyl) amino] cyclobutyl / carbamate [0110] To a solution of potassium carbonate ( 20.47 g, 148 mmol) in water (180 mL) benzyl [cis-3- (methylamino) cyclobutyl] carbamate (13.57 g, 50.2 mmol) was added, followed by 2,4-dichloro-7H- pyrrole (2,3-d) pyrimidine (9.0 g, 47.9 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred at 95 ° C overnight. The mixture was filtered to collect the solid. The filter cake was washed with water and dried in vacuo to provide the title compound (16.5 g, 89.7%) as a yellow solid. 1 H NMR (400 MHz, DMSO-de): δ 11.81 (sm 1 H), 7.65 (d, 1 H), 7.38 (m, 5 H), 7.16 (m, 1 H ), 6.67 (d, 1 H), 5.02 (s, 2 H), 4.81 (m, 1 H), 3.85 (m, 1 H), 3.25 (s, 3 H ), 2.53 (m, 2 H), 2.25 (m, 2 H). LC / MS (exact mass) calculated for C19H20CIN5O2; 385.131, found (M + H + ); 386.1. Step 3: cis-N-Methyl-N-7H-pyrrolo [2,3-d] pyrimidin-4-ylcyclobutane-1,3-diamine hydrochloride [0111] A mixture of {cis-3 - [(2-chloro- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) (methyl) amino] cyclobutyl} carbamate (13.0 g, 34.0 mmol), Pd (OH) 2 (40.3 g, 40.8 mmol) and cyclohexene (72.5 mL, 0.71 mol) in ethanol (300 mL) was stirred at reflux for 3 hours. The reaction mixture was filtered through a pad of Celite® and the pad was washed with. The filtrate was concentrated in vacuo to provide the title compound (4.8 g, 66%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.68 (br, 1H), 8.11 (s, 1H), 7.67 (br, 2H), 7.17 (d, 1H), 6.65 (d, 1H), 5.08 (m, 1 H), 3.45 (m, 1H), 3.26 (s, 3H), 2.31 (m, 4H). LC / MS (exact mass) calculated for CnH 15 N 5 ; 217,133, found (M + H + ); 218.1. Step 4: 2,2,2-Trifluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl / ethanesulfonamide 50/111 [0112] To a solution of cis-N-methyl-N-7H-pyrrolo [2,3-d] pyrimidin-4ylcyclobutane-1,3-diamine hydrochloride (100 mg, 0.39 mmol) in tetrahydrofuran ( 0.8 ml) lithium bis (trimethylsilyl) amide (1M solution in tetrahydrofuran) (0.9 ml, 0.9 mmol) and chlorotrimethylsilane (94 mg, 0.88 mmol) were added at room temperature. The reaction mixture was stirred for 45 minutes and then 2,2,2-trifluoroethane chloron sulfonyl (86 mg, 0.47 mmol) was added slowly. The mixture was stirred at room temperature for 18 hours and then partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were concentrated to provide the crude product as a yellow-brown solid. The crude material was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93: 7) to provide the title compound as a white solid (93 mg, 65%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.61 (br. S., 1 H), 8.20 (d, 1 H), 8.08 (s, 1 H), 7.13 (d, 1 H), 6.60 (d, 1 H), 4.80-4.94 (m, 1 H), 4.34 (q, 2 H), 3.58-3.71 (m , 1 H), 3.23 (s, 3 H), 2.55-2.67 (m, 2 H), 2.17-2.30 (m, 2 H). LC / MS (exact mass) calculated for Ci3H 16 F 3 N 5 O2S; 363.098, found (M + H + ); 363.9. The following compounds, Examples 2-7, were prepared from cis-Nmethyl-N-7H-pyrrolo [2,3-d] pyrimidin-4-ylcyclobutane-1,3-diamine hydrochloride (Example 1, Step 3) from in a similar manner to that described in Example 1, Step 4, replacing the indicated chloron sulfonyl with 2,2,2-trifluoroethanochloro sulfonyl. Example 2: N- {cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1-sulfonamide [0113] This compound was prepared using 1-propanochloro sulfonyl . The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93: 7) to provide the title compound as a yellowish brown solid (78% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.60 (br s, 1 H), 8.08 (s, 1 H), 7.46 (d, 1 H), 7.12 (d , 1 H), 6.61 (d, 1 H), 4.81 - 4.94 (m, 1 H), 3.47 - 3.62 (m, 1 H), 3.23 (s, 3 H), 2.87-2.96 (m, 2 H), 2.52-2.63 (m, 2 H), 51/111 2.14-2.27 (m, 2 Η) 1.60-1.73 (m, 2 Η) 0.96 (t, 3 H). LC / MS (exact mass) calculated for C14H21N5O2S; 323.142, found (M + H + ); 324.1. Example 3: 2-Methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl / propane-1-sulfonamide [0114] This compound was prepared using 2-methyl-1 propanochloro sulfonyl. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93: 7) to provide the title compound as a white solid (52%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.64 (br s, 1 H), 8.12 (s, 1 H), 7.51 (d, 1 H), 7.03-7 , 26 (m, 1 H), 6.65 (d, 1 H), 4.82-5.02 (m, 1 H), 3.52-3.70 (m, 1 H), 3.26 (s, 3 H), 2.87 (d, 2 H), 2.55-2.67 (m, 2 H), 2.18-2.30 (m, 2 H), 2.11 (dt , H), 1.04 (d, 6 H). LC / MS (exact mass) calculated for C15H23N5O2S; 337,157, found (M + H + ); 338.0. Example 4A and Example 4B: cis- and trans-3- (Cyanomethyl) -N- {cis-3- [methyl (7Hpyrrolo [2,3-d] pyrimidin-4-H) amino] cyclobutH} cyclobutanesulfonamide [0115] These Compounds were prepared using a mixture (~ 1: 1) of trans-3- (cyanomethyl) cyclobutanochloro sulfonyl cleavage. The crude mixture of cis and trans isomers was purified by chromatography on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 10: 1) to provide a mixture (420 mg) of the title compounds as a white solid ( 67%). The cis and trans isomers were separated by supercritical fluid chromatography. cis-isomer 4A: 160 mg (21%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.12 (s, 1H), 7.13-7.12 (d, 1H), 6.69-6.69 (d, 1 H), 4.92-4.89 (m, 1 H), 3.84-3.78 (m, 1 H), 3.76-3.67 (m, 1 H), 3.36 (s, 3 H ), 2.79-2.73 (m, 2 H), 2.65-2.64 (m, 3H), 2.58-2.52 (m, H), 2.32-2.19 (m, 4 H). LC / MS (exact mass) calculated for Ci7H 2 2N 6 O 2 S; 374,152, found (M + H + ); 375.3. trans-isomer 4B: 155 mg (20%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1H), 7.13 (d, 1H), 6.70 (d, 1H), 4.94-4.89 (m , 1H), 3.89-3.85 (m, 1H), 3.72-3.69 (m, 11/11 1H), 3.36 (s, 3H), 2.85-2.62 (m, 7H), 2.31-2.23 (m, 4H). LC / MS (exact mass) calculated for Ci7H 2 2N 6 O 2 S; 374,152, found (Μ + H + ); 374.9. [0116] The mixture of cis- and trans-3- (cyanomethyl) cyclobutanochlor sulfonyl was prepared as follows: Step 1: [3- (Benzyloxy) cyclobutylidene] acetonitrile [0117] To a cooled suspension of sodium hydride (125 mg, 3.12 mmol) in tetrahydrofuran (12 mL) at 0 ° C was added diethyl cyanomethylphosphonate (1.21 g, 3.40 mmol). The mixture was stirred at room temperature for 1 hour before adding a solution of 3- (benzyloxy) cyclobutanone (500 mg, 2.84 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at room temperature overnight, and was then quenched with water. The mixture was extracted with ethyl acetate (3 x 25mL) and the combined organic layers were dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a gradient of petroleum ether and ethyl acetate (100: 0 to 85:15) to provide the title compound (450 mg, 80%) as a yellow oil. Step 2: [3- (Benzyloxy) cyclobutyl] acetonitrile [0118] A mixture of [3- (benzyloxy) cyclobutylene] acetonitrile (10.2 g, 51 mmol,) and 10% Pd / C (2.0 g) in Dry tetrahydrofuran was pressurized to 50 psi with hydrogen and stirred at room temperature for 3 days. The mixture was then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of petroleum ether and ethyl acetate (100: 0 to 80:20) to give the title compound (7 g, 70%) as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ 7.36-7.28 (m, 5 H), 4.44-4.43 (m, 2 H), 4.30-4.09 (m, 1H), 3.98-3.95 (m, 1 H), 2.64-2.45 (m, 4 H), 1.81 to 1.759 (m, 2 H). Step 3: (3-Hydroxycyclobutyl) acetonitrile [0119] To a solution of [3- (benzyloxy) cyclobutyl] acetonitrile (1 g, 5.00 mmol) in acetonitrile (15 mL) was added dropwise iodotrimethylsilane (1.5 g, 7.50 53/111 mmol) at 0 ° C. The mixture was stirred at room temperature overnight. The mixture was quenched with triethylamine, concentrated and then purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (1: 0 to 1: 1) to provide the title compound (340 mg, 62%) like a yellow oil. 1 H NMR (400 MHz, CDCI 3 ): δ 4.55-4.15 (m, 1H), 2.49-2.46 (m, 2H), 2.25-2.21 (m, 2H) , 2.14-2.08 (m, 1H), 1.79-1.72 (m, 2H). Step 4: 3- (Cyanomethyl) cyclobutyl-4-methylbenzenesulfonate [0120] To a solution of (3-hydroxycyclobutyl) acetonitrile (333 mg, 3.0 mmol) in dry dichloromethane (25 mL) was added 4-dimethylaminopyridine (732 mg , 6.0 mmol). The mixture stirred at room temperature for 5 minutes and then ptoluenochlorine sulfonyl (859 mg, 4.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was washed with water (2 x 15mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (10: 0 to 7: 3) to provide the title compound (520 mg, 65% yield) as a colorless oil. Step 5: S- [3- (CyanometH) cyclobutH] ethanothioate [0121] The mixture of 3- (cyanomethyl) cyclobutyl 4-methylbenzenesulfonate (1.5 g, 5.7 mmol) and potassium thioacetate (1.29 g, 3.00 mmol) in N, N-dimethylformamide (8 mL) was heated to 80 ° C overnight. The mixture was diluted with ethyl acetate (15 ml), diluted with water (30 ml) and brine (2 x 30 ml), dried over sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography eluting with a mixture of petroleum ether and ethyl acetate (3: 1) to provide the title compound (750 mg, 78%) as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ 4.12-3.92 (m, 1 H), 2.86-2.77 (m, 2 H), 2.71-2.47 (m, 2 H), 2.42-2.37 (m, 2 H), 2.30-2.29 (m, 3 H), 1.97-1.90 (m, 1 H). Step 6: 3- (Cyanomethyl) cyclobutanochlorine sulfonyl 54/111 [0122] A mixture of N-chlorosuccinimide (1.6 g, 12.0 mmol) in concentrated HCI (3 mL) and acetonitrile (12 mL) was stirred at room temperature for 10 minutes. S- [3- (cyanomethyl) cyclobutyl] ethanethioate (507 mg, 3.0 mmol) in acetonitrile (3 mL) was added at 0 ° C and stirred for 10 minutes. The mixture was diluted with aqueous sodium bicarbonate (50 ml), and extracted with methyl tert-butyl ether (3 x 50 ml). The combined dry organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with a mixture of petroleum ether and ethyl acetate (100: 0 to 50:50) to provide the title compound (400 mg, 69%) as a yellow oil. 1 H NMR (400 MHz, CDCI 3 ): δ 4.45-4.40 (m, 1H), 3.06-2.71 (m, 3H), 2.61-2.49 (m, 4H) . Example 5: 1- [3- (Cyanomethyl) oxetan-3-yl] -N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} methanesulfonamide [0123] This compound was prepared from [3- (cyanomethyl) oxetan-3yl] methanochloride sulfonyl. The crude compound was purified using preparative thin layer chromatography eluting with ethyl acetate to provide the title compound as a white solid (32%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1 H), 7.14-7.13 (m, 1 H), 6.71-6.70 (m, 1 H ), 5.06-5.05 (m, 1 H), 4.85-4.81 (m, 2 H), 4.524.50 (m, 2 H), 3.77-3.75 (m, 1 H), 3.63 (m, 2 H), 3.39 (s, 3 H), 3.29-3.26 (m, 2 H), 2.85-2.78 (m, 2 H ), 2.38-2.30 (m, 2 H). LC / MS (exact mass) calculated for Ci 7 H 22 N 6 O 3 S; 390.147, found (M + H + ); 391.0. [3- (Cyanomethyl) oxetan-3-yl] methanochloride sulfonyl Step 1: [3- (Cyanomethyl) oxetan-3-yl] methyl 4-methylbenzenesulfonate [0124] This compound was prepared following the procedure of Example 4 Step 4, replacing [3- (Hydroxymethyl) -3-oxetanyl] acetonitrile with ( 3 hydroxycyclobutyl) acetonitrile. The crude compound was purified by chromatography on silica gel eluting with a mixture of petroleum ether and ethyl acetate (1: 0 to 1: 1) to provide the title compound as a white solid (10%). 1 H NMR (400 55/111 MHz, CDCh): δ 7.82-7.80 (m, 2 Η), 7.41-7.39 (m, 2 Η), 4.54-4.35 (m, 4 Η), 4, 31 (s, 2 Η), 2.79 (s, 2 Η), 2.45 (s, 3H). Step 2: [3- (Cyanomethyl) oxetan-3-yl] methyl thiocyanate [0125] A solution of [3- (cyanomethyl) oxetan-3-yl] methyl 4 methylbenzenesulfonate (150 mg, 0.53 mmol) and potassium thiocyanate (104 mg, 1.07 mmol) was stirred in ethanol (10 ml). The reaction was heated to 85 ° C and stirred for 16 hours. The solvent was evaporated to provide the crude title compound as a white solid. Step 3: [3- (Cyanomethyl) oxetan-3-H] methanochloride sulfonyl [0126] Chlorine gas was bubbled through a solution of [3 (cyanomethyl) oxetan-3-yl] methyl thiocyanate (0.53 mmol, raw ) in water (10 mL) at 0 ° C for 30 minutes. The reaction mixture was extracted with methyl tert-butyl ether (2 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated to provide the title compound (20 mg, 18%). Example 6: N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1 oxetan-3-ylmethanesulfonamide [0127] This compound was prepared using oxethan- 3-ylmethanochloro sulfonyl. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (85:15) to provide the title compound as a white solid (23%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (m, 1 H), 7.13 (d, J = 4Hz, 1 H), 6.70-6.69 (m, J = 4Hz, 1 H), 4.93-4.91 (m, 1 H), 4.84-4.83 (m, 2 H), 4.63-4.59 (m, 2 H), 3, 74-3.68 (m, 1 H), 3.58-3.56 (m, 1 H), 3.47-3.45 (m, 2 H), 3.37 (s, 3 H), 2.79-2.77 (m, 2 H), 2.32-2.29 (m, 2 H). LC / MS (exact mass) calculated for C15H21N5O3S; 351.136, found (M + H + ); 352.1. Oxetan-3-ylmethanochlorine sulfonyl Step 1: Oxetan-3-HmetH thiocyanate [0128] This compound was prepared according to the procedure of 56/111 Example 5, Step 2, replacing oxetan-3-ylmethyl 4-methylbenzenesulfonate (WO2012 / 117000A1) with [3- (cyanomethyl) oxetan-3-yl] methyl 4-methylbenzenesulfonate to provide the crude title compound as a white solid. (100%). Step 2: Oxetan-3-ylmethanochloride sulfonyl [0129] This compound was prepared in raw form (25% yield) following the procedure of Example 5 Step 3, replacing oxetan-3-ylmethyl thiocyanate with [3- (cyanomethyl) oxetan-3 -yl] methyl thiocyanate. Example 7A and 7B: cis- and trans-3- (Cyanomethyl) -3-methyl-N- {cis-3- [methyl (7Hpyrrolo [2 ^ -d] pyrimidin-4-yl) amino] cyclobutyl} cyclobutanesulfonamide [0130 ] These compounds were prepared using a mixture (~ 1: 1) of trans-3- (cyanomethyl) -3-methylcyclobutanochloro sulfonyl cleavage. The crude mixture of cis- and trans isomers was purified by chromatography on silica gel eluting with a petroleum gradient ethyl ether acetate (10: 1 to 1:15) to provide a mixture (70 mg) of the title compounds as a solid light brown (28%). The cis and trans isomers were then separated by supercritical fluid chromatography (SFC). cis-isomer (7A): 26 mg (10%); SFC retention time = 7.11 minutes; 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1 H), 7.13-7.13 (d, 1 H), 6.69 (d, 1 H), 4.934, 86 (m, 1 H), 3.91 - 3.87 (m, 1 H), 3.71 - 3.65 (m, 1 H), 3.37 - 3.33 (m, 3 H), 2.77-2.75 (m, 2 H), 2.68 (s, 2 H), 2.41-2.36 (m, 2 H), 2.26-2.21 (m, 2 H ), 1.34 (m, 3 H). LC / MS (exact mass) calculated for Ci 8 H 2 4N 6 O2S; 388.168, found (M + H + ); 389.1. transisomer (7B) 24 mg (10%); SFC retention time = 11.35 minutes; 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1 H), 7.14 (d, 1 H), 6.69 (d, 1 H), 4,934.86 (m, 1 H), 3.96-3.86 (m, 1 H), 3.72-3.65 (m, 1 H), 3.36-3.31 (m, 3 H), 2.77- 2.75 (m, 2 H), 2.71 (s, 2 H), 2.34-2.26 (m, 6 H), 1.33 (m, 3 H). LC / MS (exact mass) calculated for Ci 8 H 24 N 6 O 2 S; 388.168, found (M + H + ); 389.0. [0131] The mixture of cis- and trans-3- (cyanomethyl) -3-methylcyclobutanochlor sulfonyl was prepared as follows: 57/111 Step 1: 1-Methyl-3-methylenocyclobutanocarbonitrile [0132] To a solution of 3-methylenocyclobutanocarbonitrile (35.0 g, 373.0 mmol) in tetrahydrofuran (200 mL) was added dropwise lithium bis (trimethylsilyl) amide (450 ml, 1M) at -78 ° C. The solution was stirred for 1 hour at -78 ° C and iodomethane (30 ml, 448 mmol) was added to the reaction. After 1 hour, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with aqueous chlorine ammonium (380 ml) and extracted with methyl tert-butyl ether (3 x 400 ml). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by distillation under reduced pressure to provide the title compound (20 g, 50%) as a clear oil. 1 H NMR (400 MHz, CDCI 3 ): δ 4.90-4.89 (m, 2 H), 3.24-3.20 (m, 2 H), 2.67-2.62 (m, 2 H), 1.50 (s, 3H). Step 2: 1-Methyl-3-methylenocyclobutanecarboxylic acid [0133] To a solution of 1-methyl-3-methylenocyclobutanecarbonitrile (10.0 g, 93.3 mmol) in water (50 mL) and ethanol (50 mL) was added potassium hydroxide (25.6 g, 466.6 mmol). The reaction mixture was heated and stirred overnight. The ethanol was removed under reduced pressure, and the solution was cooled to below 10 ° C, acidified with concentrated hydrochloric acid to pH 1. The aqueous phase was extracted with ethyl acetate (3 x 150 ml). The combined organic layers were dried over sodium sulfate and concentrated to provide the title compound (9 g, 77%). 1 H NMR (400 MHz, CDCI 3 ): δ 11.90 (s, 1 H), 4.88-4.85 (m, 2 H), 3.23-3.17 (m, 2 H), 2.53-2.41 (m, 2 H), 1.45 (s, 3 H). Step 3: Ethyl 1-metH-3-metHenocyclobutanecarboxylate [0134] To a solution of 1-methyl-3-methylenocyclobutanecarboxylic acid (6 g, 47.6 mmol) in dichloromethane (30 mL) at 0 ° C was added dropwise thionyl chlorine (11.0 mL, 143 mmol). The solution was stirred at 0 ° C for 1 hour. Three drops of N, Ndimethylformamide were added to the solution. The solution was stirred at 0 ° C for 30 minutes. The solvent was evaporated and dichloromethane (20 ml) and ethanol (125 ml) were 58/111 added to the residue. The resulting solution was stirred for 16 hours at room temperature. The solvent was evaporated and water (20 ml) was added to the residue. The aqueous layer was extracted with dichloromethane (4 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (20: 1 to 10: 1) to provide the title compound (5 g, 68%). 1 H NMR (400 MHz, CDCI 3 ): δ 4.85-4.83 (m, 2 H), 4.17-4.12 (m, 2 H), 3.18-3.12 (m, 2 H), 2.48-2.42 (m, 2H), 1.41 (s, 3 H), 1.27-1.23 (m, 3 H). Step 4: (1-Methyl-3-methylenocyclobutyl) methanol [0135] A mixture of ethyl 1-methyl-3-methylenocyclobutanecarboxylate (4.55 g, 29.5 mmol) lithium aluminum hydride (2.8 g, 72 mmol ) in tetrahydrofuran (50 ml) was stirred overnight at room temperature. To a reaction mixture was added Na 2 SO 4 -10H 2 O (3.7 g, 11.5 mmol) and the resulting mixture was stirred for 1 hour at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was extracted with dichloromethane (3 x 50 ml). The combined organic extracts were dried over sodium sulfate and concentrated to provide the title compound (2.6 g, 79%) as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ 4.79-4.78 (m, 2 H), 3.48 (s, 2 H), 2.53-2.48 (m, 2 H), 2.36-2.27 (m, 2 H), 1.16 (s, 3 H). Step 5: (1-Methyl-3-methylenocyclobutyl) methyl 4-methylbenzenesulfonate [0136] This compound was prepared following 0 Example 4, Step 4, replacing (1-methyl-3-methylenocyclobutyl) methanol with (3-hydroxycyclobutyl) acetonitrile. The crude compound was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (20: 1 to 4: 1) to provide the title compound (70%). 1 H NMR (400 MHz, CDCI 3 ): δ 7.79 (d, 2 H), 7.34 (d, 2 H), 4.79-4.78 (m, 2 H), 3.90 ( s, 2 H), 2.51-2.47 (m, 2 H), 2.44 (s, 3 H), 2.35-2.31 (m, 2 H), 1.15 (s, 3 H). 59/111 Step 6: (1-Methyl-3-methylenocyclobutyl) acetonitrile [0137] A mixture of (1-methyl-3-methylenocyclobutyl) methyl 4 methylbenzenesulfonate (2.5 g, 9.4 mmol), potassium cyanide (1.3 g , 19 mmol) and N, Ndimethylformamide (8mL) was stirred overnight at 70 ° C. Water (10 ml) and methyl tertbutyl ether (20 ml) were added to a mixture and the organic layer was separated. The aqueous phase was extracted with methyl tert-butyl ether (3 x 30 ml). The combined organic layers were diluted with a saturated aqueous sodium bicarbonate solution (15 mL), dried over sodium sulfate, and concentrated. The crude product was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (10: 1 to 5: 1) to provide the title compound (1.1 g, 97%) as a brown oil clear. 1 H NMR (400 MHz, CDCI 3 ): δ 4.88-4.87 (m, 2 H), 2.62-2.54 (m, 2 H), 2.50 (s, 2 H), 1.33 (s, 3 H). Step 7: (1-Methyl-3-oxocyclobutyl) acetonitrile [0138] Ozone gas was bubbled through a solution of (1-methyl-3-methylenocyclo-butyl) acetonitrile (1.08 g, 8.91 mmol) in dichloromethane (30 mL) -78 ° C for 10 minutes. After purging a solution with nitrogen gas, dimethylsulfide (10 mL) was added dropwise to a solution at -78 ° C. The solution was stirred for 30 minutes at -78 ° C and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (20: 1 to 8: 1) to provide the title compound (920 mg, 84%) as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ 3.11 - 3.06 (m, 2 H), 2.96-2.91 (m, 2 H), 2.69 (s, 2 H), 1.53 (s, 3 H). Step 8: (3-Hydroxy-1-methylcyclobutyl) acetonitrile [0139] To a solution of (1-methyl-3-oxocyclobutyl) acetonitrile (400 mg, 3.25 mmol) in tetrahydrofuran (15 mL) was added sodium borohydride (246 mg, 6.5 mmol). The mixture was stirred for 3 hours at room temperature. Acetone (2 ml) was added and then the solvent was evaporated. Water (10 mL) was added to the residue 60/111 and an aqueous phase was extracted with dichloromethane (4x15 ml). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (10: 1 to 1: 1) to provide the title compound (300 mg, 74%) as a colorless oil. 1 H NMR (400 MHz, CDCI 3 ): δ 4.38-4.34 (m, 2 H), 2.462.27 (m, 4 H), 1.94-1.86 (m, 2 H), 1.33-1.12 (m, 3 H). Step 9: 3- (Cyanomethyl) -3-methylcyclobutyl 4-methylbenzenesulfonate [0140] This compound was prepared following Example 7, Step 5, replacing (3-hydroxy-1-methylcyclobutyl) acetonitrile with (1-methyl-3-methylenocyclobutyl )methanol. The crude compound was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (20: 1 to 4: 1) to provide the title compound (36%). 1 H NMR (400 MHz, CDCI 3 ): δ 7.77 (d, 2 H), 7.35 (d, 2 H), 4.89-4.81 (m, 1 H), 2.45 ( s, 3 H), 2.43-2.34 (m, 3 H), 2.26-2.21 (m, 1 H), 2.152.11 (m, 2 H), 1.33 (s, 3 H). Step 10: S- [3- (Cyanomethyl) -3-methylcyclobutyl] ethanothioate [0141] This compound was prepared in 89% yield (crude) following the procedure of Example 4, Step 5, replacing 3- (cyanomethyl) -3 -methylcyclobutyl 4methylbenzenesulfonate by 3- (cyanomethyl) cyclobutyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, CDCI 3 ): δ 3.12 (s, 1 H), 2.46-2.30 (m, 4 H), 2.19 (s, 2 H), 1.29 ( s, 1 H) 1.26-1.24 (m, 1 H), 1.18-1.14 (m, 1 H), 1.13 (s, 3H). Step 11: 3- (Cyanomethyl) -3-methylcyclobutanochloride sulfonyl [0142] This compound was prepared following Example 4 Step 6, replacing S- [3- (cyanomethyl) -3-methylcyclobutyl] ethanothioate with S- [3- (cyanomethyl) ) -cyclobutyl] ethanothioate. The crude compound was purified using silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (90:10 to 30:70) to provide the title compound as a yellow liquid (66%). 1 H NMR (400 MHz, CDCI 3 ): δ 4.45-4.38 (m, 1 H), 2.67-2.55 (m, 4 H), 2.46-2.40 (m, 2 H), 1.42-1.40 (m, 3 61/111 Η). Example 8: 4-Cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyridine-2-sulfonamide Step 1: 2- (Benzylthio) isonicotinonitrile [0143] A 60% suspension of sodium hydride in mineral oil (8.36 g, 210.0 mmol) was suspended in tetrahydrofuran (100 mL). A solution of benzyl mercaptan (21.5 g, 173 mmol) in tetrahydrofuran (50 mL) was then added dropwise. A thick sludge formed during the addition. 4-Cyano-2-chloropyridine (12.5 g, 90.2 mmol) was added and the resulting mixture was stirred for 3 hours at room temperature. After carefully quenching with water, the mixture was partitioned between water and diethyl ether. The ether layer was washed with an aqueous saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. Heptane was added to the residue with solids forming quickly. The solids were collected by filtration, diluted with heptane, and dried to give (33.02 g, 84%) the title compound as an off-white solid. 1 H NMR (400 MHz, CDCI 3 ): δ 8.61 (d, 1 H), 7.25-7.46 (m, 6 H), 7.16-7.22 (m, 1 H), 4.47 (s, 2 H). LC / MS (exact mass) calculated for Ci 3 H 10 N 2 S; 226.056, found (M + H + ); 227.1. Step 2: 4-cyanopyridine-2-chloro sulfonyl [0144] To a mechanically stirred mixture of 2- (benzylthio) isonicotinonitrile (8.92 g, 39.4 mmol) in dichloromethane (139 mL) and water (31 mL) was Sulfuryl chloride (22.5 mL, 278 mmol) is added dropwise, keeping the temperature of a mixture below 3 ° C. After the addition was complete, the mixture was stirred for 30 minutes with continuous cooling in an ice bath. A sludge of water (50 mL) and ice (20 g) was added. The aqueous phase was extracted twice with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure to provide the crude title compound. 62/111 Step 3: 4-Cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} pyridine-2-sulfonamide [0145] A solution of 4-cyanopyridine- 2-chloro sulfonyl (9.7 g, 47.9 mmol) in N, N-dimethylformamide (10 mL) was added to a solution of cis-N-methyl-N-7Hpyrrolo [2,3-d] pyrimidin-4 -ylcyclobutane-1,3-diamine hydrochloride (8.0 g, 36.8 mmol) and 4-dimethylaminopyridine (150 mg, 0.03 mmol) in N, N-dimethylformamide (90 mL) at room temperature. Diisopropylethylamine (13 mL, 77 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml) and the aqueous saturated sodium bicarbonate solution was added. Water was added to dissolve the precipitated solids. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were washed four times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A 1: 1 mixture of ethyl acetate and hexanes was added to the residue. The solids were collected by filtration and then dissolved in dichloromethane and a minimal amount of methanol. The resulting solution was passed through a plug of silica gel eluting with 5% methanol in dichloromethane solution. The solvents were evaporated to provide a solid to which a solution of 10% methanol in dichloromethane was added. The mixture was briefly stirred and then left to stand overnight. The solids were filtered, diluted with dichloromethane and dried to provide the title compound (5.58 g, 39%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.62 (br. S „1 H), 9.02 (d, 1 H), 8.52 (d, 1 H), 8.38 ( s, 1 H), 8.17 (dd, 1 H), 8.07 (s, 1 H), 7.10-7.15 (m, 1 H), 6.59 (dd, 3.41 Hz , 1 H), 4.80-4.91 (m, 1 H), 3.58-3.71 (m, 1 H), 3.19 (s, 3 H), 2.25-2.36 (m, 2 H), 2.10 (m, 2 H). LC / MS (exact mass) calculated for C17H-17N7O2S; 383.116, found (M + H + ); 384.1. Example 9: 3- (1-Hydroxy-1-methylethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin4-yl) amino] cyclobutyl} benzenesulfonamide 63/111 Step 1: Methyl 3 - [({cis-3- [metH (7H-pyrrolo [2,3-d] pyrimidin-4-H) amino] cyclobutyl} amino) -sulfonyl] benzoate [0146] To a cis suspension -N-methyl-N-7H-pyrrolo [2,3-d] pyrimidin-4ylcyclobutane-1,3-diamine hydrochloride (1.8 g, 8.29 mmol) in N, N-dimethylformamide (100 mL) was added in small portions triethylamine (6.7 mL, 49 mmol) at 0 ° C. Methyl 3- (chlorosulfonyl) benzoate (2.3 g, 9.9 mmol) was added at 0 ° C. The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with a gradient of methanol in dichloromethane (3% to 10%) to provide the title compound (1.6 g, 47%) as a yellow solid. Step 2: 3- (Hydroxymethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclo-butyl} benzenesulfonamide [0147] To a solution of methyl 3- [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} amino) sulfonyl] benzoate (800 mg, 1.92 mmol) in tetrahydrofuran (120 mL) was added lithium aluminum hydride (0.25 g, 6.7 mmol) at 0 ° C. The reaction was heated to 25 ° C and stirred for 3 hours. The reaction was quenched with water (2 ml) and stirred for 15 minutes. The reaction mixture was filtered. The filter cake was stirred in tetrahydrofuran (50 ml) and filtered again. The combined filtrate was concentrated to dryness to provide the title compound (430 mg, 58%) as a yellow solid. Step 3: 3-Formyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl / benzenesulfonamide [0148] To a solution of 3- (hydroxymethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} benzenesulfonamide (400 mg, 1.03 mmol) in chloroform (50 mL) and methanol (5 mL ) manganese dioxide (0.89 g, 10.0 mmol) was added. The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was filtered and the filter cake was washed with chloroform (3 x 25 ml). The filtrates with 64/111 pieces were concentrated. The residue was chromatographed on silica gel eluting with a gradient of methanol in dichloromethane (2% to 8%) to provide the title compound (240 mg, 60%) as an oil. Step 4: 3- (1-Hydroxyethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} benzenesulfonamide [0149] To a solution of 3-formyl -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} benzenesulfonamide (260 mg, 0.68 mmol) in tetrahydrofuran (20 mL) methylmagnesium bromide was added (1.8 mL, 5.4 mmol) at 0 ° C under nitrogen. The reaction was stirred at 25 ° C overnight and was then quenched with aqueous ammonium chloride (10 ml). The reaction mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by preparative high performance liquid chromatography to provide the title compound (60 mg, 22%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.6 (s, 1 H), 8.08 (s, 1 H), 8.03 (d, 1 H), 7.86 (s, 1 H), 7.70 (m, 1 H), 7.55 (m, 2 H), 7.15 (m, 1 H), 6.61 (m, 1 H), 5.44 (m, 1 H), 4.85 (m, 1 H), 3.56 (m, 1 H), 3.18 (s, 3 H), 2.18 (m, 2 H), 2.04 (m, 2 H), 1.32 (d, 3 H). LC / MS (exact mass) calculated for C19H23N5O3S; 401.152, found (M + H + ); 402.2. Step 5: 3-Acetyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl / benzenesulfonamide [0150] To a solution of 3- (1- hydroxyethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} benzenesulfonamide (60 mg, 0.15 mmol) in chloroform (30 mL) and methanol ( 5 ml) manganese dioxide (190 mg, 2.2 mmol) was added. The reaction mixture was stirred at 45 ° C overnight. Then the reaction mixture was filtered and the filter cake was washed with chloroform (3 x 25 ml). The combined filtrates were concentrated. The residue was purified by preparative high performance liquid chromatography to provide the title compound (15 mg, 65/111 25%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.58 (s, 1 H), 8.31 (s, 1 H), 8.21 (m, 2 H), 8.16 (m, 2 H), 7.76 (m, 1 H), 7.09 (d, 1 H), 6.56 (s, 1 H), 4.82 (m, 1 H), 3.54 (m, 1 H), 3.14 (s, 3 H), 2.81 (m, 3 H), 2.26 (m, 2 H), 1.98 (m, 2 H). LC / MS (exact mass) calculated for C19H21N5O3S; 399.136, found (M + H + ); 400.1. Step 6: 3- (1-Hydroxy-1-methylethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} benzenesulfonamide [0151] To a solution of 3-acetyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} benzenesulfonamide (240 mg, 0.58 mmol) in tetrahydrofuran (20 mL) was Methylmagnesium bromide (2.4 mL, 7.2 mmol) was added at 0 ° C under nitrogen. The reaction was stirred at 25 ° C for 2 hours and was quenched with an aqueous ammonium chloride solution (10 mL). The reaction mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by preparative high performance liquid chromatography to provide the title compound (101 mg, 42%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.6 (s, 1 H), 8.05 (s, 1 H), 7.97 (m, 2 H), 7.67 (m, 2 H), 7.52 (m, 1 H), 7.12 (m, 1 H), 6.57 (m, 1 H), 5.29 (s, 1 H), 4.85 (m, 1 H), 3.53 (m, 1 H), 3.15 (s, 3 H), 2.24 (m, 2 H), 1.98 (m, 2 H), 1.44 (s, 6 H), LC / MS (exact mass) calculated for C20H25N5O3S; 415.168, found (M + H + ); 416.0. Example 10: 1-Cyclopropyl-N- {trans-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4H) amino] cyclobutH} methanesulfonamide [0152] This compound was synthesized starting from benzyl [trans -3 (methylamino) -cyclobutyl] carbamate (Example 1, Step 1), following procedures similar to those described for example 1, Steps 2 and 3 to obtain trans-N-methylN-7H-pyrrolo [2,3-d] pyrimidin-4-ylcyclobutane-1,3-diamine hydrochloride. To the resulting hydrochloride (60 mg, 0.28 mmol) in THF (10 mL) was added potassium carbonate 66/111 (76 mg, 0.55 mmol), H2O (5 mL) and cyclopropylmethanochloride sulfonyl (52 mg, 0.33 mmol). The mixture was stirred for two hours, diluted with dichloromethane, diluted with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography to provide the title compound as a white solid (7 mg; 8%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.14 (s, 1 H), 7.16 (d, 1 H,), 6.72 (d, 1 H), 5.44-5 , 40 (m, 1 H), 4,074.06 (m, 1 H), 3.41 (s, 3 H), 3.01-2.99 (m, 2 H), 2.81-2.74 (m, 2 H), 2.54-2.49 (m, 2 H), 1.15-1.13 (m, 1 H), 0.720-0.69 (m, 2 H), 0.42 -0.41 (m, 2 H). LC / MS (exact mass) calculated for C15H21N5O2S; 335.142, found (M + H + ); 336.1. Example 11: N - {(1S, 3R) -3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclopentyl} propane-1-sulfonamide [0153] This compound was prepared following 0 Example 10 replacing (1 S, 3fí) -N-benzyl-N'-methylcyclopentane-1,3-diamine with benzyl [trans-3- (methylamino) cyclobutyl] carbamate, (1 R, 3S) -N-methyl-N- 7H-pyrrolo [2,3-d] pyrimidin-4-ylcyclopentane1,3-diamine hydrochloride by trans-N-methyl-N-7H-pyrrolo [2,3-d] pyrimidin-4-ylcyclobutane1,3-diamine hydrochloride, and propane-1-chloro sulfonyl by cyclopropylmethanochloro sulfonyl to provide the title compound as an off-white solid (11%). The raw compound was purified using preparative high performance liquid chromatography. 1 H NMR (400 MHz, methanol-d 4 ): δ 8.08 (s, 1 H), 7.08 (s, 1 H), 6.65 (s, 1 H), 5.27-5 , 23 (m, 1 H), 3.81 - 3.76 (m, 1 H), 3.31 (s, 3 H), 2.33-2.29 (m, 1 H), 2.13 -2.04 (m, 1 H), 1.98-1.92 (m, 2 H), 1.82-1.75 (m, 4 H), 1.06 (t, 3 H), 0 , 42-0.41 (m, 2 H). LC / MS (exact mass) calculated for C15H23N5O2S; 337,157, found (M + H + ); 337.8. (1S, 3R) -N-benzyl-N'-methylcyclopentane-1,3-diamine was prepared as follows: Step 1: Benzyl [(1 R, 3S) -3-aminocyclopentH] carbamate [0154] Trifluoroacetic acetic acid (15 mL, 190 mmol) was added to a solution 67/111 benzyl tert-butyl (1 F ', 3S) -cyclopentane-1,3-diylbiscarbamate (prepared as described in WO2011 / 086053A1) (5.02 g, 15.0 mmol) in dichloromethane (75 mL) a room temperature. The reaction was stirred for 2 hours and was then concentrated to provide the title compound as a light brown oil (6.70 g, crude) Step 2: Benzyl [(1 R, 3S) -3- (benzHamino) cyclopentH] carbamate [0155] Sodium triacetoxyhydroborate (4.38 g, 20.0 mmol) was added to a benzyl solution ((1 µ, 3S ) -3-aminocyclopentyl] carbamate (5.23 g, 15.0 mmol) and benzaldehyde (1.7 mL, 16.0 mmol) in dichloromethane (75 mL) at room temperature. The mixture was stirred for 21 hours and then an aqueous 1 M sodium hydroxide solution (75 mL) was added to make a basic solution. The aqueous layer was extracted with dichloromethane (2 x 25 ml). The combined organic layers were diluted with brine (50 ml), dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel eluting with a mixture of dichloromethane and methanol (100: 0 to 88:12) to provide the title compound as a yellow oil (3.47 g, 71%). 1 H NMR (400 MHz, CDCI 3 ): δ 7.35-7.31 (m, 5 H), 7.30-7.26 (m, 5 H), 5.07 (s, 2 H), 4.17-4.07 (m, 1 H) 3.76-3.68 (m, 2 H), 3.27-3.20 (m, 1 H), 2.02-1.51 (m , 6 H). Step 3: (1 S, 3Fl) -N-BenzH-N'-metHcyclopentane-1,3-diamine [0156] Lithium aluminum hydride (1.02 g, 26.9 mmol) was added in portions to a solution of benzyl [(1 R, 3S) -3- (benzylamino) cyclopentyl] carbamate (3.47 g, 10.7 mmol) in tetrahydrofuran (70 mL) at room temperature. The reaction was heated to reflux for 3.5 hours. The mixture was then cooled in an ice bath and sequentially quenched with water (1.0 ml), a 15% aqueous sodium hydroxide solution (1.0 ml) and water (3.0 ml). The suspension was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated and the residue was taken up in a 0.5 M aqueous hydrochloric acid solution. The mixture was washed with diethyl ether (2 x 20 ml) and the aqueous solution became basic (pH ~ 11) with sodium hydroxide. The mixture The resulting 68/111 was extracted with dichloromethane (3 x 25 ml). The combined organic layers were dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel eluting with a mixture of dichloromethane and methanol (90:10) to provide the title compound as a yellow oil (204 mg, 9%). 1 H NMR (400 MHz, CDCI 3 ): δ 7.33-7.20 (m, 5 H), 3.74 (s, 2 H), 3.19-3.13 (m, 1 H), 3.083.02 (m, 1 H) 2.39 (s, 3 H), 2.09-2.03 (m, 1 H), 1.87-1.81 (m, 2 H), 1.67 -1.54 (m, 2 H), 1.46-1.39 (m, 1 H). LC / MS (exact mass) calculated for Ci 3 H 2 oN 2 ; 204.163, found (M + H + ); 205.1. Example 12: 1- (3,3-Difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} methanesulfonamide Step 1: Benzyl [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin4-H} amino) cyclobutH] carbamate [0157] 4-Chlorine-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidine (15 g, 48.7 mmol) and benzyl [cis-3- (methylamino) cyclobutyl] carbamate (17.2 g, 63 , 5 mmol) were mixed with isopropyl alcohol (180 mL) and diisopropylethylamine (28 mL, 161 mmol). The resulting sludge was heated to 75 ° C for 6 hours. The reaction was cooled to room temperature, filtered, diluted with isopropyl alcohol (150 ml) and dried in an oven at 50 ° C to give the title compound (23.5 g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.38 (s, 1 H), 8.03 (d, 2 H), 7.45 (d, 1 H), 7.38-7.28 (m, 4 H) , 7.26 (s, 1 H), 7.25 (d, 1 H), 6.61 (d, 1 H), 5.08 (s, 2 H), 4.96 (d, 1 H), 4.77 (m, 1 H), 3.88 (m, 1 H), 3.23 (s, 3 H), 2.71 (m, 2 H), 2.36 (s, 3 H), 2.18 (m, 2 H). Step 2: cis-N-Methyl-N- {7 - [(4-metHphenyl) sulfonH] -7H-pyrrolo [2,3-d] pyrimidin-4yl} cyclobutane-1,3-diamine dihydrobromide [0158] Benzyl [ cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] carbamate (15.2 g, 30.1 mmol) was suspended in ethyl acetate (45 ml) and acetic acid (45 ml). To a slurry, a 4M solution of HBr in acetic acid (45 mL, 180 mmol) was added slowly, keeping the temperature below 69/111 ° C. The resulting slurry was stirred at room temperature for 2 hours. The solids were collected by filtration, diluted with ethyl acetate (450 ml), and dried at 40 ° C to provide the title compound (16 g; 100%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.31 (s, 1 H), 8.20 (s, 2 H), 7.97 (d, 2 H), 7.72 (d, 1 H), 7.44 (d, 2 H), 7.08 (d, 1 H), 4.93 (m, 1 H), 3.54 (m, 1 H), 3.30 (s, 3 H), 2.50 (m, 4 H), 2.35 (s, 3 H). LC / MS (exact mass) calculated for C18H21N5O2S; 371.142, found (M + H + ); 372.1. Step 3: ({[(3,3-Difluorocyclobutyl) methyl] thio} methyl) benzene [0159] A mixture of (3,3-difluorocyclobutyl) methyl 4-methylbenzenesulfonate (see W02010 / 032200A1) (4 g, 14.5 mmol), benzyl imidothiocarbamate (3.53g, 17.4 mmol), a solution of sodium hydroxide (1.45 g, 36.2 mmol, dissolved in 16 mL of water) and N, N-dimethylformamide (16 mL) it was stirred at 60 ° C for 16 hours. Water (40 ml) and ethyl acetate (150 ml) were added. The organic layer was washed with water (40 ml), separated, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a gradient of petroleum ether and ethyl acetate (100: 0 to 95: 5) to provide the title compound as a colorless oil (3.2 g, 81%). 1 H NMR (400 MHz, CDCI 3 ): δ 7.34-7.24 (m, 5 H), 5.71 (s, 2 H), 2.71-2.61 (m, 2 H), 2.57-2.55 (m, 2 H), 2.30-2.14 (m, 3 H). Step 4: Sulfonyl (3,3-Difluorocyclobutyl) methanochloride [0160] This compound was prepared following the procedure of Example 8 Step 2, replacing S- [3- (cyanomethyl) -3-methylcyclobutyl] ethanothioate with 2 (benzylthio) isonicotinonitrile for providing the title compound as a colorless oil (93%). 1 H NMR (400 MHz, CDCI 3 ,): δ 3.88-3.86 (m, 2 H), 3.03-2.94 (m, 3 H), 2.61 2.49 (m, 2 H). Step 5: 1- (3 ; 3-Difluorocyclobutyl) -N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpirrolo [2 ; 3-d] pyrimidin-4-yl} amino) cyclobutyl] methanesulfonamide [0161] A solution of sulfonyl (3,3-difluorocyclobutyl) methanochloride (2.5 g, 70/111 12.19 mmol) in 10 mL dichloromethane was added dropwise to a solution of cis-N-methyl-N- {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin- 4-yl} cyclobutane-1,3diamine dihydrobromide (3.25 g, 6.10 mmol) and triethylamine (3.08 g, 30.49 mmol) in dichloromethane (150 mL) at 0 ° C for 15 minutes. The reaction was stirred at room temperature for 4 hours. Water (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 150 ml), and the combined organic layers were separated, dried over sodium sulfate. The crude compound was purified by chromatography on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 90:10) to provide the title compound as a white solid (2.0 g, 61%). LC / MS (exact mass) calculated for C23H27F2N5O4S2; 539.147, found (M + H + ); 540.1. Step 6: 1- (3,3-Difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methanesulfonamide [0162] A solution of 1- (3,3-difluorocyclobutyl) -N- [cis-3- (methyl {7 - [(4methylphenyl) -sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methanesulfonamide ( 2 g, 3.71 mmol) and lithium hydroxide monohydrate (780 mg, 18.6 mmol) in ethanol (40 mL) and water (20 mL) was stirred at 60 ° C for 4 hours. Ethanol was evaporated and the remaining aqueous layer was neutralized to pH 7 with hydrochloric acid and subsequently extracted with dichloromethane (2 x 200 ml). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by preparative high performance liquid chromatography to provide the title compound (800 mg, 56%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ): δ 8.15 (s, 1H), 8.13 (s, 1 H), 7.16-7.15 (m, 1 H), 6.73 -6.62 (m, 1 H), 4.95-4.88 (m, 1 H), 3.73-3.71 (m, 1 H), 3.38 (s, 3 H), 3 , 28-3.26 (m, 2 H), 2.87-2.78 (m, 4 H), 2.63-2.61 (m, 1 H), 2.56-2.48 (m , 2 H), 2.35-2.28 (m, 2 H). LC / MS (exact mass) calculated for Ci 6 H 2 iF2N 5 O2S; 385.138, found (M + H + ); 386.1. [0163] The following compounds, Examples 13-14, were prepared from 71/111 cis-N-methyl-N- {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} cyclobutane1,3-diamine dihydrobromide (Example 12, Step 2) in a similar manner to that described in Example 12, Step 5, replacing the indicated chloron sulfonyl with (3,3difluorocyclobutyl) methanochloride sulfonyl and using the deprotection method illustrated in Example 12, Step 6. Example 13: 3,3-Difluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} cyclobutanesulfonamide [0164] This compound was prepared using 3,3- difluorocyclobutanochlor sulfonyl using the procedure in PCT Publication No. WO2011 / 068881. The crude compound was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (80:20 to 10:90) to provide the title compound as an off-white solid (22% over 2 steps). 1 H NMR (400 MHz, metanold 4 ): δ 8.13 (s, 1 H), 7.13 (d, 1 H), 6.70 (d, 1 H), 4.86-4.81 ( m, 1H), 3.78-3.72 (m, 2 H), 3.35 (s, 3 H), 3.01-2.93 (m, 4 H), 2.78-2.76 (m, 2 H), 2.32-2.25 (m, 2 H). LC / MS (exact mass) calculated for C15H-19F2N5O2S; 371,123, found (M + H + ); 372.1. Example 14: 1-Cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methanesulfonamide [0165] This compound was prepared as a white solid using sulfonyl cyclopropylmethanochloride (73% over 2 steps). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.64 (br. S., 1 H), 8.11 (s, 1 H), 7.53 (d, 1 H), 7.12 -7.19 (m, 1 H), 6.64 (m, 1 H), 4.84-4.97 (m, 1 H), 3.54-3.70 (m, 1 H), 3 , 26 (s, 3 H), 2.93 (d, 2 H), 2.55-2.66 (m, 2 H), 2.292.22 (m, 2 H), 0.96-1.09 (m, 1 H), 0.53-0.64 (m, 2 H), 0.29-0.39 (m, 2 H). LC / MS (exact mass) calculated for C15H-19F2N5O2S; 335.142, found (M + H + ); 336.0. Example 15: 1-Cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} azetidine-3-sulfonamide Step 1: tert-Butyl 3 - ({[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] amino} sulfonyl ) azetidine-1-carboxylate 72/111 [0166] cis-N-Methyl-N- {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} cyclobutane-1,3-diamine dihydrobromide (7 , 0 g, 18.8 mmol) was free from stirred base in an excess 1N aqueous sodium hydroxide solution for 3 minutes and then extracted in dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The remaining free base became dichloromethane (200 ml), cooled to 0 ° C and treated with triethylamine (13 ml, 94 mmol) and tert-butyl 3 (chlorosulfonyl) azetidine-1-carboxylate. The reaction was allowed to stir at room temperature for 10 minutes. The crude mixture was washed with water and brine, then dried over sodium sulfate and concentrated to provide the crude product as a white solid. The solid was crystallized using a mixture of dichloromethane and diethyl ether to provide the title compound as a white solid (9.61 g, 90%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.19 (s, 1 H), 7.92-8.01 (m, 2 H), 7.54 (d, 1 H), 7, 35 (d, 2 H), 6.86 (d, 1 H), 4.76-4.65 (m, 1 H), 4.18 (br., 2 H), 3.99-4 , 10 (m, 3 H), 3.66-3.78 (m, 1 H), 3.25 (s, 3 H), 2.64-2.78 (m, 2 H), 2.37 (s, 3 H), 2.10-2.25 (m, 2 H), 1.41 (s, 9 H). LC / MS (exact mass) calculated for C26H34N 6 O 6 S 2 ; 590,198, found (M + H + ); 591.45. Step 2: N- [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] azetidine-3-sulfonamide [0167] Acetyl chlorine (0.20 mL, 2.8 mmol) was added to a solution of tertbutyl 3 - ({[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrole [2,3 -d] pyrimidin-4yl} amino) cyclobutyl] amino} sulfonyl) azetidine-1-carboxylate (1.64 g, 2.78 mmol) in anhydrous dichloromethane (18 mL) and methanol (7 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The white precipitate was filtered and taken up in a saturated aqueous sodium bicarbonate solution (20 mL). The resulting solution was extracted with dichloromethane (3 x 20 ml) and the combined organic layers were dried over sodium sulfate and concentrated to provide the title compound (810 mg, 60%) as a white solid. LC / MS (exact mass) calculated for 73/111 C 2 iH 26 N 6 O 4 S 2 ; 490.146, found (Μ + H + ); 491.0. Step 3: 1-Cyclopropyl-N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] azetidine-3- sulfonamide [0168] N- [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] azetidine-3-sulfonamide (810 mg, 1.65 mmol), methanol (10 mL), molecular sieves, and [(1-ethoxycyclopropyl) oxy] (trimethyl) silane (0.53 mL, 2.64 mmol) were combined in a sealable reaction vessel. The reservoir was purged with nitrogen and acetic acid (1.28 mL, 8.26 mmol) was added. The reservoir was sealed and then heated to 80 ° C for 2 hours. After the mixture was cooled to room temperature, sodium cyanoborohydride (273 mg, 4.13 mmol) was added. The reservoir was sealed and slowly heated to 40 ° C for 1.5 hours. The crude mixture was filtered over a bed of Celite, rinsing with methanol. The filtrate was concentrated and the residue became an aqueous saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane (5 x 20 ml), and the combined organic layers were dried over sodium sulfate and concentrated to provide the title compound (576 mg, 74%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ): δ 8.23 (s, 1 H), 7.95-8.05 (m, 2 H), 7.58 (d, 1 H), 7, 39 (d, 2 H), 6.90 (d, 1 H), 4.69-4.83 (m, 1 H), 3.94-4.09 (m, 1 H), 3.65- 3.75 (m, 3 H), 3.543.64 (m, 2 H), 3.29 (s, 3 H), 2.67-2.79 (m, 2 H), 2.41 (s, 3 H), 2.15-2.29 (m, 2 H), 2.02-2.15 (m, 1 H), 0.43-0.51 (m, 2 H), 0.29- 0.39 (m, 2 H). LC / MS (exact mass) calculated for C 24 H 3 oN 6 0 4 S 2 ; 530.177, found (M + H + ); 531.0. Step 4: 1 - Cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} azetidine-3-sulfonamide [0169] A solution of cesium carbonate ( 976 mg, 3.0 mmol) in water (5 mL) was added to a solution of 1-cyclopropyl-N- [cis-3- (methyl {7 - [(4methylphenyl) sulfonyl] -7H-pyrrole [2,3 -d] pyrimidin-4-yl} amino) cyclobutyl] azetidine-3sulfonamide (530 mg, 1.0 mmol) in ethanol (10 mL). The reaction mixture was heated to reflux for 16 hours. After the solvent was removed, the remaining material was made up in water and extracted with a mixture of dichloromethane and methanol (96: 4; 3x10 ml). The combined organic layers were dried over sodium sulfate and concentrated. The crude solid was crystallized from methanol to provide the title compound (225 mg, 59%) as a white solid. 1 H NMR (400 MHz, metanold 4 ): δ 8.10 (s, 1 H), 7.09 (d, 1 H), 6.66 (d, 1 H), 4.88-4.80 ( m, 1 H), 4.03-3.96 (m, 1 H), 3.73-3.65 (m, 3 H), 3.61-3.57 (m, 2 H), 3, 32 (s, 3 H), 2.77-2.68 (m, 2 H), 2,282.19 (m, 2 H), 2.08-2.03 (m, 1 H), 0.46- 0.41 (m, 2 H), 0.34-0.31 (m, 2 H). LC / MS (exact mass) calculated for Ci7H 24 N 6 O 2 S; 376.168, found (M + H + ); 377.0. Example 16: N- (Cyclopropylmethyl) -N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} sulfamide Step 1: N- [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] -2-oxo-1,3 -oxazolidine-3-sulfonamide [0170] To a solution of chlorosulfonyl isocyanate (1.76 mL, 20.6 mmol) in dichloromethane (150 mL) was added dropwise a solution of 2-bromoethanol (1.43 mL, 20.6 mmol) in dichloromethane (80 mL) at 0 ° C. After 30 minutes at 0 ° C, a solution of cis-N-methyl-N- {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} cyclobutane-1,3 -diamine dihydrobromide (11.0 g, 20.6 mmol) and triethylamine (10.42 g, 103.2 mmol) in dry dichloromethane (80 mL) was added dropwise, and the reaction mixture was allowed to warm to temperature environment at night. The reaction solution was dissolved in dichloromethane (1 L), diluted with a 1M solution of aqueous hydrochloric acid (2 x 800 ml) and brine (500 ml). The solution was dried over sodium sulfate and concentrated to provide the title compound as a white solid (8.5 g, 79%). 1 H NMR (400 MHz, CD 3 OD): δ 8.22 (s, 1 H), 8.00 (d, 2 H), 7.58 (d, 1 H), 7.38 (d, 2 H), 6.91 (d, 1 H), 4.88 (m, 1 H), 4.45-4.41 (m, 2 H), 4.06-4.02 (m, 2 H) , 3.75 (m, 1 H), 3.29 (s, 3 H), 2.72-2.69 (m, 2 H), 2.40 (s, 3 H); 2.30-3.27 (m, 2 H). LC / MS (exact mass) calculated for C 2 iH 24 N 6 O 6 S 2 ; 520,120, found (M + 75/111 H + ); 521.4. Step 2: N- (Cyclopropylmethyl) -N '- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] sulfamide [0171] A solution of N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] -2-oxo- 1,3-oxazolidine-3-sulfonamide (150 mg, 0.29 mmol), cyclopropanomethylamine (51 mg, 0.72 mmol) and triethylamine (116 mg, 1.15 mmol) in acetonitrile (3 mL) was stirred for 15 minutes at 100 ° C using microwave heating. The reaction mixture was concentrated to provide the crude title compound (146 mg, 100% crude yield) as a yellow oil. LC / MS (exact mass) calculated for C22H28N6O4S2; 504.161, found (M + H + ); 505.2. Step 3: N- (Cyclopropylmethyl) -N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} sulfamide [0172] A solution of N- (cyclopropylmethyl) -N '- [cis-3- (methyl {7 - [(4methylphenyl) su Ifon il] -7H-pyrrolo [2,3-d] pyrimidi-4-yl} amine) cyclobutyl] su If amide (146 mg, 0.29 mmol), lithium hydroxide monohydrate (48 mg, 1.15 mmol) in ethanol (5 mL) and water (2.5 mL) was stirred at 100 ° C for 1 h . The reaction mixture was concentrated in vacuo and the crude product was purified by preparative high performance liquid chromatography to provide the title compound (14 mg, 14%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ): δ 8.12 (s, 1 H), 7.13 (d, 1 H), 6.90 (d, 1 H), 4.90-4, 86 (m, 1 H), 3.63-3.59 (m, 1 H), 3.37 (s, 3 H), 2.85-2.83 (m, 2 H), 2.78- 2.71 (m, 2 H), 2.33-2.26 (m, 2 H), 1.05-1.03 (m, 1 H), 0.57-0.52 (m, 2 H ); 0.30-0.25 (m, 2 H). LC / MS (exact mass) calculated for Ci5H 2 2N 6 O 2 S; 350,152, found (M + H + ); 351.2. [0173] The following compounds, Examples 17-18, were prepared from N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin- 4il} amino) cyclobutyl] -2-oxo-1,3-oxazolidine-3-sulfonamide (Example 16, Step 1) in a similar manner to that described in Example 16, Step 2, replacing the amine 76/111 indicated by cyclopropanomethylamine, and using the deprotection method illustrated in Example 16, Step 3. Example 17A and 17B: (R) - and (S) -3-Cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} pyrrolidine-1- sulfonamide [0174] These compounds were prepared using racemic pyrrolidine-3-carbonitrile hydrochloride. The raw racemic mixture was purified by high performance liquid chromatography to provide a white solid (60 mg, 52% over 2 steps). The enantiomers were separated by supercritical fluid chromatography. A (17A) enantiomer: 24 mg (21%): 1 H NMR (400 MHz, CD 3 OD): δ 8.13 (s, 1 H), 7.13 (d, J = 3.2 Hz, 1 H), 6.69 (d, 1 H, J = 3.6 Hz, 1 H), 4.87-4.84 (m, 1 H), 3.733.67 (m, 1 H), 3.65 -3.57 (m, 1 H), 3.53-3.50 (m, 2 H), 3.48-3.44 (m, 2 H), 3.405 (s, 3 H), 2.77 -2.75 (m, 2 H), 2.42-2.20 (m, 4 H). LC / MS (exact mass) calculated for C16H21N7O2S; 375.148, found (M + H + ); 376.1. Chiral HPLC retention time = 5.97 minutes. B-enantiomer (17B); 25 mg (21%). 1 H NMR (400 MHz, CD 3 OD): δ 8.13 (s, 1 H), 7.13 (d, J = 3.2 Hz, 1 H), 6.69 (d, 1 H, J = 3.6 Hz, 1 H), 4.87-4.84 (m, 1 H), 3.733.67 (m, 1 H), 3.65-3.57 (m, 1 H), 3, 53-3.50 (m, 2 H), 3.48-3.44 (m, 2 H), 3.405 (s, 3 H), 2.77-2.75 (m, 2 H), 2, 42-2.20 (m, 4 H). LC / MS (exact mass) calculated for C16H21N7O2S; 375.148, found (M + H + ); 376.1. Chiral HPLC retention time = 5.16 minutes. Example 18: 2-Methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4H) amino] cyclobutH} 2,6-dihydropyrrolo [3,4-c] pyrazole-5 (4H) -sulfonamide [0175] This compound was prepared using 2-methyl-2,4,5,6tetrahydropyrrolo [3,4-c] pyrazole hydrochloride. The crude compound was purified by high performance liquid chromatography to provide the title compound as an off-white solid (24% over 2 steps). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.08 77/111 (s, 1 Η), 7.38 (s, 1 Η), 7.10 (d, 1 Η), 6.66 (d, 1 Η), 4.87-4.86 (m, 1 Η), 4.42-4.41 (m, 4 Η), 3.87 (s, 3 Η), 3.71 - 3.67 (m, 1 Η), 3.31 (s, 3 Η ), 2.68-2.61 (m, 2 Η), 2.27-2.22 (m, 3H). LC / MS (exact mass) calculated for Οι 7 Η 22 Ν 8 Ο 2 5; 402.159, found (M + H + ); 403.2 and (M + Na); 425.1. Example 19: N- {cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -6oxa-3-azabicyclo [3.1.1] heptane-3-sulfonamide Step 1: N- [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] -6-oxa-3-azabicycle [3.1.1] heptane-3-sulfonamide [0176] A mixture of N- [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl } amino) cyclobutyl] -2-oxo-1,3-oxazolidine-3-sulfonamide (208 mg, 0.40 mmol), 6-oxa-3-azabicyclo [3.1.1] heptane (50 mg, 0.50 mmol ), triethylamine (220 μΙ_, 1.58 mmol) in acetonitrile (15 mL), was heated in a 20 mL microwave flask in a microwave reactor for 1 hour at 120 ° C. The excess solvent was evaporated and the resulting oil was processed in dichloromethane. The solution was washed with ammonium chloride and brine. The raw material was dried over sodium sulfate and concentrated to give an oil. This was chromatographed on silica gel eluting with a gradient of methanol in dichloromethane (0: 100 to 5: 100) to provide the title compound as a foam (82 mg, 30%). 1 H NMR (CDCI 3 ): δ 8.38 (s, 1 H), 8.04 (d, 2 H), 7.48 (d, 1 H), 7.28 (d, 2 H), 6 , 63 (d, 1 H), 4.78-4.69 (m, 1 H), 4.62 (d, 1 H), 4.47 (d, 1 H), 3.69-3.61 (m, 1 H), 3.58 (d, 3 H), 3.26-3.17 (m, 1 H), 3.24 (s, 3 H), 2.83-.275 (m, 2 H), 2.37 (s, 3 H), 2.18-2.11 (m, 2 H), 2.04 (d, 1 H), 1.18 (t, 1 H). LC / MS (exact mass) calculated for C 2 3H 2 8N 6 O5S 2 ; 532,156, found (M + H + ); 533. Step 2: N- {cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -6-oxa3-azabicyclo [3.1.1] heptane-3-sulfonamide [ 0177] N- [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] -6-oxa-3-azabicycl [ 3.1.1] heptane-3-sulfonamide (229 mg, 0.43 78/111 mmol) was added to a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (6.5 mL, 6.4 mmol). The reaction was stirred at room temperature for 10 hours. The mixture was concentrated and the remaining material was chromatographed on silica gel eluting with a mixture of methanol in ethyl acetate (1: 9). A yellow oil was isolated and was ground with a mixture of ethyl acetate and heptane to give a yellow solid. The solid was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were diluted with brine, dried over sodium sulfate and concentrated to provide an almost white solid. This was triturated with diethyl ether and then isopropyl alcohol to provide the title compound as a white solid (14 mg, 9%). 1 H NMR (CD 3 OD) δ 8.08 (s, 1 H), 7.09 (d, 1 H), 6.66 (s, 1 H), 4.90-4.81 (m, 1H ), 4.62 (d, 2 H), 3.86-8.84 (m, 1 H), 3.66 (t, 1 H), 3.56-3.49 (m, 3 H), 3.33 (s, 3 H), 3.19-3.13 (m, 1 H), 2.75-2.70 (m, 2 H), 2.32-2.24 (m, 2 H ), 2.05-2.03 (d, 1 H). LC / MS (exact mass) calculated for Ci 6 H22N 6 O 3 S; 378.147, found (M + H + ); 379.5. [0178] The following compounds, Examples 20-24, were prepared from N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin- 4il} amino) cyclobutyl] -2-oxo-1,3-oxazolidine-3-sulfonamide (Example 16, Step 1) in a similar manner to that described in Example 16, Step 2, replacing the indicated amine with cyclopropanomethylamine, and using The deprotection method illustrated in Example 19, Step 2. Example 20: 3-Cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl / azetidine-1-sulfonamide [0179] This compound was prepared using azetidine-3-carbonitrile. The crude compound was purified by high performance liquid chromatography to provide the title compound as a white solid (23% over 2 steps). 1 H NMR (400 MHz, CD 3 OD): δ 8.10 (s, 1 H), 7.11 (d, 1 H), 6.68 (d, 1 H), 4.80 (m, 1 H), 4.02 (m, 2 H), 3.90 (m, 2 H), 3.58 (m, 2 H), 3.32 (s, 3 H), 2.72 (m, 2 H), 2.25 (m, 2 H). 79/111 LC / MS (exact mass) calculated for C15H-19N7O2S; 361,132, found (M + H + ); 362.1. Example 21: N- {cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -4 (1 H-pyrazol-3-yl) piperidine-1-sulfonamide [0180] This compound was prepared using 4- (1 H-pyrazol-3-yl) piperidine. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9: 1). The isolated material was triturated with diethyl ether and then ethyl acetate to provide the title compound as a white solid (10% over 2 steps). 1 H NMR (300 MHz, CD 3 OD): δ 8.09 (s, 1 H), 7.48 (s, 1 H), 7.12-7.05 (m, 1 H), 6.71 -6.60 (m, 1 H), 6.22-6.08 (m, 1 H), 4.92-4.73 (m, 1H), 3.80-3.55 (m, 3H) , 3.41 (s, 3H), 2.90-2.65 (m, 5 H), 2.38-2.19 (m, 2 H), 2.09-1.90 (m, 2 H ) and 1.83-1.65 (m, 2 H). LC / MS (exact mass) calculated for C19H26N8O2S; 430,190, found (M + H + ); 431.1. Example 22: N- (2-Cyanoethyl) -N-methyl-N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin4-yl) amino] cyclobutyl} sulfamide [0181] This compound was prepared using 3-methylaminopropionitrile. The crude compound was purified by high performance liquid chromatography to provide the title compound (7% over 2 steps). LC / MS (exact mass) calculated for C15H21N7O2S; 363,148, found (M + H + ); 364.0. Example 23 and 27: (1 S, 5S) -1 -Cyan-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin4-H) amino] cyclobutyl} -3-azabicyclo [3.1 .0] hexane-3-sulfonamide and (1R, 5R) -1 -Cyan-N {cis-3- [metH (7H-pyrrolo [2,3-d] pyrimidin-4-H) amino] cyclobutH} -3 -azabicyclo [3.1.0] hexane3-sulfonamide [0182] These compounds were prepared using a racemic 3azabicyclo [3.1.0] hexane-1-carbonitrile. The raw racemic compound was purified as a white solid (92 mg, 21% over 2 steps) by chromatography on silica gel eluting with a gradient of dichloromethane and methanol (30: 1 to 5: 1). 80/111 The title enantiomers were separated by supercritical fluid chromatography. Enantiomer 23: 41 mg (9%); SFC retention time = 4.28 minutes; 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1 H), 7.13 (d, 1 H), 6.70 (d, 1 H), 4.61 (s, 1 H), 3.57 - 3.72 (m, 2 H), 3.43 - 3.51 (m, 3 H), 3.36 (s, 3 H), 2.70 - 2.77 ( m, 2 H), 2.24 - 2.38 (m, 3 H), 1.41 - 1.48 (m, 1 H), 1.32 (t, 1 H). LC / MS (exact mass) calculated for C17H21N7O2S; 387,148, found (M + FT); 388.1. Enantiomer 27: 40 mg (9%); SFC retention time = 4.84 minutes 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1 H), 7.13 (d, 1 H), 6.70 (d, 1 H), 4.61 (s, 1 H), 3.57 - 3.72 (m, 2 H), 3.43 - 3.51 (m, 3 H), 3.36 (s, 3 H) , 2.70 - 2.77 (m, 2 H), 2.24 - 2.38 (m, 3 H), 1.41 - 1.48 (m, 1 H), 1.32 (t, 1 H). LC / MS (exact mass) calculated for C17H21N7O2S; 387.148, found (M + H + ); 388.1. Racemic 3-azabicyclo [3.1.0] hexane-1-carbonitrile was prepared as follows. Step 1: racemic tert-butyl rac-1-formyl-3-azabicyclo [3.1.0] hexane-3-carboxylate [0183] 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1 H) -one (6.5 g, 15.2 mmol) was added to a solution of racemic tert-butyl-1 - (hydroxymethyl) -3azabicyclo [3.1.0] hexane-3-carboxylate (Synlett 2009, 921 ) (2.5 g, 11.7 mmol) in anhydrous dichloromethane (60 mL). The reaction mixture stirred for 2 hours at room temperature. The mixture was diluted with dichloromethane (60 ml), diluted with a saturated aqueous solution of sodium sulfite, saturated sodium bicarbonate (30 ml) and brine (50 ml). The organic layer was dried over sodium sulfate and concentrated to provide the title compound as a colorless oil (1.7 g, 68%). 1 H NMR (400 MHz, CDCI 3 ): δ 9.01 (d, 1 H), 3.83 (d, 1 H), 3.68 (t, 1H), 3.59 (dd, 1 H) , 3.50-3.36 (m, 1 H), 2.25-2.09 (m, 1 H), 1.63 (t, 1 H), 1.43 (s, 9 H), 1 , 19-1.06 (m, 1 H). Stage 2: tert-butyl-1 - [(hydroxyimino) methyl] -3-azabicyclo [3.1.0] hexane-381/111 racemic carboxylate [0184] Potassium carbonate (3.89 g, 28.2 mmol) and hydroxylamine hydrochloride (671 mg, 9.7 mmol) were added to a solution of racemic tert-butyl 1-formyl3-azabicyclo [3.1.0] hexane-3-carboxylate (1.7 g, 8.05 mmol) in anhydrous dichloromethane (40 mL) at room temperature and then stirred for 16 hours. The mixture was diluted with ethyl acetate (80 ml), and diluted with water (30 ml) and brine (30 ml). The organic layer was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a gradient of petroleum ether and ethyl acetate (0: 100 to 83:17) to provide the title compound as a yellow oil (1.6 g, 88%). 1 H NMR (400 MHz, CDCI 3 ): δ 7.18 (s, 1 H), 3.74-3.55 (m, 3 H), 3.44-3.40 (m, 1 H), 1.74-1.72 (m, 1 H), 1.44 (s, 9 H), 1.10 (t, 1 H), 0.86-0.83 (m, 1 H). Step 3: racemic tert-butyl-1-cyano-3-azabicyclo [3.1.0] hexane-3-carboxylate [0185] To a solution of tert-butyl-1 - [(hydroxyimino) methyl] -3azabicyclo [3.1.0 ] racemic hexane-3-carboxylate (925 mg, 4.09 mmol) in anhydrous tetrahydrofuran (100 mL) was added methyl A / - (triethylammonium sulfonyl) carbamate (2.92 g, 12.3 mmol). The reaction mixture was heated to reflux for 3 hours. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with a mixture of petroleum ether and ethyl acetate (5: 1) to provide the title compound as a colorless oil (570 mg, 67%). 1 H NMR (400 MHz, CDCI 3 ): δ 3.84 (dd, 1 H), 3.64 (dd, 1 H), 3.50 (d, 1 H), 3.46 (dd, 1 H ), 2.21 - 2.12 (m, 1 H), 1.44 (s, 9 H), 0.96 (t, 1 H). Step 4: Racemic 3-azabicyclo [3.1.0] hexane-1-carbonitrile [0186] A solution of racemic tert-butyl-1-cyano-3-azabicyclo [3.1.0] hexane-3carboxylate in acetic trifluoroacid (1 mL) and dichloromethane (10 ml) was stirred at room temperature for 1 hour. The solvent was removed to provide the title compound (205 mg, 100%) as a brown oil. Example 24: 3-cyano-N- {trans-3- [metH (7H-pyrrolo [2,3-d] pyrimidin-482/111 yl) amino] cyclobutyl} pyrrolidine-1-racemic sulfonamide [0187] This compound was synthesized following procedure of Example 10, replacing 3-cyanopyrrolidine-1-chloro sulfonyl with cyclopropylmethanochloro sulfonyl. The crude product was purified using preparative high performance liquid chromatography to provide the title compound as an off-white solid (5%). 1 H NMR (400 MHz, CD 3 OD): δ 8.13 (s, 1 H), 7.14 (d, 1 H), 6.67 (d, 1 H), 5.45-5.41 (m, 1 H), 4.00-3.64 (m, 1 H), 3.62-3.52 (m, 1 H), 3.51-3.47 (m, 2 H), 3 , 45-3.39 (m, 2 H), 3.369 (s, 3 H), 2.78-2.70 (m, 2 H), 2.53-2.47 (m, 2 H); 2.39-2.36 (m, 1 H); 2,272.24 (m, 1 H). LC / MS (exact mass) calculated for Ci 6 H 2 iN 7 O2S; 375.148, found (M + H + ); 375.9. Racemic 3-cyanopyrrolidine-1-chloron sulfonyl [0188] A solution of racemic pyrrolidine-3-carbonitrile (53 mg, 0.4 mmol) and triethylamine (101 g, 1 mmol) in dry dichloromethane (1.0 mL) was added dropwise to a stirred solution of sulfuryl chloride (64.8 mg, 0.48 mmol) in dichloromethane (3.0 mL) was added at -78 ° C. The reaction was stirred at -78 ° C for 30 minutes, and then allowed to warm to room temperature for 1 hour. The reaction solution was washed with 1M aqueous hydrochloric acid (5 ml) and brine (5 ml), dried over sodium sulfate and concentrated to provide the title compound as a colorless oil (68 mg, crude). Example 25: N- (cis-3 - {[(4,4-Difluoropiperidin-1 -yl) sulfonyl] methyl} cyclobutyl) -Nmethyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine Step 1: cis / trans-Ethyl 3 - [(tert-butoxycarbonH) amino] cyclobutanecarboxylate [0189] To a solution of a mixture of cis- and trans-ethyl 3aminocyclobutanecarboxylate hydrochloride (cis / trans = 10: 1) (W02009 / 60278 ) (10 g, 55.7 mmol) and triethylamine (19.4 mL, 139.1 mmol.) In dichloromethane (370 mL) at 0 ° C was added dropwise di-butyl dicarbonate (15.8 g , 72.3 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. The solvent 83/111 was evaporated under reduced pressure and the resulting residue was chromatographed on silica gel eluting with a gradient of petroleum ether and ethyl acetate (10: 1 to 3: 1) to provide the title mixture as a white solid (19 g , 92%). 1 H NMR (400 MHz, CDCI 3 ): δ 4.77 (s, 1 H), 4.13 (q, 3 H), 2.68 - 2.82 (m, 1 H), 2.60 ( d, 2 H), 1.99 2.17 (m, 2 H), 1.43 (s, 9 H), 1.25 (t, 3 H). Step 2: cis / trans- [3- (Methylamino) cyclobutyl] methanol [0190] Lithium aluminum hydride (9.14 g, 240.4 mmol) was suspended in dry tetrahydrofuran (350 ml). The mixture was cooled to 0 ° C and a cis / trans ethyl solution 3- [(tert-butoxycarbonyl) amino] cyclobutanecarboxylate (cis / trans = 10: 1) (11.7 g, 48.1 mmol) in dry tetrahydrofuran (170 mL) was added dropwise. After the addition was complete, the resulting mixture was heated to reflux overnight. After being cooled to room temperature, the reaction was diluted with tetrahydrofuran (1.5 L) and then cooled to 0 ~ 5 ° C. small portions of Na 2 SO 4 .10H 2 O were added until the evolution of the gas has ceased. The mixture was filtered to remove the solids, which were diluted with more tetrahydrofuran (500mL). The filtrate was concentrated to dry providing the title mixture (cis / trans = 10: 1) as an oil (10 g,> 100%). 1 H NMR (400 MHz, CDCI3): δ 3.58 (d, J = 3.8 Hz, 2 H), 3.06-3.17 (m, 1 H), 2.34-2.43 ( m, 3 H), 2.32 (s, 3 H), 1.48-1.57 (m, 2 H). Step 3: cis / trans- [3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin- 4-yl} amino) cyclobutyl] methanol [0191] potassium lodide (173 mg) and triethylamine (13 ml, 93.8 mmol) were added to a cis / trans- [3- (methylamino) cyclobutyl] methanol solution ( 6.0 g, 52.1 mmol) in acetone (250 mL). 4-Chloro-7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidine (14.4 g, 46.9 mmol) was then added and the resulting mixture was heated to reflux overnight. After evaporating the solvent under reduced pressure, the residue was diluted with dichloromethane (500 ml). The solution was washed sequentially with water (300 ml), 2% aqueous citric acid (300 ml) and brine (300 ml), and 84/111 then dried over sodium sulfate. After filtration, the solution was filtered and concentrated to provide the title mixture as a clear solid (15.3 g, 85%). A portion (5.0 g) of the cis / trans- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) -cyclobutyl mixture] methanol was separated by supercritical fluid chromatography using a Chiralpak-AD column: cis isomer, 4.6 g: 1 H NMR (400 MHz, methanol-d 4 ): δ 8.20 (s, 1 H), 7.98 (d, 2 H), 7.53 (d, 1 H ), 7.34 (d, 2 H), 6.83 (d, 2 H), 4.99-4.95 (m, 1 H), 3.56 (d, J = 5.6 Hz, H), 3.24 (s, 3 H), 2.36 (s, 3 H), 2.34-2.28 (m, 2 H), 2.24-2.19 (m, 1 H) , 2.11 - 2.03 (m, 2 H). LC / MS (exact mass) calculated for C19H22N4O3S: 386.14, found (M + H + ): 387.3 trans isomer, 0.4 g: 1 H NMR (400 MHz, methanol-d 4 ): δ 8, 20 (s, 1H), 7.98 (d, H), 7.55 (d, 1H), 7.35 (d, 2H), 6.84 (d, 2H), 5.26-5.22 (m, 1H), 3.69 (d, 1H ), 3.30 (s, 3H), 2.46-2.41 (m, 3H), 2.39 (s, 3H), 2.19-2.14 (m, 2H). LC / MS (exact mass) calculated for Ci9H 2 2N 4 O 3 S: 386.14, found (M + H + ): 387.3 Step 4: cis- [3- (Methyl {7 - [(4-methylphenyl) sulfonyl] - 7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methyl 4-methylbenzenesulfonate [0192] To a solution cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] methanol (20 g, 51.8 mmol) and N , N-dimethylaminopyridine (12.6 g, 103.6 mmol) in dichloromethane (500 mL) at 0 ° C was added toluene sulfonyl p-chloride (14.8 g, 77.7 mmol). The reaction mixture was stirred at room temperature for 16 hours and then diluted with water (500 ml). The combined aqueous washes were extracted with dichloromethane (2 x 800 ml). The combined organic layers were dried, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 95: 5) to provide the title compound (23 g, 82%) as a white solid. LC / MS (exact mass) calculated for C26H28N 4 O 5 S 2 : 540,150, found (M + H + ): 541.3. 85/111 Step 5: S - {[cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methyl} ethanothioate [0193] A a solution of potassium thioacetate (678 mg, 5.93 mmol) in N, N-dimethylformamide (5 mL) was added a solution of [cis-3- (methyl {7 - [(4methylphenyl) sulfonyl] -7H-pyrrole [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl 4 methylbenzenesulfonate (2.0 g, 3.70 mmol) in N, N-dimethylformamide (6 ml) dropwise over 5 minutes at room temperature. The mixture was then heated to 5055 ° C overnight. The mixture was cooled to room temperature and quenched by pouring into a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (3 x 30 ml) and the combined organic layers were diluted with water (3 x 30 ml), brine (30 ml). After drying over Na 2 SO 4 the solution was concentrated. The residue was chromatographed on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 80:20) to provide the title compound (1.2 g, 73%) as a yellow solid. 1 H NMR (400 MHz, CDCI 3 ): δ 8.39 (s, 1H), 8.04 (d, 2 H), 7.45 (d, 1 H), 7.27 (d, 2 H) , 6.63 (d, 1 H), 4,984.88 (m, 1 H) 3.22 (s, 3 H) 3.02-3.00 (m, 2 H) 2.45-2.44 ( m, 2 H), 2.47 (m, 3 H) 2.22 (m, 3 H) 2.21 - 2.24 (m, 1 H) 1.92-1.87 (m, 2 H) . LC / MS (exact mass) calculated for C 2 iH 24 N 4 O 3 S 2 : 444.129, found (M + H + ): 445.1. Step 6: [cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] - 7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methanesulfonic acid [0194] To a solution of S - {[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpirrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl} ethanothioate (580 mg, 1.31 mmol ), in formic acid (10 mL) at room temperature, 30% aqueous hydrogen peroxide solution (0.7 mL, 6.92 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was poured into 33% aqueous sodium bisulfate solution (1.12 mL) and then stirred for 10 minutes. 33% of an aqueous sodium hydroxide solution (1.8 mL) was then added to adjust 86/111 bring the pH to 5. The resulting mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, diluted with water (10 ml) and dried in vacuo at about 60 ° C to provide the title compound (634 mg, crude) as a white solid. LC / MS (exact mass) calculated for C19H22N4O5S2; 450.103, found (M + H + ); 451.3. Step 7: cis- [3- (Methyl {7 - [(4-methylphenyl) sulfonyl] - 7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methanochlorine sulfonyl [0195] Thionyl chlorine ( 0.3 ml, 3.33 mmol) was added dropwise over 5 minutes to a solution of cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpyrrolo [2,3-d] pyrimidin -4-yl} amino) cyclobutyl] methanesulfonic acid (150 mg, 0.33 mmol) in dichloromethane (20 mL) at 0 ° C. Two drops of Ν, Ν-dimethylformamide were added to the solution, which was then heated to 75 ° C for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with anhydrous dichloromethane (3 x 10 ml) to provide the crude title compound (170 mg) as a yellow solid. LC / MS (exact mass) calculated for C19H21CIN4O4S2; 468.069, found (M + H + ); 469.2. Step 8: N- (cis-3 - {[(4,4-Difluoropiperidin-1 -yl) sulfonyl] methyl} cyclobutyl) -N-methyl7 - [(4-methylphenyl) sulfonyl] - 7H-pyrrole [2,3 -d] pyrimidin-4-amine [0196] To a mixture of 4,4-difluoropiperidine (77 mg, 0.64 mmol) and triethylamine (97 mg, 0.96 mmol) in tetrahydrofuran (20 mL) at 0 ° C a solution of cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methanochloride sulfonyl (150 mg , 0.320 mmol) in tetrahydrofuran (10 mL). The mixture was allowed to warm to room temperature overnight. The solvent was evaporated and the residue was taken up in ethyl acetate (80 ml). The solution was washed with brine (30 ml), dried over sodium sulfate and concentrated to provide the crude title compound (134 mg) as a white solid. LC / MS (exact mass) calculated for C24H29F2N5O4S2; 553,651, found (M + H + ); 554.3. 87/111 Step 9: N- (cis-3 - {[(4,4-difluoropiperidin-1-yl) sulfonyl] methyl} cyclobutyl) -N-methyl7H-pyrrolo [2,3-d] pyrimidin-4-amine [0197] N- (cis-3 - {[(4,4-Difluoropiperidin-1-yl) sulfonyl] methyl} cyclobutyl) -N-methyl-7 [(4-methylphenyl) sulfonyl] -7H-pyrrole [2,3-d ] pyrimidin-4-amine (134 mg, 0.24 mmol) and lithium hydroxide monohydrate (51 mg, 1.21 mmol) were combined in a mixture of ethanol (14 mL) and water (7 mL) and then heated to 50 ° C overnight. The reaction was concentrated in vacuo and diluted with ethyl acetate (100 ml). The resulting solution was washed with brine (30 ml), dried over sodium sulfate and concentrated. The residue was chromatographed using preparative thin layer chromatography eluting with a mixture of ethyl acetate and methanol (20: 1) to provide the title compound (31 mg, 32.3%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1H), 7.13 (d, J = 3.6, 1H), 6.70 (d, J = 3.6, 1H), 5.12 (m, 1H), 3.49-3.47 (m, 4H), 3.46 (m, 3H), 3.33 (m, 2H), 2.62-2.54 (m, 3H), 2.25-2.20 (m, 1H), 2.11-2.05 (m, 2H). LC / MS (exact mass) calculated for C17H23F2N5O2S; 399,154, found (M + H + ); 400.3. [0198] Examples 26 to 29. The following compounds were made starting from cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methanochloro sulfonyl (Example 25, Step 7), according to the procedures of Example 25, Step 8 (sulfonylation) and step 9 (deprotection), replacing the appropriate amine with 4,4-difluoropiperidine in Step 8. Example 26: 1 - [({cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] -4- (trifluoromethyl) piperidin-4-ol [0199] The title compound (31 mg) was prepared using 4 (trifluoromethyl) piperidin-4-ol in the sulfonylation step and was deprotected using the method of Example 25, Step 9. The compound was purified using preparative thin layer chromatography eluting with eluting with a mixture of ethyl acetate and methanol (20: 1). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1H), 7.13 (d, J = 3.6, 1 88/111 Η), 6.70 (d, J = 3.6, 1H), 5.10-5.08 (m, 1 H), 3.74-3.71 (m, 2 H), 3.36 ( m, 3 H), 3,323.27 (m, 2 H), 3.19-3.13 (m, 2 H), 2.62-2.54 (m, 3 H), 2.25-2, 21 (m, 2 H), 1.86-1.84 (m, 4 H). LC / MS (exact mass) calculated for C18H24F3N5O3S; 447,155, found (Μ + H + ); 448.3. Example 28 and 29: (3R) and (3S) -1 - [({cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3 -carbonitrile [0200] The title compounds (330 mg total) were prepared using enriched pyrrolidine-3-carbonitrile as an 80:20 scalemic mixture of (3F ) pyrrolidine-3-carbonitrile and (3S) -pyrrolidine-3-carbonitrile enantiomers in the sulfonylation step and was deprotected using the method of Example 19, Step 2. The compound was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (10: 1 to 1:10). LC / MS m / z = 375.2 (M + 1). The enantiomers were separated by preparative supercritical fluid chromatography: 3F -Enantiomer (28): 178 mg. 1 H NMR (400 MHz, CDCI3): δ 8.31 (s, 1H), 7.06 (d, 1 H), 6.58 (d, 1 H), 5.19-5.10 (m, 1 H), 3.77-3.75 (m, 1 H), 3.61-3.54 (m, 3 H), 3.33 (s, 3 H), 3.21-3.19 ( m, 3 H), 2.69-2.66 (m, 3 H), 2.36-2.31 (m, 2 H), 2.122.11 (m, 2 H). LC / MS (exact mass) calculated for Ci7H 2 2N 6 O 2 S; 374.15, found (M + H + ); 375.2. Chiral HPLC retention time = 2.65 minutes 3S-enantiomer (29): 31 mg. 1 H NMR (400 MHz, CDCI3): δ 8.31 (s, 1H), 7.06 (d, 1 H), 6.58 (d, 1 H), 5.19-5.10 (m, 1 H), 3.77-3.75 (m, 1 H), 3.61-3.54 (m, 3 H), 3.33 (s, 3 H), 3.21-3.19 ( m, 3 H), 2.69-2.66 (m, 3 H), 2.36-2.31 (m, 2 H), 2.14-2.11 (m, 2 H). LC / MS (exact mass) calculated for Ci7H 22 N 6 O 2 S; 374.15, found (M + H + ); 375.2 Chiral HPLC retention time = 2.53 minutes Example 30: N- {cis-3 - [(Butylsulfonyl) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3d] pyrimidin-4-amine Step 1: N- {cis-3 - [(Butylthio) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3-d] pyrimidin 4-amine 89/111 [0201] A solution of cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] methyl 4-methylbenzenesulfonate from Example 25, Step 4 (23 g, 42.6 mmol) was stirred in N-methylpyrrolidine (100 ml). Then 1,8diazabicycloundec-7-ene (12.8 g, 85.2 mmol) and 1-butanethiol (7.8 g, 85.2 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 16 hours. Water (200 ml) and ethyl acetate (500 ml) were added. The aqueous layer was extracted with ethyl acetate (2 x 500 ml) and the combined organic layers were dried and concentrated. The residue was chromatographed on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 90:10) to provide the title compound (11.8 g, 91%). LC / MS (exact mass) calculated for Ci 6 H 2 4N 4 S; 304,172, found (M + H + ); 305.3. Step 2: N- {cis-3 - [(Butylsulfonyl) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3d] pyrimidin-4-amine [0202] N- {cis-3 - [(Butiltio) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4amine (12 g, 39.5 mmol) was dissolved in a mixture of tetrahydrofuran (200 ml), ethanol (200 ml) and water (200 mL). Potassium peroxomonosulfate (48.6 g, 79.0 mmol) was added and the reaction was stirred at room temperature for 1 hour. The mixture was then filtered; the solids were diluted with a mixture of tetrahydrofuran (40 ml), ethanol (40 ml) and water (20 ml). The filtrate was treated with 10% aqueous sodium bisulfite solution (200 mL) and stirred at room temperature for 20 minutes. A saturated aqueous sodium bicarbonate solution was added to adjust the pH to ~ 7. The mixture was extracted with dichloromethane (3 x 800 ml) and the combined organic layers were dried and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 95: 5) to obtain the title compound (11.4 g, 86%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.13 (s, 1 H), 7.13-7.12 (m, 1 H), 6.70-6.69 (m, 1 H ), 5.13-5.10 (m, 1 H), 3.42 (s, 3 H), 3.33 (m, 2 H), 3.11-3.07 (m, 2 H), 2.65-2.63 (m, 3 H), 2.29-2.25 (m, 90/111 Η), 1.86-1.78 (m, 2 Η), 1.55-1.50 (m, 2 Η), 1.03-0.99 (m, 3 Η). LC / MS (exact mass) calculated for Ci 6 H 2 4N 4 O2S; 336,162, found (M + H + ); 337.3 Example 31: N-Methyl-N- (trans-3 - ((propylsulfonyl) methyl) cyclobutyl) -7H-pyrrolo [2,3d] pyrimidin-4-amine [0203] The title compounds were made as a mixture of cis and trans isomers (50 mg) starting from cis and trans- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl 4- methylbenzene sulfonate (cis / trans = 10: 1) (Example 25, Step 4), following procedures similar to those in Example 30, Steps 1 and 2, using propane-1-thiol instead of butane-1-thiol in Step 2. The mixture of cis and trans isomers was purified by reverse phase high performance liquid chromatography eluting with a gradient of water and acetonitrile (95: 5 to 5:95). LC / MS (exact mass) calculated for Ci 5 H 22 N 4 O 2 S; 322.15, found (M + H + ); 323.2 [0204] The cis and trans isomers were then separated by preparative supercritical fluid chromatography. trans isomer (31), 12 mg: 1 H NMR (400 MHz, methanol-d 4 ): δ 8.12 (s, 1 H), 7.13- 7.12 (m, 1 H), 6.69-6.66 (m, 1 H), 5.45-5.41 (m, 1 H), 3.46-3.44 (m, 2 H), 3.36 (s, 3 H), 3.11-3.09 (m, 2 H), 2.88-2.86 (m, 1 H), 2.75-2.67 ( m, 2 H), 2.40-2.38 (m, 2 H), 1.91-1.86 (m, 2 H), 1.12-1.10 (m, 3 H). LC / MS (exact mass) calculated for Ci 5 H 22 N 4 O 2 S; 322.15, found (M + H + ); 323.2 cis isomer, 36 mg: 1 H NMR (400 MHz, methanol-d 4 ): δ 8.12 (s, 1 H), 7,137.12 (m, 1 H), 6.70-6.69 (m, 1 H), 5.10-5.20 (m, 1 H), 3.36 (s, 3 H), 3.33-3.32 (m, 2 H), 3.08-3 , 04 (m, 2 H), 2.64-2.61 (m, 3 H), 2.24-2.22 (m, 2 H), 1.90-1.84 (m, 2 H) , 1.13 - 1.09 (m, 3 H). LC / MS (exact mass) calculated for Ci 5 H 22 N 4 O 2 S; 322.15, found (M + H + ); 323.2. Example 32: N- (cis-3 - {[(2-Cyclopropylethyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4 -amine 91/111 Step 1: N- (cis-3 - {[(2-Cyclopropylethyl) sulfanyl] methyl} cyclobutyl) -N-methyl-7 - [(4methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4 -amine [0205] Nitrogen was bubbled through a mixture of S - {[cis-3- (methyl {7 [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl} ethanethioate Example 25, Step 5 (190 mg, 0.43 mmol) and potassium carbonate (129 mg, 0.94 mmol) in methanol (10 mL) at 0 ° C for 2 minutes. 2-Cyclopropylethyl 4methylbenzenesulfonate (159 mg, 1.53 mmol) was then added and the solution was stirred for 6 hours at room temperature. Dichloromethane (30 ml) and water (20 ml) was added and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic layers were diluted with brine, dried over sodium sulfate and concentrated. The crude product was purified by preparative thin layer chromatography using petroleum ether-ethyl acetate (1: 2) to give the title compound as a white solid (62 mg, 31%). LC / MS (exact mass) calculated for C24H30N4O2S2; 470.18, found (M + H + ); 471.1 Step 2: N- (cis-3 - {[(2-Cyclopropylethyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7 - [(4methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4 -amine [0206] The mixture of N- (cis-3 - {[(2-cyclopropylethyl) sulfanyl] -methyl} cyclobutyl) -Nmethyl-7 - [(4-methylphenyl) -sulfonyl] -7H-pyrrole [2, 3-d] pyrimidin-4-amine (24 mg, 0.051 mmol) and potassium peroxomonosulfate (49 mg, 0.079 mmol) in tetrahydrofuran (1.2 mL), water (0.6 mL) and ethanol (1.2 mL ) was stirred at room temperature for 20 minutes. Aqueous sodium disulfide was added, followed by dichloromethane (20 ml). The aqueous layer was extracted with dichloromethane (2 x 20 ml) and the combined organic layers were extracted with brine, dried over sodium sulfate and concentrated. The raw material was used directly in the next step. LC / MS (exact mass) calculated for C24H30N4O4S2; 502.17, found (M + H + ); 503.3 Step 3: N- (cis-3 - {[(2-Cyclopropylethyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4 -amine 92/111 [0207] The mixture of N- (cis-3 - {[(2-cyclopropylethyl) sulfonyl] methyl} cyclobutyl) -N-methyl7 - [(4-methylphenyl) sulfonyl] -7H-pyrrole [2,3 -d] pyrimidin-4-amine (49 mg, 0.097 mmol) and lithium hydroxide (30 mg, 1.3 mmol) in water (5 mL) and ethanol (10 mL) was stirred at 50 ° C for 2 hours. Then, dichloromethane (20 ml) was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were diluted with brine, dried over sodium sulfate and concentrated. The crude product was purified by reverse phase high performance liquid chromatography using a water gradient and gradienton acetonitrile (95: 5 to 5:95) to give the title compound (14 mg, 40%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ): δ 8.12 (s, 1 H), 7.13 (d, 2 H), 6.70 (d, 2 H), 5.12-5, 09 (m, 1 H), 3.34 (s, 3 H), 3.34-3.33 (m, 2 H), 3.20-3.17 (m, 2 H), 2.64- 2.61 (m, 3 H), 2.26-2.22 (m, 2 H), 1.75-1.69 (m, 2 H), 0.890.86 (m, 2 H), 0, 56-0.52 (m, 2 H), 0.18-0.17 (m, 2 H). LC / MS (exact mass) calculated for C17H24N4O2S; 348.16, found (M + H + ); 349.1. Example 33: N- [cis-3 - ({[(3,3-Difluorocyclobutyl) methyl] sulfonyl} -methyl) cyclobutyl] N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine Step 1: N- [cis-3 - ({[(3,3-Difluorocyclobutyl) methyl] sulfanyl} methyl) cyclobutyl] -Nmethyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine [0208] Nitrogen was bubbled through a mixture of S - {[cis-3- (methyl {7 [(4-methylphenyl) -sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl } ethanothioate, Example 25, Step 5 (250 mg, 0.56 mmol) and potassium carbonate (194 mg, 1.41 mmol) in methanol (100 mL) for two minutes at 0 ° C followed by the addition of (3, 3difluorocyclobutyl) methyl 4-methylbenzenesulfonate (prepared as described in W02004 / 032834) (310 mg, 1.12 mmol). The mixture is stirred for 6 hours at room temperature, filtered, and concentrated to give the title compound (270 mg, crude) as a white solid. LC / MS (exact mass) calculated for C17H22F2N4S; 352.15, found (M + H + ); 353.2 Step 2: N- [cis-3 - ({[(3,3-Difluorocyclobutyl) methyl] sulfonyl} methyl) cyclobutyl] -N 93/111 methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine [0209] The mixture of N- [cis-3 - ({[(3,3-difluorocyclobutyl) methyl] sulfanyl} methyl) cyclobutyl ] -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (45 mg, 0.13 mmol) and potassium peroxomonosulfate (157 mg, 0.26 mmol) in a mixture of tetrahydrofuran (20 mL), water (10 mL) and ethanol (20 mL) were stirred at room temperature for 20 minutes. Aqueous sodium disulfide was then added, followed by dichloromethane (20 ml). The aqueous layer was extracted with dichloromethane (2 x 20 ml) and the combined organic layers were extracted with brine, dried over sodium sulfate, and concentrated. The crude product was purified by reverse phase high performance liquid chromatography using a water-acetonitrile gradient (95: 5 to 5:95) to give the title compound as a white solid (34 mg, 39%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.29 (s, 1 H), 7.42 (d, 1 H), 7.03 (d, 1 H), 4.86 (m, 1 H), 3.51 (s, 3 H), 3.39-3.33 (m, 4 H), 2.84 (m, 1 H), 2.76-2.71 (m, 4 H ), 2.53 (m, 2 H), 2.37-2.34 (m, 2 H). LC / MS (exact mass) calculated for Ci7H 2 2F2N 4 O 2 S; 384.14, found (M + H + ); 385.1. Example 34A and 34B: (1R, 3R) and (1S, 3S) - [({cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclopentanecarbonitrile [0210] The mixture of the title compound of (1, 3R) and (1S, 3S) -3 - [({cis-3 [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -methyl) sulfonyl] cyclopentanecarbonitrile was prepared from S - {[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl ] methyl} ethanothioate Example 25, Step 5, according to the procedure of Example 30, steps 1 and 2. [0211] The title compound (180 mg) was separated by preparative supercritical fluid chromatography using a Chiralpak AS column: (1f, 3F ) 34A enantiomer: 60 mg, 1 H NMR (400 MHz, methanol-d 4 ): δ 8.12 (s, 1 H), 7.13-7.12 (d, 1 H), 6.70-6.69 (d, 1 H), 5.17-5.11 (m, 1H), 3.86-3.78 (m, 1H), 3.41-3.36 (m, 5 H), 3.15-3.11 (m, 1 H), 2.63-2.53 (m, 4 H), 2.37-2.13 (m, 6 H), 2.03 94/111 1.91 (m, 1 H). LC / MS (exact mass) calculated for C17H22F2N4O2S; 373.16, found (M + H + ); 374.1 (1S, 3S) 34B enantiomer: 27 mg, LC / MS (exact mass) calculated for Ci 7 H 22 F 2 N 4 O 2 S; 373.16, found (M + H + ); 374.1 [0212] The 3-cyanocyclopentyl 4-methylbenzenesulfonate intermediate used in step-1 was prepared as shown below: 3-Cyanocyclopentyl 4-methylbenzenesulfonate [0213] 4-Methylbenzene-1-sulfonyl chloride (6.9 g, 36 mmol) and N, Ndimethylpyridin-4-amine (100 mg) were added to a solution of 3-hydroxycyclopentane-carbonitrile compound ( J. Org. Chem. 2007, 72, 7423) (2 g, 18 mmol) and triethylamine (5.5 g, 54 mmol) in dichloromethane (100 mL). The reaction was stirred at room temperature for 15 hours and then the quenched mixture was quenched by the addition of a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (4 x 50 ml). The combined organic layers were dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of petroleum ether and ethyl acetate (1: 1) to give the title compound as a yellow oil (0.5 g, 11% yield). LC / MS (exact mass) calculated for C13H-15NO3S; 265.08, found (M + 23); 287.9. Example 35: N-methyl-N- [cis-3 - ({[1- (propan-2-yl) pyrrolidin-3yl] sulfonyl} methyl) cyclobutyl] -7H-pyrrolo [2,3-d] pyrimidin-4 racemic amine Step 1: tert-Butyl 3 - ({[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] methyl} sulfanyl ) pyrrolidine-1-carboxylate [0214] The cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] methyl 4-methylbenzenesulfonate from Example 25, Step 4 (2 g, 3.7 mmol) was stirred in N-methylpyrrolidine (40 ml). 1,8-Diazabicycloundec-7eno (1.13 g, 7.4 mmol) and 3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (1.13 g, 5.6 mmol) were then added to the mixture of reaction. The reaction was stirred 95/111 at room temperature for 16 hours. Water (200 ml) and ethyl acetate (500 ml) were added. The aqueous layer was extracted with ethyl acetate (2 x 500 ml). And the combined organic layers were dried and concentrated in vacuo to give the title compound as a white solid (2.6 g, 118%). LC / MS (exact mass) calculated for C28H37N5O4S2; 571.23, found (M + H + ): 572.1. Step 2: N-Methyl-7 - [(4-methylphenyl) sulfonyl] -N- {cis-3 - [(pyrrolidin-3ilsulfanyl) methyl] cyclobutyl} -7H-pyrrolo [2,3-d] pyrimidin-4- amine [0215] To a solution of tert-butyl 3 - ({[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl} sulfanyl) pyrrolidine-1-carboxylate (2.6 g, 4.5 mmol) in methanol (15 ml) 3M hydrochloric acid in methanol solution (40 ml) was added. The resulting solution was stirred at room temperature for 1 hour. The solution was concentrated to give the crude product, which was purified by chromatography on silica gel eluting with a gradient of dichloromethane and methanol (100: 0 to 85:15) to give the title compound as a colorless oil (1.7 g, 52%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.21 (s, 1 H), 7.99 (d, 2 H), 7.56 (d, 1 H), 7.37 (d, 2 H), 6.88 (d, 1 H), 4.95-4.87 (m, 1H), 3.29 (s, 1 H), 3.27 (s, 3 H), 3.21 -3.17 (m, 1 H), 3.04-3.96 (m, 1 H), 2.92-29 (m, 1 H), 2.72-2.01 (m, 3 H) , 2.50-2.43 (m, 2 H), 2.39 (s, 3 H), 2.29-2.15 (m, 2 H), 2.03-2.01 (m, 2 H), 1.98-1.65 (m, 1 H). LC / MS (exact mass) calculated for C23H29N5O2S2; 471.18, found (M + 23): 494. Step 3: N-Methyl-7 - [(4-methylphenyl) sulfonyl] -N- [cis-3 - ({[1- (propan-2-yl) pyrrolidin-3yl] sulfanyl} methyl) cyclobutyl] -7H- pyrrole [2,3-d] pyrimidin-4-amine [0216] To a solution of N-methyl-7 - [(4-methylphenyl) sulfonyl] -N- {cis-3 - [(pyrrolidin3-ylsulfanyl) methyl] cyclobutyl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (472 mg, 1 mmol) in dichloromethane (50 mL) was added acetone (174 mg, 3 mmol), 4A molecular sieves (40 mg) and sodium cyanoborohydride (189 mg, 3 mmol). The resulting solution was stirred at room temperature for 1 hour, then diluted with dichloromethane (70 ml) and water (70 ml). The aqueous layer was extracted with dichloromethane (2 x 50 ml) and 96/111 the combined organic layers were diluted with brine (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (500 mg, 97% yield) as a colorless oil. LC / MS (exact mass) calculated for C26H35N5O2S2; 513.22, found (M + H + ); 514.1. Step 4: N-Methyl-7 - [(4-methylphenyl) sulfonyl] -N- [cis-3 - ({[1- (propan-2-yl) pyrrolidin-3yl] sulfonyl} methyl) cyclobutyl] -7H- pyrrole [2,3-d] pyrimidin-4-amine [0217] The mixture of N-methyl-7 - [(4-methylphenyl) sulfonyl] -N- [cis-3 - ({[1- (propan-2il ) pyrrolidin-3-yl] sulfanyl} methyl) cyclobutyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine_ (500 mg, 1.0 mmol) and potassium peroxomonosulfate (1.23 g, 2, 0 mmol) in tetrahydrofuran (20 mL), water (10 mL), and ethanol (20 mL) was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (100 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (3 x 50 ml) and the combined organic layers were diluted with brine (100 ml), dried over sodium sulfate and concentrated to give the title compound as a colorless oil (420 mg, 90 %). LC / MS (exact mass) calculated for C26H35N5O4S2; 545.21, found (M + H + ): 546.3. Step 5: N-Methyl-N- [cis-3 - ({[1- (propan-2-yl) pyrrolidin-3-yl] sulfonyl} methyl) cyclobutyl] - 7H-pyrrolo [2,3-d] pyrimidin -4-amine [0218] The mixture of N-methyl-7 - [(4-methylphenyl) sulfonyl] -N- [cis-3 - ({[1- (propan-2yl) pyrrolidin-3-yl] sulfonyl} methyl) cyclobutyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine_ (330 mg, 0.6 mmol) and lithium hydroxide (126 mg, 3 mmol) in a mixture of water (5 mL) and Ethanol (10 mL) was stirred at 50 ° C for 2 hours. The mixture was then concentrated and the residue was taken up in ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by reverse phase high performance liquid chromatography using a gradient of water and acetonitrile (95: 5 to 5:95) to give the title compound (89 mg, 38%) as a white solid. 1 H NMR (400 MHz, CDCI 3 ): δ 8.32 (s, 1 H), 7.07 (d, 1 H), 6.57 (d, 1 H), 5.13 (m, 1H) , 3.57 (m, 1H), 3.33 (s, 3 H) 3.05-3.22 (m, 3H), 2.92 (m, 1H), 2.78 - 2.87 (m , 97/111 1H), 2.58-2.77 (m, 4H), 2.50 (m, 1H), 2.19-2.34 (m, 2H), 2.06-2.19 (m, 2H) , 1.12 (d, 6H). LC / MS (exact mass) calculated for C19H29N5O2S; 391.20, found (Μ + H + ); 392.3 Example 36: N- (cis-3 - {[(3-Chloro-4-fluorophenyl) sulfonyl] methyl} cyclobutyl) -N-methyl7H-pyrrolo [2,3-d] pyrimidin-4-amine Step 1: N- (cis-3 - {[(3-Chloro-4-fluorophenyl) sulfanyl] methyl} cyclobutyl) -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4 -amine [0219] A solution of 3-chloro-4-fluorothiophenol (93 mg, 0.55 mmol) in tetrahydrofuran (1.5 mL) was added 50% aqueous sodium hydroxide (44 mg, 0.55 mmol) and ethanol (1.5 mL). The mixture was stirred at room temperature for 1 hour. A solution of cis- [3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methyl 4-methylbenzenesulfonate from Example 25, Step 4 (200 mg, 0.37 mmol) in tetrahydrofuran (1.5 mL) was added to the reaction mixture. The combined mixture was heated to 40 ° C overnight. The reaction was concentrated and purified by a silica column eluting with a gradient of heptanes and ethyl acetate (90:10 to 0: 100) to provide the title compound (69 mg, 49.6%). 1 H NMR (400 MHz, CDCh): δ 8.18 (s, 1 H), 7.39 (dd, 1 H), 7.28 (s, 1 H), 7.03-7.08 (m , 1 H), 7.00 (d, 1 H), 6.52 (d, 1 H), 4.97-5.07 (m, 1 H), 3.35 (m, 2 H), 3 , 23 (s, 3 H), 2.89 (s, 1 H), 2.43-2.52 (m, 2 H), 2.19-2.30 (m, 2 H). Step 2: N- (cis-3 - {[(3-Chloro-4-fluorophenyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4 -amine [0220] A N- (cis-3 - {[(3-chloro-4fluorophenyl) sulfanyl] methyl} cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine solution (75 mg, 0, 2 mmol) in dichloromethane (10 ml) 3-chlorobenzoperoxoic acid (107 mg) was added. The reaction was stirred at room temperature overnight and then concentrated. The crude residue was chromatographed on silica gel eluting with a gradient of dichloromethane and 2M ammonia in methanol (80:20) to obtain the title compound 98/111 (48 mg, 59.2%). 1 H NMR (400 MHz, methanol-d 4 ): δ 8.31 (s, 1H), 8.02 (m, 1H), 7.817.83 (m, 1H) 7.37-7.27 (m, 1H), 7.09 (d, 1H), 6.65 (s, 1H), 5.18-5.10 (m, 1 H), 4.154.09 (m, 1 H), 3.32 (m , 5 H), 2.59-2.54 (m, 2 H), 2.44-2.42 (m, 2 H). LC / MS (exact mass) calculated for Ci8H 18 CIFN 4 O 2 S; 408.08, found (Μ + H + ); 409 Example 37: 2 - [({cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methyl) sulfonyl] pyridine-4-carbonitrile Step 1: 2 - ({[cis-3- (Methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4yl} amino) cyclobutyl] methyl} sulfanyl) pyridine- 4-carbonitrile [0221] 1,8-Diazabicycloundec-7-ene (24.6 g, 161 mmol) and 2-mercaptoisonicotinonitrile (16.1 g, 118 mmol) were added to a solution of [cis-3 (methyl { 7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] -methyl methanesulfonate (50 g, 110 mmol) in N-methylpyrrolidine (250 mL). The reaction was heated to 50 ° C overnight. Additional 2-mercaptoisonicotinonitrile (8.1 g, 59 mmol) was added to drive the reaction to completion. The mixture was cooled to about 0 ° C and then the reaction was quenched dropwise with the addition of water. The solids were collected by filtration, diluted with water, and vacuum dried at 50 ° C to give the title compound as a bright yellow solid (45.8 g, 82.8%). LC / MS (exact mass) calculated for C25H2 4 N 6 O 2 S2; 504.14, found (M + H + ); 505.1 Step 2: 2 - [({cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methyl) sulfanyl] pyridine-4-carbonitrile [0222] To a solution of 2 - ({[cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7Hpirrolo [2,3-d] pyrimidin-4-yl} amino) cyclobutyl] methyl} sulfanyl) pyridine-4-carbonitrile ( 45.3 g, 89.8 mmol) in tetrahydrofuran (180 ml) a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (269 ml) was added. The reaction mixture was heated to reflux for 6 hours and then cooled to room temperature. Water was added dropwise over 45 minutes. The solids were collected by filtration and diluted with a mixture of 20% tetrahydrofuran (33 mL) and water (97 mL). The wet cake 99/111 was dried in vacuo at 50 ° C to give the title compound as a yellow-brown solid (25 g, 79%). LC / MS (exact mass) calculated for Ci 8 H 18 N 6 S2; 350.13, found (M + H + ); 351.1 Step 3: 2 - [({cis-3- [Methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methyl) sulfonyl] pyridine-4-carbonitrile [0223] Potassium peroxomonosulfate (236 , 8 g, 385.2 mmol) was added slowly to a mixture of 2 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -methyl) sulfanyl ] pyridine-4-carbonitrile (22.5 g, 64.2 mmol) in methanol (337 ml) and water (56 ml) at 0 ° C. The reaction was stirred at 3 ° C for 20 hours. The reaction was quenched using 10% aqueous sodium bisulfate solution (40 ml). And the resulting slurry was stirred at room temperature for 2 hours. 10% of an aqueous potassium carbonate solution was added until the pH was 4 to 5. The material was filtered and rinsed with water. The wet filter was dried under vacuum at 40 ° C to give an off-white solid. This material was processed in tetrahydrofuran (50 mL) and heated to reflux for 3 hours. The mixture was cooled to room temperature and filtered to collect the solid, which was dried under vacuum at 40 ° C to give the title compound as a light brown powder (17.3 g, 70.46%). 1 H NMR (400 MHz, CDCI 3 ): δ 11.97 (s, 1 H), 8.95 (d, 1 H), 8.33-8.28 (m, 2 H), 7.81 ( d, 1 H) 7.1 (d, 1 H), 6.54 (d, 1 H), 5.13-5.08 (m, 1 H), 3.63 (m, 2 H), 3 , 30 (s, 3 H), 2.54-2.48 (m, 3 H), 2.09-2.07 (m, 2 H). LC / MS (exact mass) calculated for Ci 8 H 18 N 6 O 2 S2; 382.12, found (M + H + ); 383.1. Example 38.2-Methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -1,3-thiazolo-5-sulfonamide Step 1: 2-Methyl-N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrolo [2,3d] pyrimidin-4-yl} amino) cyclobutyl] -1,3 -thiazolo-5-sulfonamide [0224] Triethylamine (62, Og, 0.613 mol) is added to a solution of cis-Nmethyl-N-7H-pyrrolo [2,3-d] pyrimidin-4-ylcyclobutane-1,3- hydrochlorine diamine (22.2 g, 100/111 0.102 mol) in dichloromethane (250 ml). 2-Methylthiazolo-5-sulfonyl chloride (28, Og, 0.142 mol) in dichloromethane (250 mL) is added over 30 minutes at room temperature to the reaction mixture. After 1.5 hours the solvent is removed under reduced pressure and the resulting solid dissolved in 4: 1 ethyl acetate: dichloromethane (400 ml). The solution is filtered through 40g of silica plug, rinsing with ethyl acetate (800 mL) and dichloromethane (100 mL). The solvent from the filtrate is removed under reduced pressure to give the solid (59g). the solid is purified using silica gel column chromatography eluting from 1: 1 dichloromethane: ethyl acetate to pure ethyl acetate to give the title compound (44.4g, 81%); m / z (Cl) 533 [M + H] + . Step 2: 2-MetH-N- {cis-3- [metH (7H-pyrrolo [2,3-d] pyrimidin-4-H) amino] cyclobutH} 1,3-thiazolo-5-sulfonamide [0225] Hydroxide of lithium (12.1g, 0.550 mol) in water (290 mL) is added to 2-methyl-N- [cis-3- (methyl {7 - [(4-methylphenyl) sulfonyl] -7H-pyrrole [2, 3-d] pyrimidin-4yl} amino) cyclobutyl] -1,3-thiazolo-5-sulfonamide (43.8g, 82.2 mmol) in isopropyl alcohol (435 mL) and the mixture heated to 60 ° C overnight . After cooling to room temperature, the reaction mixture is filtered by rinsing with water (145 mL). The filtrate is adjusted to pH 6-7 using 6M aqueous hydrochloric acid. The reaction slurry is concentrated under reduced pressure. Water (370 ml) is added and the mixture cooled to 0 ° C. the solvent is collected by filtration, diluted with cold water (150 ml) then vacuum dried at 60 ° C overnight to give the title compound (25, Og, 80%); 1 H NMR (DMSO-d6): δ 11.66-11.71 (1 H), 8.44-8.47 (1 H), 8.11-8.08 (2 H), 7.16- 7.17 (1 H), 6.63-6.65 (1 H), 4.86-4.94 (1 H), 3.58-3.68 (1 H), 3.22 (3 H ), 2.74 (3 H), 2.40-2.46 (2 H), 2.10-2.18 (2H). m / z (Cl) 379 [M + H] + . BIOLOGICAL EVALUATION JAK Enzyme Assay Calibrator at 1 mM ATP [0226] The test article was solubilized in dimethyl sulfoxide (DMSO) at a stock concentration of 30 mM. A series of 11-point half log dilutions was created 101/111 in DMSO with a concentration greater than 600 μΜ. The test compound plate also contained positive control wells containing the known inhibitor to define 100% inhibition and negative control wells containing DMSO to define non-inhibition. The compound plates were diluted 1 to 60 resulting in a final test compound concentration greater than 10 μΜ and a concentration of 2% DMSO. [0227] The test article and test controls were added to a 384-well plate. The reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01% bovine serum albumin (BSA), 0.0005% Tween 20, 1 mM ATP and 1 μΜ peptide substrate. The JAK1 and TYK2 assays contained 1 μΜ of the IRStide peptide (5FAM-KKSRGDYMTMQID) and the JAK2 and JAK3 assays contained 1 μΜ of the JAKtide peptide (FITC-KGGEEEEYFELVKK). The assays were started by adding 20 nM of JAK1 enzyme, 1 nM JAK2, 1 nM JAK3 or 1 nM TYK2 and were incubated at room temperature for three hours for JAK1,60 minutes for JAK2, 75 minutes for JAK3 or 135 minutes for TYK2 . Enzyme concentrations and incubation periods have been optimized for each new enzyme preps and have been modified slightly over time to ensure 20% -30% phosphorylation. The tests 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 the appropriate separation conditions to measure the phosphorylated and non-phosphorylated peptide. Table 1. Data for the JAK Caliper ™ enzyme assay at 1 mM ATP. Structure Example JAK1 JAK2 JAK3 Tyk2 IC50 IC50 IC 50 (nM) IC 50 (nM) (nM) (nM) 102/111 HF / 7 ζΑ ζΧ 0 0 F I! jG f ^ N in H 1 22 381 > 9220 1020 o 0 = ¾ 11 —-. Λχ, .ωΜ X N '..... / H IXI H 2 29 803 > 10000 1250 O O ^ H__ / x X ^ ·· ”^ / ϊΓΖΓ ^ ^ ντ ^ ν n H 3 14 542 > 10000 479 _ HX, Z> ...... X_o7 XJl ° 1w)N 4B 6 607 > 10000 965 H, 0x. -G / Ύλ Ν ^ ° Gx to II '/ A / 4A 18 1400 > 10000 2710 C / 1Ό □4IIz 5 6 313 8090 878 103/111 , .. / 27 o'33v2o IM H 6 28 933 > 10000 2380 _, JL / Ο / κ γΛ V o Q / ϊ 13 ii N H 7Α 31 2020 > 10000 5240 H ./> ...... : ...... / K <Q f N 7Β 16 750 > 10000 2440 o 'jf η ^ 1 ϊθθ> ii »Ν Ν ΙΝ Η 8 3 700 > 10000 260 η ^ ===== / y— π - '^^ Ο ° π .. □ °' Ν 'ιι ΖΐΓ ^ ι ι Η 9 231 5630 > 10000 6670 Η ^ o ^ o ^ V Ν 1 LL ^ ΚΤ ^ Ν Ν Η 10 1030 7180 > 10000 > 10000 104/111 / X N 'H 1 X> X ^ X 11 29 574 5950 2040 μι °Χχi — X // Λ| _____ | The ZX7Á / 'ThT fη 1>^ kt ^ nIN | _ | 12 6 413 > 9670 770 o aX f ν ·· ΧΧ o xx o | f ii ZIT ^ ^ kt n IN H 13 5 177 8840 323 κ <θ M L ^ kt ^ n in H 14 42 1200 > 10000 1870 H ./2 7 ^ rX ° VN ^ 6o ^ KT ^ N in H 15 6 597 > 10000 4910 Xx ^^ oo ii XX Xkt ^ n in H 16 51 1100 > 10000 1780 105/111 HQ γ Q L / Ν Ν Η 17Α 5 308 > 10000 337 Η, 0. ' Ν 7 / τ ”> .. ^ -χ / / // ^ ν '^ 7 ° v_y ϊιΛλ | Ι J / ν 17Β 13 434 > 9770 1120 η &' χ ο Ν ° ÔxJ Η 18 46 1080 > 10000 7380 Η Ο r ~ ^ ...... Ο 03 ^ ΝΓ Ν ΙΝ Η 19 34 1150 > 10000 2030 Η ο ο ^ r f ^ Ν '' ^^ Ν LX / ^ ΚΚ ^ -Ν ι ι Η 20 4 171 5500 332 d ο Γ— Ζ / / / '' / S ^ N ^^ I ° Ν — Ν -1 ΙΜ Η 21 1 52 3120 365 106/111 // I // 7 ^ ·· ^ / Ο ο η ΖΖ ^ ΚΤ Ν ΙΝ Η 22 22 412 > 10,000 1190 λΖχΧ ζ f LJSιι Ζ / 23 8 551 > 10000 565 Η , 0 __ ΖΖ fí // f / / // ^ Ν ^ Ζ 0 LZx ιι X / 27 17 987 > 10000 1970 // /// η ^ rC ^ z ο / χ ο ίΐ χΓ ^ in Η 24 241 3370 > 10000 7870 . χ ρ Γ — γ '' Ο Ζ Χ ° ΓχΓ ίΐ χΓ ^ ^ Kr : íí ^^ 'N ι ι Η 25 9 373 > 10000 713 CH f Γ [ F J | ο Α <> ν 'όο Η 26 6 88 1880 358 107/111 ........... No / i X> 28 5 179 5270 444 ..- Ο = N ^ N Vy i X /> Υν 29 17 372 > 9930 1100 // -χ__ the °03^ kt ^ -nH 30 9 220 > 6710 553 o ..... LL ^ κΤ ^ · Ν i i H 31 67 946 > 10000 3610 O <- ^ / z X ^ i rx / LL ^ Nr 555 ^ '' - ^ H 32 14 426 > 10000 1460 i — Γ // 3 % ^ Ύ ^ ---- ρ | ___ | o ° '-Άβ ^ N' F ox ^ kt ^ n IN H 33 5 161 6570 582 108/111 ° O ^ N II X / 34B 9 309 > 10000 840 v. The z T | ......> u = N i X / 34A 37 801 > 10000 3280 ,. > 3S C ~ - < J — JO X ° N H 35 106 3760 > 10000 > 10000 n'7 <X ^ N 'I! jTz ^ Kr N In h 36 4 85 3190 242 o-o ii ^ KT ^ N ι ι H 37 6 569 > 8880 418 S '/ ΛΤ s ..-% - / O 0 li / N N 38 4.6 512 > 10000 546 STAT3 PHOSPHORILATION TEST INDUCED BY ALFA INF HWB [0228] The test articles were prepared as 30 mM storage 109/111 in 100% DMSO, and then diluted to 5 mM. A 10-point 2.5 dilution series was created in DMSO with a concentration greater than 5 mM. Another dilution was made by adding 4 μΙ_ of the test article solutions above in 96 μΙ_ of PBS with a concentration greater than 200 μΜ. [0229] To a 96-well polypropylene plate (VWR 82007-292) 90 μΙ of HWB was added per well, followed by the addition of 5 μΙ of test article solutions prepared above to give a higher concentration of 10 μΜ. The plate was mixed and incubated for 45 minutes at 37 Q C. To each well was added 5 μΙ human IFN alpha (Universal Type I IFN, R & D Systems # 11200-2; final concentration of 5000U / mL) or D-PBS ( unstimulated control), mixed and incubated 15 minutes at 37 Q C. the reaction was quenched by adding Lyse / Fix Buffer [Phosflow 5x BD Lyse / Fix buffer (BD # 558049)] to all the cells 1000 μΙ / well and incubated for 20 minutes at> / hy / t 37 Q C; after washing with FACS buffer [D-PBS (Invitrogen cat # 14190) containing 0.1% BSA and 0.1% sodium azide], 400 μΙ 90% methanol / ice water was added to each well and incubated on ice for 30 minutes. One more wash done with cold FACS buffer and all samples were finally resuspended in 250 μΙ / well of the anti-phospho-STAT3 conjugated (pY705) 647 alexa fluorine antibody 1: 125 diluted in FACS buffer. After overnight incubation at 4 degrees, all samples were transferred to a 96-well polypropylene U-bottom plate (Falcon # 353077) and checked by a flow cytometry machine. The IC 50 values obtained, for example, 1 to 9, 11 -23, 25-38 were in the range of 22 to 2610 nM. CANINE IN-VITRO T-CELL PROLIFERATION TEST [0230] T-cell activation plays an important role in a variety of autoimmune and inflammatory disorders such as asthma, allergies and itching. Since T cell activation can, in part, be triggered by cytokines that signal via the JAK-STAT pathway, a JAK inhibitor may be effective against 110/111 such diseases involving aberrant T cell activation. [0231] Methods: Canine blood as a whole was collected in sodium heparin tubes from 29 beagle dogs and 23 mixed breed dogs. Whole blood (20 pL) was plated in 96-well plates (Costar 3598) with 180 pL of medium (RPMI 1640, Gibco # 21870-076, with 1% heat-inactivated fetal bovine serum, Gibco # 10082-39 , 292 pg / ml L-glutamine, Gibco # 250030-081, 100 u / ml penicillin and 100pg streptomycin per ml, Gibco # 15140-122) containing a vehicle control or test compound (0.001 to 10 μΜ), concanavalin A (ConA; 1 pg / ml, Sigma C5275), and canine interleukin-2 (IL-2; 50 ng / ml, R&D Systems 1815-CL / CF). Wells containing all blood, medium with vehicle control and no ConA or IL-2 were used as previous controls. The plates were incubated at 37 ° C for 48 hours. Tritiated trimidine, 0.4 pCi / well (Perkin Elmer, Net027A-005MC), was added for an additional 20 hours. The plates were frozen and then thawed, washed and filtered using a Brandel MLR-96 cell thresher and pre-wetted filter mats (Wallac 1205-401, Perkin Elmer). The filters were dried at 60 ° C for one hour (Precision 16EG conventional oven) and placed in filter sample bags (Wallac 1205-411, Perkin Elmer) with 10 mL of scintillant (Wallac 1205-440, Perkin Elmer). The sealed filters were counted in a liquid scintillation counter LKB Wallac 1205 Betaplate. The data were collected using a Gterm Betaplate v1.1 program and transformed into a percentage of inhibition, calculated using the following formula: f f Msen Draa Tr eatment qmnl - (M BCA ' 100 - ——----------------- 1 —m 100 [(Afasn JVon Dro. # TreaímenS çpm) - ζΜββη S'CA cpm / j =% feàtè & àm [0232] data were displayed graphically as a percentage of inhibition using a Graph Pad Prism 4.0, and the IC 50 curves were fitted using a point-to-point analysis. [0233] Example 38 had an IC 50 of 48.5 nM in this assay. These data su 111/111 manage that the compounds of the present invention are effective in inhibiting the proliferation of T cells, a key feature in diseases resulting from JAK dysregulation.
权利要求:
Claims (19) [1] 1. Compound CHARACTERIZED by the fact that it presents formula I with the structure: [2] 2/13 X is selected from --NH-- and --CRaRb-, where (a) Ra and Rb are independently hydrogen, deuterium, Ci-Ce branched or straight chain alkyl, C3Ce cycloalkyl, aryl, (aryl) Ci -C6 straight or branched chain alkyl, heteroaryl, (C1-C straight or branched chain alkyl) heteroaryl, (heteroaryl) C1-C6 straight or branched chain alkyl, (heterocyclic) C1-C6 straight or branched chain alkyl, or (b) Ra and Rb together form a chain comprising - (CRcRd) / -, where Rc and Rd are independently hydrogen, deuterium, C1-C branched or straight chain alkyl, aryl, (C1-C6 branched chain alkyl or linear) aryl, heteroaryl, (C1-C6 branched or straight chain alkyl) heteroaryl, halo, CN, CF3, hydroxyl, CONH2 or SO2CH3; Y is -AR 5 , where A is a bond, - (CH2) k-- or - (CD2) k- and R 5 is C1-C branched or straight chain alkyl, C3-C6 cycloalkyl, aryl, or -NRaRb ', or is a partially saturated, saturated or unsaturated bicyclic or monocyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, of which 0 is said alkyl, C3-C6 cycloalkyl, aryl, or bicyclic or monocyclic ring structure is optionally further substituted by one or more substituents selected from the group consisting of deuterium, halo, C1-C6 branched or linear chain alkyl, CN, hydroxyl, CF3, -ORe, -NReRf, -S (O) P Re and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl can be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl , CONH2 and SO2CH3, where (a) Ra 'and Rb' are independently hydro genius, deuterium, C1-C6 branched or straight chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C branched or straight chain alkyl) aryl, heteroaryl or (C1-C6 straight or branched chain alkyl), in that said alkyl and cycloalkyl can be optionally substituted by one or more Rb, or (b) Ra 'and Rb' together form a chain comprising - (CRc'Rd ') / -, where Rb and Rd' are independently hydrogen , deuterium, C1-C branched or straight chain alkyl, aryl, (C1-C6 branched-chain alkyl or line Petition 870170009129, of 02/10/2017, p. 7/20 [3] 3/13 ar) aryl, heteroaryl, (C1-C branched or straight chain alkyl) heteroaryl, halo, CN, hydroxyl, CF3, CONH2, -OR and , --NReRf or -S (O) P R e ; wherein Re and Rf are independently hydrogen, deuterium, C1-C branched or straight chain alkyl or C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl may be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF 3 and CONH2; is 2, 3, 4 or 5; k is 1.2; 3 or 4; p is 0, 1 or 2; and n is 1 or 2. 2. Compound, according to claim 1, CHARACTERIZED by the fact that it is a compound of formula IA having the structure: [4] 4/13 Rb 'are independently hydrogen, deuterium, C1-C branched or straight chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 straight or branched chain alkyl) aryl, heteroaryl or (C1-C6 straight or branched chain alkyl ) heteroaryl, wherein said alkyl and cycloalkyl can be optionally substituted by one or more R C ', or (b) Ra' and Rb 'together form a chain comprising - (CRc Rd); -, where R C ' and Rd 'are independently hydrogen, deuterium, C1-C branched or straight chain alkyl, aryl, (C1-C6 straight or branched chain alkyl) aryl, heteroaryl, (C1-C6 straight or branched chain alkyl) heteroaryl, halo, CN, hydroxyl, CF3, CONH2, --OR e , --NReRf or --S (O) P R e ; wherein Re and Rf are independently hydrogen, deuterium, C1-C branched or straight chain alkyl or C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl may be optionally substituted by one or more substituents selected from a group consisting of halo, CN, hydroxyl, CF3, and CONH2; j is 2, 3, 4 or 5; k is 1.2; 3 or 4; and, p is 0, 1 or 2. 3. A compound according to claim 2, CHARACTERIZED by the fact that A is a bond and R 5 is a branched or linear C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or aryl. 4. Compound according to claim 2, CHARACTERIZED by the fact that A is a bond or - (CH2) k--, and R 5 is C3-C6 cycloalkyl, in which said C3-C6 cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6 straight or branched chain alkyl and CN, wherein said alkyl and cycloalkyl may be optionally substituted by one or more substituents selected from the group consisting of halo , CN, hydroxyl, CONH2 and SO2CH3; where k is 1,2, or 3. [5] 5. Compound according to claim 2, CHARACTERIZED by the fact that A is a bond or - (CH2) k--, and R 5 is a partially saturated, saturated or unsaturated bicyclic or monocyclic ring structure containing a total five to eleven atoms having one to three independently selected heteroatoms at Petition 870170009129, of 02/10/2017, p. 9/20 5/13 from the group consisting of oxygen, nitrogen and sulfur, in which said alkyl, C3Ce cycloalkyl, aryl or the bicyclic or monocyclic ring structure is optionally substituted by one or more substituents selected from the group consisting of deuterium, halo , C1-C branched or straight chain alkyl, CN, hydroxyl, CF3, -NRaBb ', -ORe, -S (O) P Re and C3-C6 cycloalkyl; where k is 1,2 or 3. [6] 6. Compound, according to claim 1, CHARACTERIZED by the fact that it is a compound of the formula IB having the structure: R a · [7] 7. Compound, according to claim 1, CHARACTERIZED by the fact that it is a compound of the formula IC having the structure: Frog' [8] 8. Compound according to claim 1, CHARACTERIZED by the fact that it is a compound of formula ID having the structure: [9] 9. Composed, according to claim 1, CHARACTERIZED by the fact that it is selected from the group consisting of: 4-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyridine- 2-sulfonamide; 2,2,2-trifluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} Petition 870170009129, of 02/10/2017, p. 13/20 9/13 ethanesulfonamide; 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1-sulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane-1sulfonamide; 1-cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methanesulfonamide; N- {cis-3 - [(butylsulfonyl) methyl] cyclobutyl} -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4amine; 1-cyclopropyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} azetidine-3-sulfonamide; 3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} - azetidine-1-sulfonamide; (1 R, 5S) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -6-oxa3-azabicyclo [3.1.1] heptane- 3-sulfonamide; (3R) -3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyrrolidine-1-sulfonamide; (3S) -3-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyrrolidine-1-sulfonamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1- (oxetan-3yl) methanesulfonamide; 1 - (3,3-difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} methanesulfonamide; trans-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutylcyclo-butanesulfonamide; cis-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutylcyclobutane-sulfonamide; Petition 870170009129, of 02/10/2017, p. 14/20 [10] 10/13 N- [cis-3 - ({[(3,3-difluorocyclobutyl) methyl] sulfonyl} methyl) cyclobutyl] -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4-amine; (1 S, 5S) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -3-azabicyclo [3.1.0] hexane- 3-sulfonamide; (1 R, 5R) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -3-azabicyclo [3.1.0] hexane- 3-sulfonamide; (3R) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile; 1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] -4 (trifluoromethyl) piperidin-4-ol; N- (cis-3 - {[(4,4-difluoropiperidin-1-yl) sulfonyl] methyl} cyclobutyl) -N-methyl-7Hpyrrolo [2,3-d] pyrimidin-4-amine; (3S) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile; N- (cis-3 - {[(3-chloro-4-fluorophenyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7H-pyrrolo [2,3d] pyrimidin-4-amine; N- (cis-3 - {[(2-cyclopropylethyl) sulfonyl] methyl} cyclobutyl) -N-methyl-7H-pyrrolo [2,3d] pyrimidin-4-amine; N-methyl-N- [cis-3 - ({[1 - (propan-2-yl) pyrrolidin-3-yl] sulfonyl} methyl) cyclobutyl] -7Hpyrrolo [2,3-d] pyrimidin-4-amine; 3,3-difluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} cyclobutane-sulfonamide; 1- [3- (cyanomethyl) oxetan-3-yl] -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -methanesulfonamide; cis-3- (cyanomethyl) -3-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} -cyclobutanesulfonamide; trans-3- (cyanomethyl) -3-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4Petition 870170009129, from 10/02/2017, page 15/20 [11] 11/13 yl) amino] cyclobutyl} cyclobutanesulfonamide; N- (2-cyanoethyl) -N-methyl-N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} sulfuric diamide; N - {(1S, 3R) -3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclopentyl} propane1-sulfonamide; 3- (2-hydroxypropan-2-yl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} benzene-sulfonamide; N- (cyclopropylmethyl) -N '- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl} sulfuric diamide; N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -4- (1 H-pyrazol-3i) piperidine-1-sulfonamide; 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -2,6 dihydropyrrolo [3,4-c] pyrazole-5 (4H ) -sulfonamide; N-cyclopropyl-1 - {trans-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methanesulfonamide; 2- [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] pyridine-4-carbonitrile; (1 S, 3S) -3 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclopentanecarbonitrile; (1 R, 3R) -3 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methyl) sulfonyl] cyclopentanecarbonitrile; 1-cyclopropyl-N- {trans-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} methane sulfonamide; 3-cyano-N- {trans-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} pyrrolidine-1-sulfonamide; N-methyl-N- {trans-3 - [(propylsulfonyl) methyl] cyclobutyl} -7H-pyrrolo [2,3-d] pyrimidin-4amine; and Petition 870170009129, of 02/10/2017, p. 16/20 [12] 12/13 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} -1,3thiazolo-5-sulfonamide; or a pharmaceutically acceptable salt thereof. 10. Compound according to claim 1, CHARACTERIZED by the fact that the compound is 2-methyl-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino] cyclobutyl } -1,3-thiazolo-5-sulfonamide or a pharmaceutically acceptable salt thereof. 11. Compound according to claim 1, CHARACTERIZED by the fact that the compound is N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} propane -1-sulfonamide or a pharmaceutically acceptable salt thereof. 12. Compound according to claim 1, CHARACTERIZED by the fact that the compound is trans-3- (cyanomethyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin- 4-yl) amino] cyclobutyl} cyclobutanesulfonamide or a pharmaceutically acceptable salt thereof. [13] 13. Compound according to claim 1, CHARACTERIZED by the fact that the compound is 1- (3,3-difluorocyclobutyl) -N- {cis-3- [methyl (7H-pyrrolo [2,3d] pyrimidin-4 -yl) amino] cyclobutyl} methanesulfonamide or a pharmaceutically acceptable salt thereof. [14] 14. The compound according to claim 1, CHARACTERIZED by the fact that the compound is N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] cyclobutyl} 1 - (oxetan-3-yl) methanesulfonamide or a pharmaceutically acceptable salt thereof. [15] 15. Compound according to claim 1, CHARACTERIZED by the fact that the compound is (3R) -1 - [({cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino ] cyclobutyl} methyl) sulfonyl] pyrrolidine-3-carbonitrile or a pharmaceutically acceptable salt thereof. [16] 16. Compound according to claim 1, CHARACTERIZED by the fact that the compound is 3,3-difluoro-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4yl) amino ] cyclobutyl} cyclobutanesulfonamide or a pharmaceutically acceptable salt Petition 870170009129, of 02/10/2017, p. 17/20 13/13 of this. [17] 17. Compound according to claim 1, CHARACTERIZED by the fact that the compound is (1S, 5S) -1-cyano-N- {cis-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin -4yl) amino] cyclobutyl} -3-azabicyclo [3.1.0] hexane-3-sulfonamide or a pharmaceutically acceptable salt thereof. [18] 18. Pharmaceutical or veterinary composition CHARACTERIZED by the fact that it comprises a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [19] 19. Use of the compound, as defined in claim 1, CHARACTERIZED by the fact that it is in the manufacture of a composition to treat or prevent a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, Crohn's disease, ulcerative oolitis, Alzheimer's disease, lupus, nephritis, psoriasis, atopic dermatitis, autoimmune thyroid disorders, multiple sclerosis, major depressive disorder, allergy, asthma, Sjogren's disease, dry eye syndrome, organ transplant rejection, xenotransplantation, Type I diabetes and complications of diabetes, cancer, leukemia, acute T-cell lymphoblastic leukemia, adult B-cell activated T-cell leukemia, diffuse large B-cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic obstructive pulmonary disorder, disease acute respiratory and cachexia, in a subject.
类似技术:
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同族专利:
公开号 | 公开日 ZA201505454B|2016-07-27| RS56503B1|2018-02-28| IL240132A|2020-09-30| US20150225408A1|2015-08-13| CA2900703C|2017-11-28| GEP201606600B|2017-01-10| US9035074B2|2015-05-19| NL301155I1|2021-12-22| WO2014128591A1|2014-08-28| CU20150078A7|2016-01-29| MY177476A|2020-09-16| EP3290421B1|2019-01-02| JP2016509049A|2016-03-24| MD20150073A2|2016-01-31| CN107089985A|2017-08-25| CN107089985B|2019-06-07| NL301155I2|2022-02-23| PT2958921T|2017-11-20| PL3290421T3|2019-05-31| CY1121468T1|2020-05-29| EA201591255A1|2016-03-31| JP2017165762A|2017-09-21| PH12015501779A1|2015-12-02| SI3290421T1|2019-03-29| HRP20171599T1|2017-12-01| TWI507408B|2015-11-11| ES2713052T3|2019-05-17| TN2015000355A1|2017-01-03| PH12015501779B1|2015-12-02| TW201443055A|2014-11-16| HUE041778T2|2019-05-28| NZ710411A|2017-11-24| IL240132D0|2015-09-24| CN105008362B|2017-06-06| US20140243312A1|2014-08-28| AU2014220357A1|2015-08-06| HRP20190152T1|2019-03-22| JP6145179B2|2017-06-07| DK3290421T3|2019-03-18| DOP2015000206A|2016-02-15| SG11201505816UA|2015-09-29| CY1119502T1|2018-03-07| US9549929B2|2017-01-24| KR20150109434A|2015-10-01| EA027879B1|2017-09-29| MA38347A1|2017-10-31| HK1213881A1|2016-07-15| EP3290421A1|2018-03-07| CA2900703A1|2014-08-28| MX2015010928A|2015-10-29| KR101787858B1|2017-10-18| EP2958921B1|2017-09-20| MD4735B1|2020-12-31| ES2647525T3|2017-12-22| AP2015008664A0|2015-08-31| LT2958921T|2017-11-27| PL2958921T3|2018-01-31| NO3052752T3|2018-06-16| CL2015002303A1|2015-12-18| UA111804C2|2016-06-10| US9545405B2|2017-01-17| ME03301B|2019-07-20| AR094857A1|2015-09-02| US20150246048A1|2015-09-03| HUE037192T2|2018-08-28| PT3290421T|2019-03-01| MD4735C1|2021-07-31| CU24275B1|2017-10-05| ME02904B|2018-04-20| PE20151764A1|2015-12-03| HRP20171599T2|2018-11-16| AU2014220357B2|2017-04-27| DK2958921T3|2017-11-06| CN105008362A|2015-10-28| TR201902525T4|2019-03-21| RS58245B1|2019-03-29| UY35337A|2014-09-30| CR20150395A|2015-09-23| SI2958921T1|2017-12-29| LT3290421T|2019-02-25| EP2958921A1|2015-12-30|
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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2019-08-20| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI | 2019-09-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]| 2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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申请号 | 申请日 | 专利标题 US201361767947P| true| 2013-02-22|2013-02-22| PCT/IB2014/058889|WO2014128591A1|2013-02-22|2014-02-11|Pyrrolo [2, 3 -d]pyrimidine derivatives as inhibitors of janus- related kinases | 相关专利
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